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Background Polycystic ovary syndrome (PCOS) is considered one of the most common endocrine disorders affecting females in their reproductive age. In PCOS, an imbalance between androgens, anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH), cause a halt of follicular growth. Insulin resistance (IR) is another important component of PCOS. There is increasing evidence that vitamin D affects insulin and glucose metabolism, Vitamin D plays a vital role in the regulation of glucose-insulin homeostasis. Objectives to assess the efficacy of vitamin D supplementation in improving ovulation induction in PCOS women (1ry outcome) and increasing pregnancy rate (secondary outcome). Patients and Methods 120 women diagnosed PCOS according to Rotterdam criteria and were resistant to CC treatment were randomly allocated into equal two groups: Group V: number of 60 patients received cholecalciferol + Metformin for 2 months. Group C: 60 patients received Metformin 2 months. After two months from the start:Both study groups started induction with Clomiphene Citrate added every month starting from the 3rd month to the 5th month (3 cycles of ovulation induction) in addition to previous drugs mentioned. Results In our study results, regulation of menstrual cycle occured in 63.6% of women who recieved vitamin D + metformin (group V) and ovulation was confirmed in 34.5% of the total number (55 women). Later, 18% of them got pregnant after 3 months of treatment. Added to that 16 women out of 39 (41%) got pregnant by the end of the follow up period with cumulative pregnancy rate (53%). On the other hand menstrual regularity in (group C: metformin) recorded 61% with ovulation percentage of 26.9% (n = 54). Followed by 14.8% pregnancy rate at the 3rd month., which increased to 27.5% by the end of the study out of 47.5% ovulated women (n = 40). Cumulative pregnancy rate 40%. Conclusion From the current study we can conclude that there is no significant difference of adding vitamin D to CC resistant PCOS regarding ovulation and pregnancy rates. However, it can augment metformin action and improves its outcome.

Summary Background Quadruple therapy using a single capsule formulation of bismuth, metronidazole and tetracycline (BMT; Pylera®), associated with omeprazole for the eradication of Helicobacter pylori, represents the reintroduction of bismuth in France after 40 years. Objective To describe the real-life patterns of use of BMT following a request from the French health authorities. Methods Patients with a first BMT dispensing (index date, ID), with one year of data before and after ID, were identified in the French nationwide claims database 1/97 sample. Misuse of BMT was defined as dispensing >1 pack of BMT at ID or absence of a diagnostic test in the preceding year. Results In total, 540 patients were included. Prescribers were gastroenterologists (n = 243; 45%) and general practitioners (n = 160; 30%). A proton pump inhibitor was co-dispensed to 504 patients (96%). Ten patients (2%) had contraindications to BMT. Fifty-nine patients (11%) met the misuse criteria: ten (2%) were dispensed > 1 pack of BMT and 49 (9%) had not had a diagnostic test for H. pylori in the previous year. During follow-up, 27 patients (5%) required retreatment (treatment failure). Conclusion In this real-life study, most patients were dispensed only one pack of BMT, consistent with recommendations. Misuse related principally to the absence of prior diagnostic test for H. pylori.

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a logistic regression models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]) and did not show any significant difference when compared with FTY The risk of the progression of MS specific disability was not significantly different for any matched cohorts. Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Clinical trials have indicated that the direct-acting oral anticoagulants dabigatran and rivaroxaban have better risk/benefit profiles than do vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (NVAF). Our objective was to compare the 1-year real-life risk of major clinical events with dabigatran or rivaroxaban versus VKAs for NVAF. This was a high-dimensional propensity score (hdPS)-matched cohort study of new users of dabigatran, rivaroxaban or VKAs for NVAF in the French national healthcare systems database in 2013 followed-up for 1 year [22]. Hazard ratios (HRs) with 95% confidence intervals (CIs) for clinical events and death were determined during exposure. In 2013, a total of 103,101 new anticoagulant users had definite NVAF: 44,653 VKA, 27,060 dabigatran, and 31,388 rivaroxaban. In matched populations, HRs were as follows for dabigatran versus VKAs (20,489 per group): stroke and systemic embolism (SSE) 0.75 (95% CI 0.63–0.88), clinically relevant bleeding (CRB) 0.58 (95% CI 0.51–0.66), hemorrhagic stroke (HS) 0.22 (95% CI 0.14–0.36), gastrointestinal bleeding (GIB) 0.98 (95% CI 0.80–1.19), acute coronary syndrome (ACS) 0.79 (95% CI 0.65–0.95), death 0.74 (95% CI 0.67–0.82), composite (any of the above) 0.71 (95% CI 0.66–0.76). For matched rivaroxaban versus VKA (23,053 per group) HRs were as follows: SSE 0.98 (95% CI 0.85–1.14), CRB 0.83 (95% CI 0.75–0.92), HS 0.65 (95% CI 0.49–0.87), GIB 1.08 (95% CI 0.90–1.30), ACS 0.84 (95% CI 0.71–1.00), death 0.77 (95% CI 0.71–0.84), composite 0.84 (95% CI 0.79–0.89). Numbers needed to treat to observe one fewer death were 49 ± 0.05 with dabigatran or rivaroxaban versus VKAs. Consistent with results from clinical trials and other observational studies, dabigatran and rivaroxaban were at least as effective and safer than VKAs for the prevention of thromboembolic events in NVAF over 1 year in the French population. European Medicines Agency EUPAS 13017 (www.encepp.eu) Clinicaltrials.gov id NCT02785354.

Background Hypertension is a multifactorial disease involving both environmental and genetic Factros. G894 T eNOS polymorphism has been suggested to be responsible for reduced NO synthesis, and EH development. The objective of our case-control study is to evaluate the potential association of G894 T eNOS polymorphism with Essential Hypertension (EH) susceptibility, among a sample of Moroccan patients. Methods One hundred forty five hypertensive patients were recruited from the department of Cardiology, University Hospital Center Ibn Rochd, Casablanca, Morocco, and compared to 184 apparently healthy subjects. DNA samples were genotype by PCR-RFLP method using MboI restriction enzyme. Results Our results showed a positive correlation between G894 T eNOS distribution and Alcohol and Obesity rik factors (P = 0.009 and 0.02 respectively). Patients with elevated Cardio Vascular Risk (CVR) carried out the higher frequency of homozygous mutant genotype TT (62.2%) and T mutant allele (77.8%), compared to median and low CVR groups. G894 T eNOS distribution was significantly associated to a high risk of EH occurrence under the GT and TT genotypes (OR [95% CI] = 20.2 [7.7–52.4], P

Objective The aim of the present study was to investigate the association of I/D polymorphisms of ACE gene is associated with resistant hypertension and essential controlled hypertension. Results Our results show that the homozygous mutant genotype DD was more represented among resistant than controlled (58.1% vs 41.9% respectively), however the homozygote wild was more represented among controlled than resistant (70.6% vs 29.4% respectively). But more heterozygous ID among controlled than resistant patients (63.6% vs 36.4% respectively). The difference was statistically significant (p = 0.04). Analysis of clinical parameters indicated that physical activity contributes to resistant hypertension (P Based on our findings, the homozygous mutant for DD of ACE gene is associated with resistant hypertension in our population. Further studies with larger sample sizes are needed to confirm the results of this study.

Dabigatran and rivaroxaban at standard or reduced doses have been compared to warfarin in nonvalvular atrial fibrillation (NVAF), but not to each other. This was a new user study of standard dose and reduced dose dabigatran or rivaroxaban for NVAF in the French healthcare database, matched on gender, age, date of first dispensing, and high-dimensional propensity score, followed 2 years. Hazard ratios (HRs; 95% confidence intervals (CI)) of stroke or systemic embolism (SSE), major bleeding (MB), or death were computed. In matched standard-dose patients (8,290 per arm), mean age 67 years, HRs for dabigatran vs. rivaroxaban were SSE 0.92 (95% CI = 0.67-1.26), MB 0.59 (95% CI = 0.39-0.90), and death 0.84 (95% CI = 0.65-1.11). In reduced-dose patients (7,639 per arm), mean age 80 years, HRs for dabigatran vs. rivaroxaban were SSE 0.73 (95% CI = 0.59-0.94), MB 0.74 (95% CI = 0.57-0.96), and death 0.95 (95% CI = 0.83-1.09). In conclusion, at either dose, dabigatran had similar or better effectiveness than rivaroxaban but lower bleeding risk. Death rates were not different.

AIMS: We compared the 1‐year safety and effectiveness of dabigatran 110 mg (D110) or 150 mg (D150) twice daily to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation. METHODS: New user cohort study of patients dispensed D110 or D150 vs. VKA in 2013 for nonvalvular atrial fibrillation, followed 1 year in the French Système National des Données de Santé (66 million persons). D110 and D150 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing and high‐dimensional propensity score. Hazard ratios [HR (95% confidence intervals)] for stroke and systemic embolism (SSE), major bleeding (MB) and death were computed using Cox proportional hazards or Fine and Gray models during exposure. RESULTS: In 14 442 matched D110 and VKA patients, mean age 79, 49% male, 91% with CHA(2)DS(2)‐VASc ≥2 and 8% with HAS‐BLED score >3, incidence rates of SSE were 1.9% and 2.6% person‐years [HR 0.69 (0.56–0.84)], MB 1.8% and 2.9% [0.62 (0.51–0.76)], death 7.2% and 8.6% [0.84 (0.76–0.94)]. In 8389 matched D150 and VKA patients, mean age 67, 67% male, 65% with CHA(2)DS(2)‐VASC ≥2; < 5% HAS‐BLED >3, incidence rates were for SSE 1.4% and 1.9% [0.76 (0.56–1.04)], MB 0.6% and 1.9% [0.30 (0.20–0.46)], death 1.6% and 3.6% [0.46 (0.35–0.59)]. Numbers needed to treat to observe one fewer death were 78 for D110, 88 for D150. CONCLUSION: In real life D110 and D150 were at least as effective, and safer than VKA.

Aims This study aimed to describe the real-life incidence of bleeding, arterial thrombotic events and death during vitamin K antagonist (VKA) treatment in atrial fibrillation (AF). Methods This was a cohort study in Echantillon Generaliste de Beneficiaires, the 1/97 sample of the French national healthcare claims and hospitalization database, of new VKA users with definite or probable AF and no other indication, and of patients without AF, from 2007 to 2011. Prespecified outcomes were all-cause death, hospitalization for bleeding, arterial thrombotic event (ATE), or acute coronary syndrome (ACS) or any of the above (composite outcome). Results Of 8894 new VKA users, 3345 had probable or certain AF, 51.7% were male, mean age was 75.1 years, 87.1% had a CHA2DS2-VASc score ≥ 2 and 11.6% a HAS-BLED score > 3. Among AF patients, during VKA exposure the incidence rate of bleeding was 2.8 [95% confidence interval (CI) 2.2, 3.4] per 100 patient-years, including 0.6 (95% CI 0.3, 0.8) cerebral, 1.0 (95% CI 0.7, 1.3) digestive and 1.4 (95% CI 1.0, 1.7) other bleeds. There were 1.6 (95% CI 1.2, 2.0) ACS, 1.5 (95% CI 1.1, 1.8) ATE and 3.8 (95% CI 3.2, 4.4) deaths per 100 patient-years. The incidence rate of the composite outcome was 9.1 per 100 patient-years (95% CI 8.2, 10.0). When patients stopped VKA, bleeding decreased (RR 0.67, 95% CI 0.43, 1.04)), but death or thrombosis increased (RR 3.06, 95% CI 2.46, 3.81 and 1.75, 95% CI 1.14, 2.70, respectively). During VKA exposure non-AF patients had similar rates of bleeding, but fewer deaths, ACS and ischaemic events. Conclusions Real-life rates for bleeding, arterial thrombotic events, ACS and deaths in AF patients treated with VKA were similar to those observed in clinical trials.

Non-steroidal anti-inflammatory drugs are associated with a dose and duration-dependent coronary risk. There is little information concerning analgesic-dose ibuprofen, among the most widely used drugs worldwide. Our objective was to measure the risks of acute coronary syndrome (ACS) after dispensing of ibuprofen, versus paracetamol. Propensity score 1:2-matched cohorts of ibuprofen or paracetamol treatment episodes (TEs) in Echantillon Generaliste de Beneficiaires (EGB), the 1/97 sample of Systeme National des Donnees de Sante (SNDS), the French nationwide claims database, from 2009 to 2014, were compared. Outcomes were hospital admissions for ACS during the 3 months after the dispensing of ibuprofen or paracetamol. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated overall and stratified on low-dose aspirin dispensing. A total of 315,269 ibuprofen TEs in 168,400 persons were matched to 630,457 paracetamol TEs in 395,952 patients. Event rates were 50–100 times higher in low-dose aspirin users (27 vs 0.28 per 1000 patient years). Overall there was no difference in risk of ACS at 3 months (HR 0.94, 95% CI 0.74–1.20) despite a transient increase in the first 2 weeks in ibuprofen users (HR 1.70, 95% CI 1.11–2.59). In the stratified analysis, this short-term risk was only found in aspirin users (5% of population, HR 1.84, 95% CI 1.24–3.24), but not in non-aspirin users (HR 1.09, 95% CI 0.40–2.94). There was no evidence for an increased risk of ACS in patients dispensed ibuprofen compared to paracetamol.

Background Dabigatran (D) and rivaroxaban (R) showed better benefit-risk than VKA for stroke prevention in non-valvular atrial fibrillation (NVAF), but no randomized trial compared D versus R. Purpose To compare the 2-year risk of major events for D vs. R new users for NVAF in real-life: standard dosage (D150 mg vs. R20 mg) and reduced dosage (D110 mg vs. R15 mg). Methods Cohort of D or R new users for NVAF in 2013 identified and followed for 2 years in the SNDS French nationwide claims database. NVAF was defined from long-term disease registration, hospitalisation diagnosis or procedure for atrial fibrillation without valvular disease (3-year database history). D and R patients were 1:1 matched according to standard or reduced dosage, on gender, age, drug start date and high-dimensional propensity scores (hdPS) including individual stroke and bleeding risk factors from CHA2DS2-VASc and HAS-BLED. Hazard ratios (HR) [95% confidence interval] were estimated on treatment using Cox proportional hazard risk or Fine and Gray models. Results From the 10,847 D150, 15,532 D110, 18,829 R20 and 11,195 R15 new users for NVAF in 2013, 8290 D150/R20 per arm, and 7639 D110/R15 per arm were matched, i.e. 76% and 68% of patients of the lowest group (D150 and R15 groups), respectively; with very good overlap of hdPS distributions, all standardized differences Conclusion This nationwide study of new anticoagulant users for NVAF shows a better benefit-risk of dabigatran standard and reduced dosages compared to rivaroxaban in real-world setting.

Aims Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or ‘over-the-counter (OTC)’ NSAIDs may influence risks, but are not commonly described. Methods The Echantillon Generaliste de Beneficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009–2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users. Results Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years. Conclusions Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised.

Objective Estimate the effect of lifestyle adjustment activities in patients with metabolic syndrome treated by prescribed balneotherapy. Methods Observational pilot cohort study with 12-month follow-up after multidimensional lifestyle training (physical, dietary, educational) during 3-week standard stay in the spa town of Eugenie-les-Bains. Results Of 145 eligible patients, 97 were included; 63 were followed and analysable. At inclusion all had ≥ 3 National cholesterol education program-Adult treatment panel III (NCEP-ATPIII) criteria defining metabolic syndrome, 76.2% were female, mean age was 61.2 years. At the end of follow-up (median:10.4 months, Inter-Quartile Range: [6.7;11.4]), 48 of these 63 patients (76.2%) no longer had metabolic syndrome (95%CI [65.7;86.7]). These 48 patients without metabolic syndrome at the end of follow-up represented 49.5% of the 97 included (95%CI [39.5;59.4]). Conclusions Future studies of lifestyle interventions taking advantage of the spa environment can be expected to find least one third of patients free of metabolic syndrome at the end of 12-month follow-up in the intervention group.

Purpose To determine healthcare claim patterns associated using nonsteroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis (RA). Methods The CADEUS study randomly identified NSAID users within the French health insurance database. One-year claims data were extracted, and NSAID indication was obtained from prescribers. Logistic regression was used in a development sample to identify claim patterns predictive of RA and models applied to a validation sample. Analyses were stratified on the dispensation of immunosuppressive agents or specific antirheumatism treatment, and the area under the receiver operating characteristic curve was used to estimate discriminant power. Results NSAID indication was provided for 26 259 of the 45 217 patients included in the CADEUS cohort; it was RA for 956 patients. Two models were constructed using the development sample (n = 13 143), stratifying on the dispensation of an immunosuppressive agent or specific antirheumatism treatment. Discriminant power was high for both models (AUC > 0.80) and was not statistically different from that found when applied to the validation sample (n = 13 116). Conclusions The models derived from this study may help to identify patients prescribed NSAIDs who are likely to have RA in claims databases without medical data such as treatment indication. Copyright © 2012 John Wiley & Sons, Ltd.

Aims/hypothesis Using the Echantillon Généraliste de Bénéficiaires: random 1/97 permanent sample of the French national healthcare insurance system database (EGB), we investigated whether, as previously suspected, the risk of cancer in insulin glargine (A21Gly,B31Arg,B32Arg human insulin) users is higher than in human insulin users. The investigation period was from 1 January 2003 to 30 June 2010. Methods We used Cox proportional hazards time-dependent models that were stratified on propensity score quartiles for use of insulin glargine vs human insulin, and adjusted for insulin, biguanide and sulfonylurea possession rates to assess the risk of cancer or death in all or incident exclusive or predominant (≥80% use time) users of insulin glargine compared with equivalent human insulin users. Results Only type 2 diabetic patients were studied. Exposure rates varied from 2,273 and 614 patient-years for incident exclusive users of insulin glargine or human insulin, respectively, to 3125 and 2341 patient-years for all patients predominantly using insulin glargine or human insulin, respectively. All-type cancer HRs with insulin glargine vs human insulin ranged from 0.59 (95% CI 0.28, 1.25) in incident exclusive users to 0.58 (95% CI 0.34, 1.01) in all predominant users. Cancer risk increased with exposure to insulin or sulfonylureas in these patients. Adjusted HRs for death or cancer associated with insulin glargine compared with human insulin ranged from 0.58 (95% CI 0.32, 1.06) to 0.56 (95% CI 0.36, 0.87). Conclusions/interpretation There was no excess risk of cancer in type 2 diabetic patients on insulin glargine alone compared with those on human insulin alone. The overall risk of death or cancer in patients on insulin glargine was about half that of patients on human insulin, thereby excluding a competitive risk bias.

Background Imatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined. The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST. Patients and methods Advanced GIST patients (n = 96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively. Results Small bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p = 0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p = 0.0256) and for both stomach (p = 0.043) and small bowel (p = 0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p = 0.0271) in the whole population independently of the anatomical localisation. Conclusion Concentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.

Background: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems. Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents. Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma. Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p< 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn’s disease were more prevalent in published cases than in pharmacovigilance reports (p< 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001). Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • To our knowledge, no study has ever described the intensity of nonsteroidal anti-inflammatory drug (NSAID) utilization in an employed population by occupation. • As the use of NSAIDs carries a well-known risk of adverse effects, this risk adds to the burden of musculoskeletal disorders in employed populations. • Information on utilization of NSAIDs in this context will help to better characterize and prevent this risk. WHAT THIS STUDY ADDS • In spite of a previous history of dyspepsia, blue collar workers had the highest rate of chronic and continuous utilization of nonselective NSAIDs. • No clustering of cyclooxygenase-2 selective NSAID utilization according to a previous history of dyspepsia was observed among blue collar workers. • The association between chronicity of NSAID utilization and occupation was independent of medical indication for the prescription and other lifestyle factors. AIM The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population. METHODS This was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as ‘over four dispensations in one year with less than two months between any two’. RESULTS Factors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6–1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5–2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5–2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2–1.6). Blue collar workers also had a 20% higher prevalence of 5-year history of dyspepsia. No difference was observed between sexes or in the use of COX-2 selective inhibitors between occupations. CONCLUSION Factors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication.

Purpose We describe drug–drug interactions (DDIs) encountered with antifungals in clinical practice. Methods Retrospective observational study of hospitalized adults receiving systemic antifungal treatment in the intensive care unit (ICU) and in the infectious diseases unit (IDU) of the University Hospital of Bordeaux, France between 1996 and 2001. All treatment episodes with antifungal agent were examined and all prescribed concomitant medication identified for potential drug–drug interactions (PDDI)-serious events occurring during treatment were adjudicated for clinical DDI. Results There were 150 treatment episodes with antifungal agent in 105 patients. Fluconazole was used in 48% of the treatment episodes, amphotericin B in 46%, itraconazole in 4.7% and flucytosine in 1.3%. One hundred and sixteen PDDIs were identified related to the use of amphotericin B (81.0%), fluconazole (17.2%) or itraconazole (1.7%). Of these, 22 were associated with a clinical evidence of adverse interaction (hypokalemia, increased creatininemia or nephrotoxicity). All these clinical drug–drug interactions (CDDIs) were with amphotericin B. They were due to furosemide (36.4%), cyclosporine (31.8%) and hydrocortisone (18.2%). PDDIs were mostly associated with leukaemia (40.4%), HIV infection (24.6%) and cancer (10.5%). Conclusions In ICU and IDU, systemic antifungal treatments lead to many PDDIs, mainly related to the type of antifungal used and to the pathology treated. Clinical DDI seem more common with amphotericin. Copyright © 2007 John Wiley & Sons, Ltd.

Objective: To assess whether current use of psychoactive substance(s) is a prognostic factor during hospitalization for intentional drug overdose (IDO). Method: Current intoxication with psychoactive substance(s) [cannabis, opiate, buprenorphine, amphetamine/ecstasy, cocaine, lysergic acid diethylamide (LSD)] was identified using toxicological urinalysis in 671 patients with IDO. An IDO was a priori defined as serious if associated with one of the following events: death, hospitalization in intensive care unit longer than 48 h, respiratory support, use of vasopressive drugs, cardiac massage or dialysis. Results: Subjects positive for toxicological assays were twice as likely to present with serious IDO (OR = 1.9, 95% CI: 1.3–2.8, P = 0.001), independently from a large range of confounding factors. The risk of serious IDO was especially marked in subjects using LSD, buprenorphine or opiates. Conclusion: Systematic investigation of substance use could be important to adapt medical management of subjects with IDO in general hospital, but also in primary care and psychiatric settings.

Objective: To assess the accuracy of self-reported substance use and toxicological assays in subjects admitted for Intentional Drug Overdose (IDO), using as a reference diagnosis of substance use disorder. Method: Self-reported substance use was collected and toxicological assays were carried out in urine samples in 507 patients with IDO. A standardized psychiatric evaluation was performed in 100 randomly selected subjects. Results: In routine practice, the emergency department staff did not investigate substance use in nearly one of two patients. Patients’ statements and toxicological assays were more specific than sensitive, with lower scores for toxicological assays. Patients’ statements made it possible to detect nearly 80% of subjects with substance use disorder. Conclusion: Identification of substance use disorder in subjects with IDO has strong clinical consequences regarding treatment and prevention of suicidal behaviour. Thus, emergency department staff should be made aware of the value of more systematically exploring self-reported substance use.

The recommended pharmacotherapy for secondary prevention of acute coronary syndrome (ACS) is long-term treatment with a combination of four therapeutic classes: beta-blockers, antiplatelet agents (including aspirin), statins or other lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The aim of this study was to describe use and persistence of the recommended drug combination after the first occurrence of ACS in France.This was a database cohort study of patients with first registration for ACS between 2004 and 2007 in a representative sample of the French healthcare insurance database (Echantillon Généraliste de Bénéficiaires, EGB). The drugs of interest were those recommended. Persistence was assessed for patients dispensed three or all four drug classes within 2 months following ACS. Discontinuation was defined by a gap of more than 6 weeks between two dispensations. The follow-up period was 24 months after ACS occurrence.Of 2,057 patients with incident ACS, 872 (42.4 %) had at least one dispensation of each of the four recommended drug classes, and 684 (33.3 %) had three of the four classes. Persistence to treatment at 24 months was 57.4 % (95 % CI [54.0-60.6]) for patients with four classes, and 55.5 % (95 % CI [51.6-59.1]) with three classes. Discontinuation of initial combination was higher in patients aged ≥ 65 years at ACS occurrence, those with associated ongoing chronic disease, and in those who did not suffer myocardial infarction.Post-ACS secondary prevention in France is not optimal, especially in patients who did not have myocardial infarction.

To investigate the effect of chronic oral arginine aspartate on the growth hormone (GH), GH-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) secretions in healthy volunteers. Twenty-three healthy non-athlete volunteer males were administered arginine aspartate (30 g) orally once daily at 21:00 h for 21 consecutive days. Subjects were hospitalized on days 0, 1, 3, 5, 7, 14 and 21 of treatment. At each hospitalization, concentrations of GHRH, GH, IGF-1 and IGFBP-3 were measured over 4 h after arginine aspartate intake. GH, IGF-1 and IGFBP-3 concentrations were also determined over 12 h at days 0, 1 and 21. Compared with day 1, 4 h GH levels dropped at day 5 and subsequently rose to levels not significantly different from initial ones. The latter was substantiated by 12 h GH levels that did not significantly change from days 1 to 21. GHRH levels were not statistically different, although there was a trend in median values that seemed to inversely mirror those of GH. This dynamic over the course of the study for GH and GHRH was accompanied by a general decrease in IGF-1 and IGFBP-3. In healthy volunteers, a chronic oral treatment with 30 g/day arginine aspartate is followed by a decrease in IGF-1 and IGFBP-3 secretions.

August 2015 e11 −3.5 to 11.7; 26.8; CI, 17.6 to 36.8, respectively), a subjective visual analogue scale for alertness (−1.3; CI, −3.7 to 1.2; −2.5; CI, −4.8 to −0.2; −5.3; CI, −7.7 to −2.9, respectively) and saccadic peak velocity (−14.3; CI, 33.5 to 4.8; −10.9; CI, −29.0 to 7.1; −25.4 (CI, −44.2 to −6.6, respectively), a marker for sedation. Mecamylamine was well tolerated and had linear pharmacokinetics over the dose range tested. Conclusion: The pharmacological challenge model with mecamylamine 20 mg in healthy subjects leads to a reproducible pattern of cognitive disturbance that is nicotinic receptor specific. This model may be more suitable for proof of pharmacology and dose finding studies of nicotinic receptor agonists than the frequently used scopolamine model.

Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised.

10013 Background: Imatinib (IM) as front-line treatment has dramatically changed the evolution of GIST. Demetri et al. (JCO, 0927. 3141-7) previously showed that patients with trough IM plasma concentrations (Cmin) below 1110 ng/mL (Quartile 1) had shorter time to progression. We prospectively performed routine analysis of I in advanced GIST pts in which we investigated the relationships between Cmin and progression-free survival (PFS). Methods: A clinical database of advanced GIST pts for whom Cmin measurements has been prospectively set. The concentration decile boundary that produced the most statistically significant difference in PFS for patients with Cmin values above and below the value was defined using a log-rank test. Cox regression analysis was performed to evaluate factors associated with longer PFS. Results: We evaluated 102 patients treated by IM 400 mg/day (41 stomach, 34 small bowel and 27 other or unreported primary site localizations) with 253 trough plasma determinations. Median Cmin af...