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In contrast to statins, the risk of diabetes with fibrates was not clearly studied. This study investigates a putative signal of diabetes associated with the use of fibrates using the World Health Organization (WHO) global individual case safety reports database, VigiBase ® . We included all reports registered until the 31st December 2017 in VigiBase ® to measure the risk of reporting 'hyperglycemia or new onset of diabetes' (SMQ term) compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for fibrates, statins, and the combination fibrates + statins. The likelihood that diabetes resulted from statin-fibrate interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug-drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and after exclusion of putative competitive (hyperglycemic) drugs. We included 19 149 patients exposed to fibrates (without statins), 177 323 to statins (without fibrates) and 3 247 to statins plus fibrates. In contrast to statins (ROR = 1.75, 95% CI 1.72-1.78), no association was found for fibrates (ROR = 0.76, 95% CI 0.71-0.82). The ROR value was lower for the combination statins plus fibrates (ROR = 1.46, 95% CI 1.28-1.67). Similar trends were found in sensitivity analyses. This study, performed in the real conditions of use, failed to find a signal of diabetes with fibrates. It strengths the association previously described with statin without any evidence for a statin-fibrate DDI., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Objective: General practitioners (GPs) report little adverse drug reactions (ADR), although it is mandatory in France. The objective was to evaluate the satisfaction of the GPs who participated to a pharmacovigilance ADR declaration support network via a clinical research assistant (CRA) moving to their GP office in the French South-West region of Midi-Pyrénées., Study Design: A satisfaction questionnaire was sent to the 59 active GPs of this network in November 2016., Results: A total number of 44 GPs responded to the survey (mean age 44±11years; 48% of women). The overall satisfaction grade was rated 9/10 (SD±1). The personalized help from a CRA was highly appreciated (n=39; 89%), reduced time-loss (n=35; 90%), and facilitated communication with the local pharmacovigilance department (n=33; 85%). Most GP (95%; n=35) stated that they would keep reporting ADRs, 83% (n=35) stated to declare ADRs via the CRA, the others stated to declare ADRs directly to the Regional Pharmacovigilance Center, mainly via numerical or online tools. For 59% (n=26) their participation to the network had a positive impact on their relationship with patients through the improvement of their vigilance to ADR., Discussion: Most of the active GP answered. They were very satisfied of the pharmacovigilance CRA network helping ADR reports. It may corroborate the increase of ADRs reporting in Midi-Pyrénées since this network was set up., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: As the ear development extends from the 4th to the 30th week of pregnancy, in utero exposure to ototoxic drugs might lead to hearing impairment in the fetus. The main study objective was to assess the association between in utero drug exposure and the occurrence of hearing impairment in 2-year-old children., Methods and Materials: A case-control study was carried out using the EFEMERIS database, recording medications dispensed during pregnancy and the compulsory health certificates for child at 8 days, 9 and 24 months. Cases were defined as children with an abnormal hearing examination recorded on the 24-month certificate and controls as children with a normal hearing examination. Exposure was defined as at least one prescription and dispensation to the mother of drugs grouped at the 3rd level of the Anatomical Therapeutic and Chemical Classification level, compared to no exposure. Univariate logistic regressions were carried out. If the 95% confidence interval (95% CI) of the odds ratio (OR) was significant, a multivariable logistic regression was performed, adjusted on confounders., Results: A total of 1,245 cases with abnormal hearing evaluation and 28,046 controls were selected for analysis. Case and control mothers were comparable in terms of age, education and congenital infection. Cases and controls were comparable in terms of prematurity, asphyxia and weight at birth. However, among cases (versus controls), there were more ear deformities (0.6% vs 0.0% p≤0.001), and more recurring otitis (11.3% vs 5.3% p≤0.0001). When adjusted on confounders, the following drugs remained significant versus no exposure: acetylsalicylic acid at low dosage (OR 95% CI 1.61 [1.09-2.37]), valproic acid or valpromide (OR 95% CI 5.20 [1.93-14.00]), systemic corticosteroids (OR 95% CI 0.75 [0.61-0.93]. In a sensitivity analysis which excluded children with recurrent otitis at 24 months, these three results remained significant., Conclusions: This is the first study evaluating the risk of hearing disorders due to in utero exposure to drugs. Hearing loss was associated with valproic acid and low-dose acetylsalicylic acid exposure during pregnancy. Conversely, children with normal hearing were more likely to have been exposed in utero to corticosteroids than children with hearing loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure., Objectives: To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018., Methods: Among women ≥ 55 years, we measured the risk of reporting "Parkinsonism" compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors., Results: During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71-0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33-0.46)., Conclusion: This study did not find evidence for Parkinsonism associated with tamoxifen.

Despite clear advances in characterizing marine biofilms, details on their formation and species succession remain scarce particularly during the early stage of development. We investigated the microbial community composition and succession in coastal marine biofilms on plastic. Samples were collected over 75 days of immersion with strengthened samplings during the early stages of biofilm establishment. Biofilm composition was estimated using Illumina Miseq and microbial community interactions were assessed through microbial association network analysis. In silico analyses showed that primers used in most of previous studies considerably underestimated marine biofilm diversity. Unintentionally ignored so far, we showed that Flavobacteriia might be key actors in the functioning of marine biofilms. Gamma-proteobacteria from the genus Oleibacter strongly dominated microbial communities during the first hours of biofilm formation. These pioneer communities were quickly replaced by alpha-proteobacteria and Flavobacteriia. Bacterial communities exhibited fast temporal structure dynamics with taxa displaying rapid increases and declines. A total of 90% of operational taxonomic units (OTUs) were intermittent or ephemeral reinforcing the conclusion that marine biofilms are highly dynamics. With 2/3 of positive significant connections between bacterial OTUs, microbial biofilm communities appear to be more inclined to develop inter-specific cooperation rather than competition and might thus form sets of functional guilds with mutual metabolic exchanges.

Introduction: The use of mobile apps is increasing in medicine. In pharmacovigilance, mobile apps may help to increase adverse drug reaction reporting and improve the communication of safety issues. The Toulouse University Pharmacovigilance Center has developed VigiBIP ® , a free smartphone app available on Android and Apple stores, for reporting adverse drug reactions and requesting drug safety information., Objective: The present study was performed to compare the main characteristics of spontaneous adverse drug reaction reports received through VigiBIP ® with classical methods of reporting (phone, e-mail, fax, letter, website) during 25 months (2015-17)., Methods: Using the Chi squared test, we compared the type of reporter, adverse drug reaction seriousness, drugs involved and reported ADRs using VigiBIP ® and classical methods of reporting RESULTS: A total of 4102 reports were received by the Toulouse University Pharmacovigilance Center, including 4.7% through VigiBip ® . Patients' reports were significantly more frequent with VigiBip ® (6.7%) than with classical methods (3.4%) [p = 0.01]. Reported adverse drug reactions and involved drugs differed according to the method of reporting used., Conclusion: Our study shows that a mobile app is an additional tool used in pharmacovigilance. Types of reporters and adverse drug reactions in VigiBIP were different to those seen in classical methods of reporting.

The characteristics of pharmacology and drug evaluation in the pediatric age group highlight the necessity for the pharmacovigilance community to adjust to the specific features of children. At the time of marketing a medicinal product intended for children, the product's safety profile is sometimes less well known than for adults due to fewer or small sample clinical trials. Furthermore, the frequent off-labeled drug use, the use of unsuitable dosage forms and the need for continuous dose adjustments increase the risk of medication errors and thus lead to avoidable adverse drug reactions (ADRs). The occurrence of child-specific ADRs (such as growth disorders) or ADRs more commonly occurring in children than in adults make it necessary to monitor the safety of child-specific drugs. Pediatric pharmacovigilance includes also the consequences of in utero exposure, whether manifestations are present from birth or occur in early childhood (such as neurodevelopmental disorders). The incidence of ADRs varies with age, setting of medical care (in- or out-patients, pediatric specialties) and by country in which the study was carried out. The drugs most frequently reported with ADRs are those most commonly used in the pediatric age group, i.e. antibiotics and vaccines. The ADRs most often reported are skin, neurological and general disorders. As in adults, spontaneous notification is essential to generate alerts and child-specific pharmacoepidemiological studies are necessary and should be developed., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Off-label (OL) and unlicensed (UL) drug use is widely developed in the pediatric population according to previous reviews published in the early 2010s. The present study is a narrative review of the literature of OL-UL drug use from 2013., Methods: We performed a literature search of research articles assessing OL-UL drug use in children (<18 years-old) published in Medline ® from January 2013 until May 2017., Results: Twenty-seven studies were included. OL drug use was defined by inappropriate age, indication, dosage or way of administration according to the summary of product characteristics in >80% of studies. UL drug used was defined by the use of drugs not licensed in the country or modifications of licensed drugs in >70% of studies. Among in- and out-patients, the frequency of patients exposed to at least one OL-UL drug ranged from 36.3 to 97.0% and from 18.6 to 40.2%, respectively. Drug use was categorized as OL mostly due to inappropriate age, dosage or indication. OL-UL drug use was the most prevalent in newborns (mainly preterms) and pre-school children (aged 2-5years). Various drugs were involved, depending on patients' age. Polypharmacy and long hospital stays were risk factors for OL-UL drug use. Whether OL-UL drug use leads to a higher incidence of adverse drug reactions is a controversial finding., Conclusions: OL-UL drug use is frequent in children. A standardized definition of OL-UL drug use is needed to better assess its frequency, risk factors and impact., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To examine and compare the experiences and attitudes of primary care physicians in three different regulatory environments (United States, Canada, and France) towards interactions with pharmaceutical sales representatives, particularly their perspectives on safety information provision and self-reported influences on prescribing., Methods: We recruited primary care physicians for 12 focus groups in Montreal, Sacramento, Toulouse and Vancouver. A thematic analysis of the interview data followed a five-stage framework analysis approach., Results: Fifty-seven family physicians (19 women, 38 men) participated. Physicians expected a commercial bias and generally considered themselves to be immune from influence. They also appreciated the exchange and the information on new drugs. Across all sites, physicians expressed concern about missing harm information; however, attitudes to increased regulation of sales visits in France and the US were generally negative. A common solution to inadequate harm information was to seek further commercially sourced information. Physicians at all sites also expressed sensitivity to critiques from medical students and residents about promotional interactions., Conclusions: Physicians have contradictory views on the inadequate harm information received from sales representatives, linked to their lack of awareness of the drugs' safety profiles. Commonly used strategies to mitigate information bias are unlikely to be effective. Alternate information sources to inform prescribing decisions, and changes in the way that physicians and sales representatives interact are needed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nutrient loadings from either point or non-point sources to the environment are related to the growing global population. Subsequent negative impacts of nutrient loading to aquatic environments requires a better understanding of the biogeochemical cycling and better tools to track their sources. This study examines the carbon (C), nitrogen (N) and phosphorus (P) discharge and cycling in a Mediterranean coastal area from rivers to marine sediments and assesses the anthropogenic contributions. Carbon and N concentrations and isotope compositions in rivers particles, surface sediments, and sediment cores were investigated to build up a quantitative multiple-end-member mixing model for C and N isotopes. This model predicts the contribution of four natural and one anthropogenic sources to the sediments and highlighted the anthropogenic fraction of P based on the relationship with anthropogenic δ 15 N. Although P is a monoisotopic element and total P concentration has been the sole index to study P loading, this study suggests an alternative approach to differentiate anthropogenic and non-anthropogenic (diagenetic) P, revealed point and non-point sources of P, and the corresponding P loading. Also, the diagenetic P background has been calculated for the 50-cm sediment layer of the whole Bay., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Antipsychotic drugs possess side atropinic (anticholinergic) properties that may induce several adverse drug reactions (ADRs), such as memory loss or cognitive impairment. The aim of this study was to investigate anticholinergic burden in patients treated with antipsychotic drugs. All ADR reports including at least one antipsychotic and registered between 2000 and 2015 in the Midi-Pyrénées PharmacoVigilance Database were extracted and analyzed using the Anticholinergic Duran's list. The primary objective of this cross-sectional study was to calculate anticholinergic burden in antipsychotic-treated patients; the secondary one was to investigate associated factors. Among the 1948 reports, the average number of atropinic drugs per report was 2.4 ± 1.4. At least one atropinic drug was found in 59.4% of reports (1158), in addition to antipsychotic drugs. The mean anticholinergic burden per report was 3.9 ± 2.9. A value ≥3 was found in 61.7% of the reports. A significant association between anticholinergic burden, age, and male gender of patients was found. The mean value of anticholinergic burden remained stable during the study period. This study showed high values of anticholinergic burden in patients receiving antipsychotics. Thus, considering the potential noxious clinical impact of atropinic properties on cognitive functions, an appropriate approach should be used to reduce prescription of antipsychotics with a high anticholinergic burden but also coprescription of other frequently associated atropinic drugs, such as antiparkinsonians, H1 antihistamines, or imipraminic antidepressants in these patients., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: Studies that evaluate the safety of non-prescription drugs in children remain scarce., Objectives: The aim of the present study was to compare adverse drug reactions (ADRs) due to prescription versus non-prescription drugs in children., Methods: We conducted a retrospective analysis of ADR notifications for a pediatric population (aged <18 years) registered in the French PharmacoVigilance Database (FPVD) between January 1985 and December 2016 by the Midi-Pyrénées PharmacoVigilance Center (in the south of France). We compared ADR profiles according to drug prescription status using a Chi-squared test., Results: We included 2218 notifications concerning 3687 ADRs in the study. Non-prescription drugs were involved in 506 notifications (22.8%). Patients were younger in the non-prescription drug group (6.7 ± 5.3 vs. 8.4 ± 5.7 years in the prescription drug group). No difference by sex was found. Neurological ADRs were more frequent with prescription drugs (21.0%) than with non-prescription drugs (14.2%, p = 0.0008), whereas dermatological disorders (37.2 vs. 29.1%, respectively) and general ADRs (30.8 vs. 20.1%, respectively) were more frequent with non-prescription than with prescription drugs (p = 0.0006 and p < 0.0001, respectively). The frequency of "serious" ADRs was higher with prescription drugs than with non-prescription drugs (40.9 vs. 34.2%, p = 0.007). The non-prescription drugs most frequently implicated with serious ADRs were ibuprofen (n = 37; 4.2%), tuberculosis vaccine (n = 23; 2.6%), aspirin (n = 20, 2.3%), and paracetamol (n = 17; 1.9%). ADRs from prescription drugs involved asparaginase (n = 27; 3.1%), immunoglobulins (n = 25; 2.9%), and amoxicillin (n = 23; 2.4%)., Conclusions: Non-prescription drugs, usually considered safe, were frequently responsible for ADR notifications. The non-prescription medication most frequently involved in serious ADRs was ibuprofen.

Background: QT interval prolongations were described with citalopram and escitalopram. However, the effects of the other serotonin reuptake inhibitors (SRIs) remained discussed. In order to identify a putative signal with other SRIs, the present study investigates the reports of QT interval prolongation with SRIs in two pharmacovigilance databases (PVDB)., Methods: Two kinds of investigations were performed: (1) a comparative study in VigiBase®, the WHO PVDB, where notifications of QT prolongation with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were selected. Cases with overdose or pregnancy were excluded. The relationship between the "suspected" SRI and occurrence of QT prolongation was assessed by calculating reporting odds ratio (ROR) in a case/non-case design. (2) A descriptive study of QT prolongation reports with citalopram and escitalopram in the French FPVD., Results: In VigiBase®, 855 notifications were identified (mean age 56.2 years, mainly women 73%). Among them, 172 (20.1%) were associated to escitalopram; 299 (35.0%), to citalopram; 186 (21.8%), to fluoxetine; 94 (11.0%), to sertraline; 66 (7.7%), to paroxetine; and 38 (4.4%) to fluvoxamine. A significant ROR value (higher than 1) was only found for citalopram (3.35 CI95% [2.90-3.87]) or escitalopram (2.50 [2.11-2.95]). In the FPVD, eight reports of QT prolongation were found with citalopram and 27 with escitalopram, mainly in women (77.1%) with a mean age of 73.2 years. In 23 cases (66%), SRIs were associated with other suspected drugs, mainly cardiotropic or psychotropic ones. Hypokalemia was associated in six patients., Conclusion: This study, performed in real conditions of life, shows a clear signal of QT prolongation with only two SRIs, citalopram and escitalopram, indicating that QT prolongation is not a SRI class effect.

The main limitation of adverse drug reactions (ADRs) reporting, particularly by general practitioners (GP), to the regional pharmacovigilance centers is under-reporting. The Midi-Pyrénées Regional Pharmacovigilance Center (South western, France) sets up regular visits by a clinical research assistant (CRA) to GP in order to increase the number of ADR reports. The aim of this pilot study was to assess the effect of regular visits of a CRA in GPs offices on the rate of ADR reporting. After one year, CRA visits permit a two-fold increase in ADR reporting., (Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The potential favorizing role of drugs in sleep apnea syndrome (SAS) is unknown. This study investigates drugs associated with SAS in a pharmacovigilance database. SAS recorded as adverse drug reactions (ADRs) in VigiBase ® , the WHO pharmacovigilance database (more than 11 million reports), from 1978 to 2015 was selected. The risk of SAS reports was estimated using the case-noncase method, with cases being SAS and noncases all other recorded ADRs. During this 37-year period, 3325 ADRs including the word SAS were registered (0.05% of the database). Mean age was 51.2 ± 16.9 years with 52% men. ADRs were 'serious' in around 82% of cases. The case-noncase study found an association between SAS and exposition with sodium oxybate, rofecoxib, quetiapine, and clozapine for individual drugs and coxibs, antipsychotics, benzodiazepines, and opium alkaloids for drug classes. The potential role of other drugs is discussed. This study suggests that SAS can be associated with some drugs (mainly psychotropics) that are able to reveal or aggravate such a disease. Physicians should take into account the role of drugs in the etiological appraisal and management of SAS., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Aim: The aim of this study was to assess the risk of adverse drug reactions (ADRs) with botulinum neurotoxin type A (BoNT-A) in children with cerebral palsy (CP) using the World Health Organization global individual case safety report (ICSR) database, VigiBase., Method: We extracted all children ICSRs for ADRs with BoNT-A used as anti-spastic drug in CP recorded between 1995 and 2015 in VigiBase. We also performed a case/non-case method (disproportionality analysis) to assess the link between exposure to BoNT-A and each ADR of interest in children and adults, calculating reporting odds ratios (RORs)., Results: In VigiBase, 162 ICSRs were registered. They involved mainly males (n=95, 59%) and mean (SD) age was 7 years 11 months (4y 4mo). The most frequent ADR was dysphagia (27 ICSRs, 17%) followed by asthenia and muscular weakness (25 ICSRs each, 16%). Nineteen ICSRs (12%) were lethal. There was a significant association between BoNT-A and death in children (ROR=11.1 95%, confidence interval [CI] 7.0-17.7) but not in adults., Interpretation: In children with CP, most ADRs seem to be linked to a systemic spread of BoNT-A. Our study suggests a higher risk of ADRs with BoNT-A in children than in adults., (© 2016 Mac Keith Press.)

Introduction: Spontaneous reporting of adverse drug reactions (ADRs) remains the cornerstone of postmarketing drug safety surveillance (pharmacovigilance); however, one of its main limitations is incomplete data, thus limiting conclusions about causality assessment., Objective: The primary aim of this study was to assess the completeness of ADR reports sent by general practitioners (GPs) to regional pharmacovigilance centres and the secondary objective was to identify factors associated with complete ADR reports., Methods: All ADR reports sent by GPs to the Midi-Pyrénées Regional Pharmacovigilance Center (Toulouse, France) from 1 January 2010 to 31 December 2013 were reviewed. Healthcare professionals and patients can forward an ADR using either an online form through the Pharmacology Information Bulletin website ( http://www.bip31.fr ) or 'traditional' ADR reports (i.e. email, letter or fax). According to information provided in ADR reports (i.e. patient identification, ADR, date of occurrence, clinical description, drugs, etc.), reports were classified into three groups: 'well-documented', 'slightly documented' or 'poorly documented'. A multivariate logistic regression was performed to investigate potential factors associated with a 'well-documented' ADR report., Results: During the study period, 613 ADR reports were analysed. Among these reports, only 12.7 % were classified as 'well-documented', 68.5 % as 'slightly documented' and 18.8 % as 'poorly documented'. An association between a 'well-documented' ADR report and its 'seriousness' was found (odds ratio = 1.70 [95 % CI 1.04-2.76], p = 0.01). No association between report completeness ('well-documented' report) and GP practice location or mode of ADR reporting was found., Conclusions: The study shows that only one out of eight ADR reports from GPs was 'well-documented'. Therefore, it appears to be important to promote further information being available regarding the data required in ADR reports to optimise the evaluation of drug causality.

Water quality can be evaluated using biomarkers such as tissular enzymatic activities of endemic species. Measurement of molluscs bivalves activity at high frequency (e.g., valvometry) during a long time period is another way to record the animal behavior and to evaluate perturbations of the water quality in real time. As the pollution affects the activity of oysters, we consider the valves opening and closing velocities to monitor the water quality assessment. We propose to model the huge volume of velocity data collected in the framework of valvometry using a new nonparametric extreme values statistical model. The objective is to estimate the tail probabilities and the extreme quantiles of the distribution of valve closing velocity. The tail of the distribution function of valve closing velocity is modeled by a Pareto distribution with parameter 𝜃 t,τ , beyond a threshold τ according to the time t of the experiment. Our modeling approach reveals the dependence between the specific activity of two enzymatic biomarkers (Glutathione-S-transferase and acetylcholinesterase) and the continuous recording of oyster valve velocity, proving the suitability of this tool for water quality assessment. Thus, valvometry allows in real-time in situ analysis of the bivalves behavior and appears as an effective early warning tool in ecological risk assessment and marine environment monitoring.

Use of atropinic drugs remains controversial in Parkinson's disease (PD) because there is insufficient evidence about their efficacy and they can induce serious adverse drug reactions. Atropinic risk scales were developed to help to identify atropinic drugs in prescription forms and to evaluate their burden in clinical practice. In the present review, we discuss the few studies investigating atropinic burden in PD and present the results of our study indicating that atropinic drugs are still widely prescribed in PD (almost 3 of 5 prescriptions) with a clinically significant atropinic burden in around 1 of 6 PD patients. Drugs mainly responsible for high values of atropinic burden were those used for nonmotor symptoms. Clinically significant atropinic burdens were mainly induced by associations of several "low-risk" drugs. Physicians must be aware that in addition to classical atropinic antiparkinsonian drugs, many others (psychotropics) can contribute to increased atropinic burden in PD patients. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Self-medication means resorting to one or more drugs in order to treat oneself without the help of a doctor. This phenomenon is developing fast. In this review, we will discuss the main definitions of self-medication; we will then present a few important characteristics of this therapeutic practice: prevalence, reasons, populations involved and drugs used. Whilst the theoretical risks of self-medication have been abundantly discussed in the literature (adverse effects, interactions, product, dosage or treatment duration errors, difficulty in self-diagnosis, risk of addiction or abuse…), there is in fact very little detailed pharmacovigilance data concerning the characteristics and the consequences of this usage in real life. This study therefore describes the all too rare data that is available: patients, clinical characteristics, "seriousness" and drugs involved in the adverse effects of self-medication. It also discusses leads to be followed in order to minimize medication risks, which are obviously not well known and clearly not sufficiently notified., (Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Heavily contaminated sediments are a serious concern for ecosystem quality, especially in coastal areas, where vulnerability is high due to intense anthropogenic pressure. Surface sediments (54 stations), 50 cm interface cores (five specific stations), river particles, coal and bulk Pb plate from past French Navy activities, seawater and mussels were collected in Toulon Bay (NW Mediterranean Sea). Lead content and Pb stable isotope composition have evidenced the direct impact of sediment pollution stock on both the water column quality and the living organisms, through the specific Pb isotopic signature in these considered compartments. The history of pollution events including past and present contaminant dispersion in Toulon Bay were also demonstrated by historical records of Pb content and Pb isotope ratios in sediment profiles. The sediment resuspension events, as simulated by batch experiments, could be a major factor contributing to the high Pb mobility in the considered ecosystem. A survey of Pb concentrations in surface seawater at 40 stations has revealed poor seawater quality, affecting both the dissolved fraction and suspended particles and points to marina/harbors as additional diffuse sources of dissolved Pb.

Although self-medication is widely developed, there are few detailed data about its adverse drug reactions (ADRs). This study investigated the main characteristics of ADRs with self-medication recorded in the Midi-Pyrénées PharmacoVigilance between 2008 and 2014. Self-medication included first OTC drugs and second formerly prescribed drugs later used without medical advice (reuse of previously prescribed drugs). Among the 12 365 notifications recorded, 160 (1.3%) were related to SM with 186 drugs. Around three-forth of the ADRs were 'serious'. Mean age was 48.8 years with 56.3% females. The most frequent ADRs were gastrointestinal and neuropsychiatric and main drug classes involved NSAIDs, analgesics, and benzodiazepines. Phytotherapy-homeopathy accounted for 9.1% of drugs., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

A survey of the mercurial exposure of residents of Santarém and Oriximiná showed a differential mercurial impregnation between men and women. At the level of both cities, the mean hair mercury concentrations were 1.5 ± 0.5 (90th and 95th percentiles: 2.8 and 4.3) and 2.52 ± 0.09 μg g Hg/g (90th and 95th percentiles: 4.7 and 8.1) for women and men, respectively. The mercurial contamination appeared significantly closely linked to the daily amount of consumed fish. Carnivore species pescada branca (Plagioscion squamosissimus) and apapá (Pellona castelnaeana) and non-carnivore species pacú (Mylossoma duriventre) and aracú (Schizodon fasciatus) were consumed by 22, 19, 55 and 25% of people, respectively, and the mean mercury concentrations within fish flesh were 1.44 ± 0.11, 1.66 ± 0.19, 0.48 ± 0.09 and 0.49 ± 0.06 μg/g dry weight, respectively. Men aged above 35 were significantly more contaminated than those below. The mean hair concentrations of men were 5.20 ± 1.25 and 1.50 ± 0.22 μg/g, for those aged above 35 and below, respectively. The probability for women of childbearing age from both cities to present a hair mercury concentration above 1 μg Hg/g (corresponding to the US Environmental Protection Agency reference dose) was equal to 0.30 (95% confidence interval of 0.24-0.36). The probability of hair mercury concentration to be above the lowest observable adverse effect level (LOAEL) (0.3 μg Hg/g) was equal to 0.79 (95% confidence interval: 0.73-0.86).

The combination of analysis, multivariate treatment (PCA) and chemical speciation calculation confirmed the control of Fe, Mn, sulphide and organic matter on metals dynamics in coastal sediments (0-5 cm surface sediments and sediments cores) of Toulon Bay (NW Mediterranean). The temporal monitoring of the physic-chemical parameters as well as the dissolved/particulate minor (Fe/Mn) and trace elements (i.e. Ag, Cd, Co, Cu, Ni, Pb, Zn, …) concentrations in porewaters and sediments were assessed. Multivariate treatment revealed different behaviours for marine elements, terrestrial ones and contaminants. Seasonal variations of metals mobilization in porewater were observed, related to diagenesis activity. Element mobility was studied by selective extractions (ascorbate, acid and alkaline) on sediments. Thermodynamic simulation (PHREEQC) was performed to calculate the elemental dissolved speciation, the mineral saturation index and then to simulate the solid/liquid interaction through precipitation processes, studying the contrasted influence of dissolved organic matter and sulphide., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To study the characteristics of off-label prescribing and adverse drug reaction (ADR) occurrence in a sample of pediatric outpatients treated by general practitioners., Methods: A survey on pediatric drug prescribing was implemented in 46 general practices in southwestern France. All consecutive patients aged 0 to 16 years were included. Patient characteristics, reasons for consultation, and drug prescribed (including indications) were collected. ADRs occurring ≤10 days after the date of consultation were recorded by the general practitioners (spontaneous notification). Off-label prescription was defined as prescribing outside the specifications of the Summary of Product Characteristics., Results: Among the 2313 children seen between March 8, 2011 and July 31, 2011, 1960 were exposed to ≥1 prescribed drug. Mean age was 5.6 years, with a gender ratio of 1.1. Among children with prescriptions, 37.6% (n = 736) were exposed to ≥1 off-label prescription and 6.7% (n = 132) to ≥1 unlicensed drug. Off-label prescribing involved an unapproved indication in 56.4% of cases (n = 416), a lower dosage (26.5%, n = 195) or higher dosage (19.5%, n = 144) than specified, age not labeled (7.2%, n = 53), incorrect route of administration (3.5%, n = 26), and contraindication (0.3%, n = 2). A total of 23 ADRs were reported (1.5% of patients with off-label prescriptions). ADR occurrence was not significantly related to off-label drug prescribing., Conclusions: Despite the numerous initiatives implemented for promoting rational medicine use in children, the prevalence of off-label prescription in outpatient pediatric practice remains high., (Copyright © 2015 by the American Academy of Pediatrics.)

Identifying specific effects of contaminants in a multi-stress field context remain a challenge in ecotoxicology. In this context, "omics" technologies, by allowing the simultaneous measurement of numerous biological endpoints, could help unravel the in situ toxicity of contaminants. In this study, wild Atlantic eels were sampled in 8 sites presenting a broad contamination gradient in France and Canada. The global hepatic transcriptome of animals was determined by RNA-Seq. In parallel, the contamination level of fish to 8 metals and 25 organic pollutants was determined. Factor analysis for multiple testing was used to identify genes that are most likely to be related to a single factor. Among the variables analyzed, arsenic (As), cadmium (Cd), lindane (γ-HCH) and the hepato-somatic index (HSI) were found to be the main factors affecting eel's transcriptome. Genes associated with As exposure were involved in the mechanisms that have been described during As vasculotoxicity in mammals. Genes correlated with Cd were involved in cell cycle and energy metabolism. For γ-HCH, genes were involved in lipolysis and cell growth. Genes associated with HSI were involved in protein, lipid and iron metabolisms. Our study proposes specific gene signatures of pollutants and their impacts in fish exposed to multi-stress conditions.

The potential of quantile regression (QR) and quantile support vector machine regression (QSVMR) was analyzed for the definitions of quantitative structure-activity relationship (QSAR) models associated with a diverse set of chemicals toward a particular endpoint. This study focused on a specific sensitive endpoint (acute toxicity to algae) for which even a narcosis QSAR model is not actually clear. An initial dataset including more than 401 ecotoxicological data for one species of algae (Selenastrum capricornutum) was defined. This set corresponds to a large sample of chemicals ranging from classical organic chemicals to pesticides. From this original data set, the selection of the different subsets was made in terms of the notion of toxic ratio (TR), a parameter based on the ratio between predicted and experimental values. The robustness of QR and QSVMR to outliers was clearly observed, thus demonstrating that this approach represents a major interest for QSAR associated with a diverse set of chemicals. We focused particularly on descriptors related to molecular surface properties.

Background: The present study aimed to describe exposure and attitudes of French medical residents towards pharmaceutical industry. The study was performed shortly after the Mediator affair which revealed several serious conflicts of interest inside the French health system., Methods and Findings: A cross-sectional study was implemented among residents from 6 French medical faculties. Independent education in pharmacology, attitudes towards the practices of pharmaceutical sales representatives, opinions concerning the pharmaceutical industry, quality of information provided by the pharmaceutical industry, and opinions about pharmaceutical company sponsorship were investigated through a web-based questionnaire. We also assessed potential changes in resident attitudes following the Mediator affair. The mean value of exposure to drug companies was 1.9 times per month. Global opinions towards drug company information were negative for 42.7% of the residents and positive for only 8.2%. Surprisingly, 81.6% of residents claimed that they had not changed their practices regarding drug information since the Mediator affair. Multivariate analyses found that residents in anesthesiology were less likely to be exposed than others (OR = 0.17 CI95% [0.05-0.61]), exposure was significantly higher at the beginning of residence (p<0.001) and residents who had a more positive opinion were more frequently exposed to drug companies (OR = 2.12 CI95% [1.07-4.22])., Conclusions: Resident exposure to drug companies is around 1 contact every 2 weeks. Global opinion towards drug information provided by pharmaceutical companies was negative for around 1 out of 2 residents. In contrast, residents tend to consider the influences of the Mediator affair on their practice as relatively low. This survey enabled us to identify profiles of residents who are obviously less exposed to pharmaceutical industry. Current regulatory provisions are not sufficient, indicating that further efforts are necessary to develop a culture of disclosure of conflict of interest and of transparency in residents.

Background: In France, online reporting via a website is a new method for notifying adverse drug reactions (ADRs). The French Midi-Pyrénées Regional Pharmacovigilance Center (RPVC) set up in July, 2010 a Web-based ADR reporting tool in order to improve ADR reporting rate., Objectives: To assess feasibility, use and performances of this new ADR reporting system. To evaluate the main characteristics of these online reports., Methods: In a retrospective study, we evaluated characteristics (numbers, ADR reporting and file processing times, type of reporters, suspected drugs, "seriousness" and nature of ADRs) of online notifications reported to the RPVC between July 7(th), 2010 (first online notification) and December 31(th), 2011. We performed comparisons to a random sample of "conventional" notifications, i.e. spontaneously reported to the RPVC via traditional tools (post, fax, e-mail or telephone) during the same period., Results: The total number of online reports was 312 over the 18-month period. There was a 45% increase in numbers of reports from ambulatory healthcare professionals after the implementation of the new reporting tool. Online reports were transmitted to the French Medicine Agency on average almost one month (26 days) earlier than "conventional" ones. This difference was mainly due to a faster ADR notification process via the online form (on average, the reporting period was decreased by 19 days with the new tool). In comparison to "conventional" notifications, online reports came more often from ambulatory healthcare professionals, and involved more frequently neuropsychiatric drugs and neuropsychiatric ADRs. None difference was observed for "seriousness" of ADRs., Conclusions: It is feasible to deploy an online ADR reporting system used by health professionals in current practice. We underline the efficiency of this new online reporting tool for increasing ADRs reporting. Moreover, this is the first published study demonstrating that an online reporting tool can help to save time on the ADR reporting period and file processing, which is essential to generate early safety signals., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

It has been suggested that the risk of acute kidney injury (AKI) increases with the number of drugs associated between non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEis) [or angiotensin receptor blockers (ARBs)] and diuretics. We aimed to investigate whether the number of drugs associated between NSAIDs, ACEis, ARBs and diuretics was associated to disproportionate reporting of AKI in the French Pharmacovigilance Database. In reports of Adverse Drug Reactions (ADRs) recorded between 01 January 2008 and 31 December 2010, we selected patients whose medications included at least one oral antihypertensive drug. We used a case/non-case methodology. Cases were AKI and non-cases were all the remaining reports. Among the 11,442 ADR reports in patients under antihypertensive drug recorded in the French Pharmacovigilance Database, 837 ADRs were AKI (7.3%, 95% CI 6.8-7.8). AKI and the number of drugs associated were disproportionately reported (one drug alone: adjusted ROR 2.19, 95% CI: 1.65-2.89, two drugs: adjusted ROR 5.27, 95% CI: 4.00-6.94, three and more: adjusted ROR 16.46, 95% CI: 11.38-23.80). There was no significant association between NSAIDs' half-lives and reporting of AKI (adjusted ROR=0.54, 95% CI: 0.25-1.15). Given the widespread use of these hazardous drugs in general population, caution is needed when they are associated.

This paper provides a review of recent applications of quantile regression to the fields of genetic and the emerging -omic studies. It begins with a general background about this statistical approach following the seminal paper of Koenker and Bassett (Econometrica 46:33-50, 1978). Applications are described, as diverse as genetic association studies, penetrance estimation, gene expression, CGH array experiments, RNAseq experiments, methylation data and proteomics. This paper also introduces recent extensions of quantile regression with a particular focus on the Copula-quantile regression, an approach we recently proposed for sib-pair analysis. A real data example from eQTL analysis is then presented and the [Formula: see text] codes, which run the analyses are provided. Finally, we conclude with some statistical software presentation and some general statements about the potential and interests of quantile regression in modern biological experiments.

This study aimed at evidencing contaminant inputs from a rapidly growing population and the accompanying anthropogenic activities to river sediments. The Fez metropolitan area and its impacts on the Sebou's sediments (the main Moroccan river) were chosen as a case study. The Fez agglomeration is surrounded by the river Fez, receiving the wastewaters of this developing city and then flowing into the Sebou. The sediment cores from the Fez and Sebou Rivers were extracted and analysed for major elements, butyltins and toxic metals. Normalised enrichment factors and geoaccumulation index were calculated. Toxicity risk was assessed by two sets of sediment quality guideline (SQG) indices. A moderate level of contamination by butyltins was observed, with monobutyltin being the dominant species across all sites and depths. The lowest level of metal pollution was identified in the Sebou's sediments in upstream of Fez city, whilst the Fez' sediments were heavily polluted and exhibited bottom-up accumulation trends, which is a clear signature of recent inputs from the untreated wastewaters of Fez city. Consequently, the sediments of Fez and Sebou at the downstream of the confluence were found to be potentially toxic, according to the SQG levels. This finding is concerned with aquatic organisms, as well as to the riverside population, which is certainly exposed to these pollutants through the daily use of water. This study suggests that although Morocco has adopted environmental regulations aiming at restricting pollutant discharges into the natural ecosystems, such regulations are neither well respected by the main polluters nor efficiently enforced by the authorities.

Drug-drug interactions (DDIs) between antihypertensive drugs and non-steroidal anti-inflammatory drugs (NSAIDs) can lead to adverse drug reactions (ADRs). Guidelines are available to help prescribers deal with these drug associations, but their implementation is not well evaluated. The aims of this study were to assess the prevalence of NSAIDs exposure in patients treated with antihypertensive drugs, using the French Pharmacovigilance database, and explore the ADRs related to DDIs between antihypertensive drugs and NSAIDs. Over the 11, 442 notifications of ADRs recorded in this database in patients treated with oral antihypertensive drugs between 2008 and 2010, 517 (4.5 and 95% CI: 4.1-4.9) also included exposure to NSAIDs. These subjects were more frequently women, took more drugs in general, and were younger and less frequently treated with antiplatelet drugs. In 24.2% of them (125 patients), a DDI between NSAIDs and antihypertensive drugs was potentially the cause of the reported ADR. Acute renal failure caused by DDIs between NSAIDs and angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or diuretics was the most frequently reported ADR (20.7%). Finally, in the French Pharmacovigilance database, around one-fourth of associations NSAIDs  +  antihypertensive drugs are associated with a 'serious' ADR (mainly acute renal failure), suggesting that this well-known DDI is not enough taken into account by prescribers., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.)

A detailed study on arsenic (As) in rocks and water from the Var River watershed was undertaken aiming at identifying (i) the origin and the distribution of As in this typical Alpine/Mediterranean basin, and (ii) As input into the Mediterranean Sea. Dissolved As concentrations in the Var River range from 0.1 to 4.5 μg⋅L(-1), due to high hydrological variability and the draining through different geological formations. In the upper part of the Var drainage basin, in the Tinée and the Vésubie valleys, high levels of dissolved As concentrations occur (up to 263 μg⋅L(-1)). The two main sources of As in rocks are the Hercynian metamorphic rocks and the Permian argilites. Highly heterogeneous distribution of As in waters draining through metamorphic rocks is probably related to ore deposits containing arsenopyrite. As, U, W and Mo concentrations in water and rocks correspond to the formation of As-rich ore deposits around Argentera granite by hydrothermal fluids deposited at the end of the Hercynian chain formation, which occurred about 300 My ago. In 2009, weekly monitoring was performed on the Var River (15 km upstream of the mouth), highlighting an average dissolved As concentration (<0.45 μm) of 2.7 ± 0.9 μg⋅L(-1), which is significantly higher than the world-average baseline for river water (0.83 μg⋅L(-1)). Taking the average annual discharge (49.4 m(3)⋅s(-1)) into account and the As levels in the dissolved phase and in deposits of the Var River, dissolved As input into the Mediterranean Sea would be 4. 2± 1.4 tons⋅year(-1) which represents 59% of the total As flux. This study also reveals a probable non-conservative As behaviour, i.e., possible transfer between aqueous and solid phases, during the mixing of the Var River with a tributary., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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 82.0 ± 8.0 years (46-108); 61.3% suffered from AD. Mean number of drugs was 6.3 ± 3.1. Anti-dementia drugs were given to 66.4% 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.)

Background: Our knowledge on cancers related to drugs remains limited. Among the different pharmacoepidemiological approaches assessing this risk, analysis of reports to pharmacovigilance (PV) system is uncommon., Objectives: To review cancers registered as adverse drug reactions (ADRs) in the French Pharmacovigilance Database (FPVDB)., Methods: This study was based on spontaneous reports of ADRs submitted to the French PV system. All cases of cancers reported in the FPVDB between 1995 and 2006 were reviewed. Cases with transgenerational effects, cases from patients with an history of primary cancer and cancers associated with antineoplastic drugs were excluded. Drugs were classified according ATC classification. Results. Out of 207 000 notifications, 414 cases of cancer (998 citations of drugs) were identified. Report s increased from 19 cases in 1995 to 70 in 2006. Patients' age ranged from 2 to 95 years. Gender was equally distributed. Most frequently reported cancers were lymphomas (22.7%), b asal or squamous cell carcinomas (16.4%) and leukemias (13.8%). Immunosuppressants (37.6%) were ranked in the first position followed by corticosteroids (9.3%). Potential drug-cancer associations, previously described in the literature (immunosuppressants, hydroxycarbamide, mitoxantrone, cyproterone and hormone replacement therapy) were found in the database. Other potential drug-cancer associations (leukemia and non-Hodgkin's lymphoma after exposition to nucleoside reverse-transcriptase inhibitors or interferon) were also identified., Conclusions: Cancer notifications in a PV database, although usually considered as poorly generalizable to the general population, appears to be useful in the surveillance of cancer risk associated to drugs. It allows both confirmation of already known data and detection of new signals. Combination of present data with pharmacoepidemiological studies and collaborations with cancer registries would allow better identification of these risk signals., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

Quantification and characterization of chronic inputs of trace metals and organic carbon in a coastal Mediterranean area (the city of Marseille) during the dry season was carried out. The 625 km(2) watershed includes two small coastal rivers whose waters are mixed with treated wastewater (TWW) just before their outlet into the sea. Dissolved and particulate Cu, Pb, Cd, Zn, Co, Ni and organic carbon concentrations in the rivers were comparable to those in other Mediterranean coastal areas, whereas at the outlet, 2- to 18-fold higher concentrations reflected the impact of the TWW. A non-conservative behavior observed for most of the studied metals in the mixing zone was validated by a remobilization experiment performed in the laboratory. The results showed that sorption/desorption processes could occur with slow kinetics with respect to the mixing time in the plume, indicating non-equilibrium in the dissolved/particulate metal distribution. Thus, a sample filtration immediately after sampling is strictly required., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Our aim was to characterize Adverse Drug Reactions (ADRs) related to drug-drug interactions (DDIs) related to involvement of cytochrome P450 (CYP450) isoenzymes in a pharmacovigilance database., Methods: ADRs recorded by Midi-Pyrénées PharmacoVigilance center (France) between 1 January and 31 August 2008 were extracted from the French PharmacoVigilance Database (FPVD)., Results: Among the 1,205 reported ADRs, 16 (1.3 %), can be explained by involvement of CYP450 isoenzymes (including 4 "serious"). All interactions involved CYP inhibitors, mainly for CYP3A4/5., Conclusion: The percentage of ADRs reported in the pharmacovigilance database and related to CYP450-induced DDIs appears to be relatively low (~ 1-2 %).

Objective: Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency., Methods: All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed., Results: During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled » SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis., Conclusion: This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia., (Copyright © 2013 Société Française de Pharmacologie et de Thérapeutique. Publié par Elsevier Masson SAS.)

Objective: Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency., Methods: All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed., Results: During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled » SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis., Conclusion: This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)