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Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65 years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

Aims To describe the adverse events (AEs) of recreational cannabis use in France between 2012 and 2017. Methods AEs related to recreational cannabis use, alone or in combination with alcohol and/or tobacco reported to the French Addictovigilance Network were analysed (excluding cannabidiol and synthetic cannabinoids). Results Reporting of AEs tripled between 2012 (n = 179, 6.3%, 95% confidence interval [CI] = 5.4-7.2) and 2017 (n = 562, 10.1%, 95% CI = 9.3-10.9), reaching 2217 cases. They concerned mainly men (76.4%) and users aged between 18 and 34 years (18-25: 30.9%; 26-34: 26.3%, range: 12-84 years). Cannabis was mainly inhaled (71.6%) and exposure was most often chronic (64.2%). Many types of AEs were reported: psychiatric (51.2%), neurological (15.6%), cardiac (7.8%) and gastrointestinal (7.7%), including unexpected AEs (n = 34, 1.1%). The most common effect was dependence, ranging from 10.1% (95% CI = 7.9-12.3) to 20.3% (95% CI = 17.3-23.2) over the study period. Cannabinoid hyperemesis syndrome (n = 87, 2.8%) emerged from 2015. Deaths accounted for 0.2% of all AEs (4 men and 3 women aged on average 35 years). A chronic pattern of cannabis use was reported in 4 of them (intracranial hypertension in the context of lung cancer, suicide, cerebral haematoma, neonatal death with concomitant chronic alcohol use), while in the other cases the toxicological analysis identified cannabis use (ruptured aneurysm and unknown aetiology). Conclusion This study showed a multitude of AEs related to recreational cannabis use, including unexpected AEs and deaths. It highlights the problem of dependence and the emergence of cannabinoid hyperemesis syndrome.

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

Background: The French Universal Health Cover (CMU) aims to compensate for inequalities between precarious and non-precarious populations, enabling the former to access to free healthcare. These measures rely on the principle that precarious populations&rsquo, health improves if healthcare is free. We designed a study to examine whether CMU fails to compensate for inequalities in reimbursed drugs prescriptions in precarious populations. Material and method: This retrospective pharmaco-epidemiological study compared the Defined Daily Dose relative to different reimbursed drugs prescribed by general practitioners (GPs) to precarious and non-precarious patients in France in 2015. Data were analysed using Mann&ndash, Whitney tests. Findings: 6 out of 20 molecules were significantly under-reimbursed in precarious populations. 2 were over-reimbursed. The 12 remaining molecules did not differ between groups. Interpretation: The under-reimbursement of atorvastatin, rosuvastatin, tamsulosine and timolol reflects well-documented epidemiological differences between these populations. In contrast, the equal reimbursement of amoxicillin, pyostacine, ivermectin, salbutamol and tiopropium is likely an effect of lack of compensation for inequalities. Precarious patients are more affected by diseases that these molecules target (e.g., chronic bronchitis, bacterial pneumonia, cutaneous infections). This could also be the case for the equal and under-reimbursement of insulin glargine and metformin (targeting diabetes), respectively, although this has to be considered with caution. In conclusion, the French free healthcare cover does not fail to compensate for all but only for some selective inequalities in access to reimbursed drugs prescriptions. These results are discussed with respect to the interaction of the doctor&ndash, patient relationship and the holistic nature of primary care, potentially triggering burnout and empathy decrease and negatively impacting the quality of care in precarious populations.

International audience; AIMS: Despite fluoropyrimidines (FPs) constituting the main component of the chemotherapy combination protocols in 50% of chemotherapies for solid tumour treatments, incidence data for FP-related toxicity are poorly documented in real life. This study evaluated the number of patients receiving FP-based chemotherapies in France, along with the true incidence of FP-related serious adverse effects (SAEs) before the recent mandatory dihydropyrimidine dehydrogenase (DPD)-screening was introduced by French health authorities, DPD being the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism.METHODS: Exhaustive data on the number of patients treated with FP-based chemotherapy in 2013-2014 were collected in the Centre-Val de Loire region of France. True incidence of SAEs was extracted from a cohort of 513 patients with incident solid tumours receiving first-line FP-based chemotherapy.RESULTS: After extrapolation at national level, we estimated that 76,200 patients are currently treated annually with 5FU (53,100 patients, 62% digestive system-related versus 26% breast cancers versus 12% head and neck cancers) or capecitabine (23,100 patients, 45% digestive system-related versus 37% breast cancers versus 18% non-documented). Earlier (in the first two cycles) the SAE incidence rate was 19.3% (95% confidence interval (CI) 16-23%) including one toxic death (0.2%, 95%CI 0-1%). SAE incidence rate was 32.2% (95%CI 28-36%) over the first 6 months of treatment. Incidence of death, life-threatening prognosis or incapacity/disability was 1.4% (95%CI 0.4-2.4%) and 1.6% (95%CI 0.5-2.6%) during first two cycles and first 6 months, respectively.CONCLUSION: These data highlight the significant public health issue related to FP toxicity, with around 1200 patients developing FP-related life-threatening prognosis or incapacity/disability annually in France, including 150 toxic deaths. It is hoped that DPD-deficiency screening will reduce such iatrogenic events and eradicate toxic deaths.

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number of grade 1–5 adverse events), especially if used in monotherapy. However, the pattern of ICI-related adverse events is totally different, as they are characterized by the development of specific immune-related adverse events (irAEs) that are unique in terms of the organs involved, onset patterns, and severity. The decision to resume ICI treatment after its interruption due to irAEs is challenged by the need for tumor control versus the risk of occurrence of the same or different irAEs. Studies that specifically assess this point remain scarce, heterogenous and mostly based on small samples of patients or focused only on the recurrence rate of the same irAE after ICI resumption. Moreover, patients with grade ≥3 irAEs were excluded from many of these studies. Herein, we provide a narrative review on the field of safety of ICI resumption after interruption due to irAE(s).

In France, buprenorphine is at once the most widely prescribed and the most commonly misused opioid maintenance treatment (OMT). Unlike other medicines, it is seldom prescribed as a generic drug. Several studies have underlined the influence of the patient's representations when choosing brand-name rather than generic forms. We aim to prove a link between these pejorative representations and misuse, a higher degree of addiction and a preference for brand-name products.An observational study carried out at 11 sites in France using self-assessment questionnaires filled out in dispensing pharmacies by patients having come to them for buprenorphine delivery.Analysis was based on 806 usable questionnaires. There indeed exists a significant correlation between pejorative representations of OMT by means of buprenorphine, and a higher degree of addiction and misuse (p .0001 for each). Preference for the brand-name product is correlated with the representation of OMT as a "trap" (p = .020).Our results underscore the existence of a link between patients' negative representations of their OMT and their drug-taking behavior. Prescribing physicians should consequently take these representations into account to more precisely identify the relevant behaviors and help their patients to evolve positively.

Phloroglucinol is a musculotropic anti-spasmodic drug. It is frequently prescribed in many European countries with a considerable cost for health services. The purpose of this study was to review the existing randomised controlled trials (RCT) comparing the efficacy of phloroglucinol treating abdominal pain versus placebo. A literature search was carried out up to May 2017 to select RCT comparing the effect of phloroglucinol versus placebo with intensity of abdominal pain as an endpoint. Studies concerning obstetric or gynaecologic-related pain were not included. Three RCT were included and then analysed for risk of bias and meta-analysed. Only one RCT found that phloroglucinol was superior to placebo, although with a high risk of bias. The meta-analysis found a risk ratio of 1.10 (95% CI 0.95, 1.27) with no statistical significance. There is insufficient data to justify the wide-spread prescription of phloroglucinol for alleviating abdominal pain.

The aim of this study was to assess an automated detection method of serious adverse reactions induced by oral targeted therapy (OTT) in patients with cancer, performed in the French Diagnosis Related Groups (DRG) database. Patients with cancer of the Poitiers hospital who started an OTT between 2014 and 2015 were included. This study focused on adverse drug reaction which required inpatient hospitalization (ADRh ). All diagnoses coded in the DRG database for hospital stays that occurred within 3 months after OTT initiation were collected (potential ADRh ). Filters (exclusion criteria) were automatically applied on potential ADRh to exclude diagnoses that were not adverse drug reactions (false positives). A pharmacovigilance review was carried out to identify ADRh in the medical records (reported ADRh ). The sensitivity and specificity of the detection method were estimated for each filter combinations by comparison between potential and reported ADRh . This study included 129 patients. The medical records review led to identify 19 ADRh (all coded in the DRG database) in 14 patients. To maintain a 100% sensitivity of the method detection, the best specificity obtained was 58.3% (95% IC: [55.2-61.4]).The use of restrictive filters ('drug' in the diagnostic label, specific diagnosis code for adverse cancer drug reaction) resulted in a 97.8% specificity (95% IC: [96.6-98.5]) with a 38.2% sensitivity (95% IC: [23.9-55.0]). Our method has detected the third of ADRh with an excellent specificity. Complementary experimentations in pharmacovigilance centers are necessary to evaluate the interest of this tool in routine in addition to spontaneous reporting.

International audience; INTRODUCTION: In 2017, concerns regarding Adverse Events (AEs) associated with levonorgestrel Intra-Uterine Device Mirena(R) were largely echoed in medias in France. This resulted in a tremendous reporting of AEs to Pharmacovigilance Centres. OBJECTIVES: The aim of this study was to describe the reporting of AEs regarding Mirena(R) in France and to study the impact of media coverage on this reporting. METHODS: All cases reports involving Mirena(R) recorded in the French national pharmacovigilance database from marketing (21/07/1995) until 04/08/2017 were extracted. To allow studying the influence of mediatisation, reports were described separately for the periods preceding and following the observed media coverage peak (15/05/2017). RESULTS: Overall, 3,224 reports were considered, 510 (15.8%) recorded before the media coverage peak, and 2,714 (84.2%) after. Before the peak, 76.5% of reports originated from health professionals; median time-to-report was of 5.5 months (IQR: 1.7-18.6), and median number of AEs per report of 1 (min-max: 1-17). After the peak, 98.6% originated from patients; median time-to-report was 21 months (IQR: 8.1-45.5), and median number of AEs per report was 6 (min-max: 1-37). After the peak, most reports mentioned anxio-depressive disorders (38.8% vs 10.6% before) or sexual disorders (47.3% vs 6.9%). Other emphasized AEs were weight increase (42.3% vs 10.2%) and pain (gastrointestinal, 19.1% vs 3.5%; musculoskeletal, 22.2% vs 4.5%). CONCLUSION: This study highlighted the importance of mediatisation impact on spontaneous reporting with changes concerning amounts of reports, type of reporter, and type of reported AEs. For Mirena(R), this led to generate signals regarding anxio-depressive and sexual disorders.

International audience; AIMS: Pharmaco-epidemiological surveys enable the frequency of serious adverse effects-and also the determining factors of their occurrence and seriousness-to be quantified. Few studies systematically gathering post-chemotherapy adverse effects data have been conducted. The objective was to assess the incidence of post-chemotherapy serious adverse effects on the basis of cancer registry data.METHODS: The population was composed of new invasive cancer cases, with the exception of haematopoietic tumours and cutaneous carcinomas. These cancers were identified in 2012 among patients living at the time of diagnosis in a region covered by a general cancer registry and by a French regional pharmacovigilance centre, and treated with neo-adjuvant and/or adjuvant first-intention chemotherapy, followed or not by radiotherapy. The study was based on a sample of 1000 patients from the registry, followed by the collection of serious adverse effects and the required information to constitute a pharmacovigilance file.RESULTS: Chemotherapy was associated with a particularly high incidence of serious adverse effects, affecting 44.5% (41.4-47.5%) of the patients. The highest incidence rates were observed when patients were exposed to topo-isomerase II inhibitors such as etoposide and bleomycin (69.2%), vinca-alkaloids (66.7%), topo-isomerase I inhibitors (54.5%) and platinum derivatives (52.0%). The clinical context was also linked to incidence, especially in case of metastases (53.3%) and comorbidities (51.3%). Substantial differences were found according to localisation, with a particularly high incidence in bronchial-pulmonary cancers (59.0%).CONCLUSION: The high overall incidence rate of serious adverse effects should motivate a reinforcement of information about drug toxicities and improve knowledge by drawing on patient reporting.

International audience; Hearing loss is defined as a decrease in the ability to perceive sounds which can occur suddenly or gradually and affects one ear or both. It is related to various etiologies, in particular drugs. The identification of all drugs that could be associated with hearing loss is essential for the patients' life quality. The objective of our study was to identify signals of hearing loss involving drugs approved in the last 20 years. The occurrence in association with drugs known for their ototoxicity was also analyzed. We used a case/non-case method in the French Pharmacovigilance Database (FPVD). The cases were reports of hearing loss in the FPVD between January 2007 and August 2017. Non-cases were all reports over the same period. We calculated the reporting odds ratio (ROR) with 95% confidence intervals. Among the 555 reports of hearing loss, significant RORs were found for 68 drugs. The main therapeutic classes implicated were antineoplastic agents (n = 240), systemic anti-infective agents (n = 182), immunosuppressants (n = 42) loop diuretics (n = 26), and salicylate analgesics (n = 26). We found signals of hearing loss with azacitidine, vaccines and nevirapine, immunosuppressants such as leflunomide, and biotherapies such as panitumumab and vandetanib. Prescribers should be informed about the potential associations with all these drugs. The role of the pathology itself and the known ototoxic drugs that can be associated do not allow to conclude definitively. Audiograms for the early detection of hearing loss induced by drugs known to be ototoxic are rarely carried out. Preventive treatments exist and must be considered.

Introduction Le fentanyl et ses derives, agonistes du recepteur opioide μ, ont un effet pharmacologique plus puissant que l’heroine et la morphine. Ils presentent donc des risques de dependance et d’overdose [1] . Les effets indesirables de ces « fentanyloides » sont identiques a ceux observes avec le fentanyl : nausees, vertiges, vomissements et risque de depression respiratoire severe mettant en jeu le pronostic vital de l’individu. L’usage concomitant de depresseurs du systeme nerveux central comme les antalgiques opioides ou les benzodiazepines potentialise le risque de complications. Methode Nous rapportons ici le cas d’un usager de drogues qui a ete hospitalise suite a des intoxications aigues avec des fentanyloides de synthese. Ces donnees ont ete recueillies a partir des codes Programme de medicalisation des systemes d’information (PMSI) utilises par le service des urgences de l’hopital. Resultat Un homme de 26 ans, consommateur regulier de cannabis et d’heroine a ete hospitalise 5 fois en 18 mois pour des signes cliniques severes (depression respiratoire, coma) apres consommation d’une poudre blanche nommee « china white » qu’il achete sur Internet. Il a presente differentes complications telles que rhabdomyolyse, insuffisance renale, choc cardiogenique sur syndrome de TakoTsubo. Chacune de ces intoxications a ete traitee efficacement par l’antidote antagoniste opiace, la naloxone. La poudre « china white » a ete analysee a 3 reprises montrant la presence de sufentanyl pour la 1re, du compose AH-7921 (3,4-dichloro-N-[[1-(dimethylamino)cyclohexyl]methyl]benzamide, puissant agoniste des recepteurs μ) pour la seconde, et d’acetylfentanyl pour la 3e. Discussion Les fentanyloides sont des « nouveaux produits de synthese » (NPS). Dans cette famille, il existe un grand nombre de composes parfois appeles sous le meme nom comme « china white ». Depuis 2013, plus de 5000 deces par overdose ont ete rapportes aux Etats-Unis avec des fentanyloides [2] . Entre 2012 et 2017, le reseau francais d’addictovigilance rapporte 16 intoxications aigues avec des fentanyloides dont deux deces. En France, 27 derives du fentanyl sont dorenavant listes comme stupefiants. Ce cas clinique presente ici souligne le caractere dangereux de l’achat de poudre sur Internet pouvant contenir differents composes chimiques rendant alors la prise en charge medicale delicate en cas d’overdose car necessitant parfois des doses plus importantes de l’antidote.

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 SelincroWe 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.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.The effect of modifications in the SPC and the package leaflet on the use of nalmefene with ODS was real and progressive.

International audience; BACKGROUND:Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.METHODS:A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.RESULTS:A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39).CONCLUSION:There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

As a form of opioid maintenance treatment, high-dose buprenorphine is increasingly being used in the United States. On the French market since 1996, it is the most commonly prescribed and frequently employed opioid maintenance treatment. For unknown reasons, the brand-name form is used far more often than the generic form (76-24%). The objective was to show that the patients' levels of addiction were differentiated according to the form of buprenorphine currently being used and to their previous experience of a different form. An observational study in 9 sites throughout France used self-assessment questionnaires filled out in retail pharmacies by all patients to whom their prescribed buprenorphine treatment was being delivered. The 151 canvassed pharmacies solicited 879 patients, of whom 724 completed the questionnaires. Participants were statistically similar to non-participants. The patients using the brand-name form subsequent to experience with the generic form exhibited a more elevated addiction severity index and a higher dosage than brand-name form users with no experience of a different form. Compared to generic users, their doses were higher, their was addiction more severe, and their alcohol consumption was more excessive; they were also more likely to make daily use of psychotropic substances. However, the level of misuse or illicit consumption was similar between these groups. Preferring the brand-name buprenorphine form to the generic form is associated with a higher level of severe addiction, a more frequent need for daily psychotropics, and excessive drinking; but the study was unable to show a causal link.

Introduction Les observations menees aupres des usagers de substances psychoactives montrent que la consommation de plantes et de champignons hallucinogenes est en augmentation [1] . Cependant, plusieurs cas d’intoxications sont signalees chaque annee en France avec parfois des complications graves [2] , [3] , [4] . Le but de notre etude etait d’evaluer la consommation de ces substances hallucinogenes par des etudiants de la region Poitou-Charentes. Methode Un questionnaire a ete envoye par mail a 9 000 etudiants inscrits a l’universite de Poitiers ou de La Rochelle afin de decrire les pratiques de consommation : le type de plantes et de champignons hallucinogenes consommes, la frequence d’utilisation, les preparations, la voie d’administration, les effets recherches, les effets secondaires… Resultats Parmi les 1 211 etudiants ayant repondu a l’enquete, 150 ont deja consomme des produits hallucinogenes ; 41 % sont des femmes contre 59 % d’hommes. L’âge de la premiere consommation se situe entre 13 et 22 ans (21 % a 18 ans et 19 % a 17 ans). De plus, 54,5 % des etudiants consomment toujours actuellement dont 69 % de facon occasionnelle. Les substances utilisees sont principalement des champignons hallucinogenes (54 % ; psilocybes, amanites) et des plantes (37 % ; cannabis, sauge divinatoire, datura). Ces substances sont souvent consommees sous forme sechee (62 %) ou fraiche (22 %) et ingerees par voie orale (51 %) ou fumee (30 %), dans un contexte festif. Les consommateurs recherchent surtout l’euphorie, les hallucinations, la stimulation et la serenite. Les effets indesirables rapportes sont des perturbations gastro-intestinales, des sensations de panique et un mal-etre. Discussion Nos resultats ont montre que 12,4 % des etudiants ayant repondu a l’enquete, sont consommateurs de plantes ou de champignons hallucinogenes. Cette donnee est superieure aux valeurs nationales de 2010 rapportant que 5 % des 15–30 ans ont deja experimente ces substances et que 0,6 % sont des usagers actuels [5] . De plus, des donnees de Drogue Info Service obtenues par le CEIP de Paris permettent de completer et de valider les resultats de notre etude. Ainsi, le nombre important de consommateurs, la facilite d’obtention de ces composes et la possibilite de complications graves montrent que la prevention contre les intoxications liees aux produits hallucinogenes naturels semble justifiee.

Introduction Le kaolin est une argile blanche, friable et refractaire, composee principalement de kaolinite, qui est un silicate d’aluminium. Decouvert en Chine, le kaolin est a la base de la fabrication de la porcelaine, mais est egalement utilise dans l’industrie du papier, la medecine et les cosmetiques. Nous rapportons ici un cas clinique original de dependance au kaolin chez une jeune femme. Cas clinique Une femme camerounaise de 22 ans consomme regulierement du kaolin par voie orale qu’elle fait venir du Cameroun. Par cette consommation, elle recherche un effet relaxant. Cette femme presente une veritable dependance a cette argile se manifestant en particulier par une soif importante. En fevrier 2015, cette patiente a ete hospitalisee pour anemie, constipation et metrorragies. Au cours de son hospitalisation, le praticien a note que la patiente presentait un desir important (« craving ») de consommer du kaolin. L’evolution de son etat de dependance au kaolin est a ce jour inconnue. Discussion Dans la litterature, il n’existe pas de cas de dependance au kaolin decrit. Cependant, cette argile est populaire dans certains pays africains, notamment au Senegal, au Cameroun et au Mali. En effet, les femmes consomment generalement du kaolin pour ses proprietes antalgiques pour les douleurs abdominales, pour la gestion du stress, ses apports en fer et en calcium. Les femmes enceintes l’utilisent meme pour ses effets antiemetiques. Dans le cas d’une prise reguliere a des doses elevees, le kaolin pourrait induire des comportements de dependance semblables a ceux retrouves dans le syndrome de pica. Celui-ci correspond a un comportement compulsif induit par une consommation prolongee de substances non nutritives telles que la salete, du papier ou de l’argile. Ses effets indesirables comprennent une anemie par interference avec la fixation du fer sur l’hemoglobine, une lithiase renale, une constipation et possiblement des avortements spontanes. Ce premier cas rapporte aux centres d’addictovigilance francais permet aux cliniciens francais d’etre informes sur cette possible nouvelle addiction.

Resume L’incidence croissante des demences avec le vieillissement des populations en fait un enjeu majeur de sante publique. Parmi les causes envisagees, l’etiologie medicamenteuse n’est pas consideree. Nous avons estime le risque de demence associe a la prise medicamenteuse par une etude cas/non-cas en utilisant les cas notifies de la Banque francaise de Pharmacovigilance. Parmi 263 962 observations saisies entre 1985 et 2005, 79 (0,03 %) sont des demences. L’âge median est de 66 ans avec 41 femmes et 37 hommes. Les classes pharmacologiques impliquees sont majoritairement des medicaments neurotropes comme les anticonvulsivants, les medicaments antiparkinsoniens, antidepresseurs, anxiolytiques, hypnotiques, antipsychotiques et morphiniques mais egalement non neurotropes comme l’interferon alfa-2B, l’allopurinol et la vancomycine. Au niveau des mentions legales, seul l’acide valproique beneficie d’une mention « syndrome dementiel » alors que d’autres medicaments peuvent egalement entrainer une demence. L’etiologie medicamenteuse des demences existe mais est sous-estimee en particulier dans la population âgee.

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.

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by two major lesions: extracellular senile plaques and intraneuronal neurofibrillary tangles. β-Amyloid (Aβ) is known to play a major role in the pathogenesis of AD. Protein synthesis and especially translation initiation are modulated by different factors, including the PKR/eIF2 and the mTOR/p70S6K pathways. mRNA translation is altered in the brain of AD patients. Very little is known about the translation control mediated by mTOR in AD, although mTOR is a central regulator of translation initiation and also ribosome biogenesis and cell growth and proliferation. In this study, by using Western blotting, we show that mTOR pathway is down-regulated by Aβ treatment in human neuroblastoma cells, and the underlying mechanism explaining a transient activation of p70S6K is linked to cross-talk between mTOR and ERK1/2 at this kinase level. This phenomenon is associated with caspase-3 activation, and inhibition of mTOR by the inhibitor rapamycin enhances Aβ-induced cell death. Moreover, in our cell model, insulin-like growth factor-1 is able to increase markedly the p70S6K phosphorylation controlled by mTOR and reduces the caspase-3 activity, but its protective effect on Aβ cell death is mediated via an mTOR-independent pathway. These results demonstrate that mTOR plays an important role as a cellular survival pathway in Aβ toxicity and could represent a possible target for modulating Aβ toxicity. © 2006 Wiley-Liss, Inc.

Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the beta-amyloid (Abeta) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of AD, especially in Abeta-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-alpha expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Abeta25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Abeta25-35 injection. Memory function was evaluated in the water-maze (days 10-14) and Y-maze (day 9) tests. TNF-alpha levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Abeta25-35 in the water-maze and Y-maze tests, and inhibited the TNF-alpha increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Abeta both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-alpha and Abeta accumulation and may represent a potential candidate for AD treatment.

The increased incidence of dementia on the aging population makes this disease a major public health problem. Among known causes of dementia, drug etiology is under considered. We investigated the relationship between exposure to drug therapy and dementia with a case/non-case study using reports of the French Pharmacovigilance database. Among 263 962 adverse effects recorded between 1985 and 2005, 79 (0.03%) are dementia. Median age is 66 (range 3-91). There was 41 women and 37 men. The therapeutic drug class associated with dementia were anticonvulsants, antiparkinsonians, antidepressants, anxiolytics, hypnotics, antipsychotics and morphinics. An association between reporting of dementia and non neurotropic drugs were also found, i.e. interferon alfa-2B, vancomycin and allopurinol. The term "Dementia" is only mentioned in the summary of the characteristics of valproate, but it may concern other drugs. Drug etiology for dementia is a reality but is not necessarily attributed as a cause in aging population, in particular.

The increased incidence of dementia on the aging population makes this disease a major public health problem. Among known causes of dementia, drug etiology is under considered. We investigated the relationship between exposure to drug therapy and dementia with a case/non-case study using reports of the French Pharmacovigilance database. Among 263 962 adverse effects recorded between 1985 and 2005, 79 (0.03%) are dementia. Median age is 66 (range 3-91). There was 41 women and 37 men. The therapeutic drug class associated with dementia were anticonvulsants, antiparkinsonians, antidepressants, anxiolytics, hypnotics, antipsychotics and morphinics. An association between reporting of dementia and non neurotropic drugs were also found, i.e. interferon alfa-2B, vancomycin and allopurinol. The term "Dementia" is only mentioned in the summary of the characteristics of valproate, but it may concern other drugs. Drug etiology for dementia is a reality but is not necessarily attributed as a cause in aging population, in particular.

In Alzheimer's disease, neuropathological hallmarks include the accumulation of beta-amyloid peptides (Abeta) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Abeta is the major aetiological agent according to the amyloid cascade hypothesis. Translational control includes phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k which modulate cell growth, proliferation and autophagy. It is mainly part of an anti-apoptotic cellular signalling. In this study, we analysed modifications of mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, as well as in lymphocytes of patients and control individuals. Abeta 1-42 produced a rapid and persistent down-regulation of mTOR/p70S6k phosphorylation in murine neuroblastoma cells associated with caspase 3 activation. Using western blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 transgenic mice compared with control mice. These results were confirmed by immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was significantly reduced in lymphocytes of Alzheimer's patients, and levels of phosphorylated p70S6k were statistically correlated with Mini Mental Status Examination (MMSE) scores. Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease.