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International audience; Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica.Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica.Design, setting, and participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day.Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone.Main outcomes and measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone.Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group.Conclusions and relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms.

BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of

International audience; These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert-based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.\ud \ud Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.\ud \ud Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.\ud \ud Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.\ud \ud Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.\ud \ud Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Resume L’essor des therapies orales anticancereuses permet a de plus en plus de patients d’etre pris en charge a leur domicile ameliorant ainsi leur qualite de vie. Cependant les toxicites des traitements anticancereux et l’eloignement par rapport aux professionnels de sante, impliquent une autonomie des patients vis-a-vis de leurs traitements. Les programmes d’education therapeutique leur permettent de gerer les evenements indesirables et d’etre plus observants pour beneficier au mieux du traitement. Nous relatons ici les activites de pharmacie clinique oncologique realisees dans plusieurs etablissements de sante en France, presentees aux 1ere journees de pharmacie clinique oncologique qui se sont tenues en decembre 2017 a Marseille.

In this study, poly( e -caprolactone)-co-poly(ethylene glycol) copolymers grafted with a cationic ligand, propargyltrimethyl ammonium iodide (PTA), to fabricate the cationized triblock (P(CatCLCL) 2 -PEG) and diblock (P(CatCLCL)-mPEG) copolymers were investigated their potential use for oral delivery of enoxaparin (ENX). Influences of various PTA contents and different structures of the copolymers on molecular characteristics, ENX encapsulation, particle characteristics, and capability of drug transport across Caco-2 cells were elucidated. The results showed that P(CatCLCL) 2 -PEG and P(CatCLCL)-mPEG copolymers self-aggregated and encapsulated ENX into spherical particles of ∼200–450 nm. The increasing amount of PTA on the copolymers increased encapsulation efficiency of over 90%. The ENX release from both types of the cationized copolymer particles was pH-dependent which was retarded at pH 1.2 and accelerated at pH 7.4, supporting the drug protection in the acidic environment and possible release in the blood circulation. The toxicity of ENX-loaded particles on Caco-2 cells decreased when decreasing the amount of PTA. The triblock and diblock particles dramatically enhanced ENX uptake and transport across Caco-2 cells as compared to the ENX solution. However, the different structures of the copolymers slightly affected ENX transport. These results suggested that P(CatCLCL) 2 -PEG and P(CatCLCL)-mPEG copolymers would be potential carriers for oral delivery of ENX. Statement of Significance The anionic drugs such as proteins, peptides or polysaccharides are generally administered via invasive route causing patient incompliance and high cost of hospitalization. The development of biomaterials for non-invasive delivery of those drugs has gained much attention, especially for oral delivery. However, they have limitation due to non-biocompatibility and poor drug bioavailability. In this study, the novel poly( e -caprolactone)-co-poly(ethylene glycol) copolymers grafted with propargyltrimethyl ammonium iodide, a small cationic ligand, were introduced to use as a carrier for oral delivery of enoxaparin, a highly negatively charged drug. The study showed that these cationized copolymers could achieve high enoxaparin entrapment efficiency, protect drug release in an acidic environment and enhance enoxaparin permeability across Caco-2 cells, the intestinal cell model. These characteristics of the cationized copolymers make them a potential candidate for oral delivery of anionic drugs for biomaterial applications.

Background and Purpose— We aimed to determine the safety and mortality after mechanical thrombectomy in patients taking vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). Methods— In a multicenter observational cohort study, we used multiple logistic regression analysis to evaluate associations of symptomatic intracranial hemorrhage (sICH) with VKA or DOAC prescription before thrombectomy as compared with no anticoagulation. The primary outcomes were the rate of sICH and all-cause mortality at 90 days, incorporating sensitivity analysis regarding confirmed therapeutic anticoagulation. Additionally, we performed a systematic review and meta-analysis of literature on this topic. Results— Altogether, 1932 patients were included (VKA, n=222; DOAC, n=98; no anticoagulation, n=1612); median age, 74 years (interquartile range, 62–82); 49.6% women. VKA prescription was associated with increased odds for sICH and mortality (adjusted odds ratio [aOR], 2.55 [95% CI, 1.35–4.84] and 1.64 [95% CI, 1.09–2.47]) as compared with the control group, whereas no association with DOAC intake was observed (aOR, 0.98 [95% CI, 0.29–3.35] and 1.35 [95% CI, 0.72–2.53]). Sensitivity analyses considering only patients within the confirmed therapeutic anticoagulation range did not alter the findings. A study-level meta-analysis incorporating data from 7462 patients (855 VKAs, 318 DOACs, and 6289 controls) from 15 observational cohorts corroborated these observations, yielding an increased rate of sICH in VKA patients (aOR, 1.62 [95% CI, 1.22–2.17]) but not in DOAC patients (aOR, 1.03 [95% CI, 0.60–1.80]). Conclusions— Patients taking VKA have an increased risk of sICH and mortality after mechanical thrombectomy. The lower risk of sICH associated with DOAC may also be noticeable in the acute setting. Improved selection might be advisable in VKA-treated patients. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03496064. Systematic Review and Meta-Analysis: CRD42019127464.

International audience; OBJECTIVE:We aimed to assess medical practices of French infectious disease specialists or any other relevant physicians related to the management of non-necrotizing cellulitis (NNC).METHODS:We sent an online questionnaire to members of the French Infectious Diseases Society (SPILF) mailing list in September 2015.RESULTS:A total of 108 specialists took part in the survey and 10% (11/107) declared to always admit NNC patients to hospital. As for the others, 18% declared to admit patients in more than 80% of cases, 49% in 50-80% of cases, 26% in 20-50% of cases, and 7% in less than 20% of cases. The most frequent criteria for hospital admission were severe sepsis/septic shock (99%), poor social conditions (99%), rapid extension of skin lesions (93%), high level of pain (86%), and failure of first-line antibiotic therapy (84%). Participants mentioned similar criteria for reasons to initiate the intravenous (IV) antibiotic therapy. Fifty-three percent of respondents declared initiating antibiotic therapy using the IV route in more than 80% of cases. Physicians declared that the usual antibiotic therapy duration were 15 days (3%).CONCLUSION:Criteria for hospital admission and use of the IV route for antibiotic therapy as well as optimal treatment duration in patients presenting with NNC need to be detailed in guidelines and evaluated in prospective studies.

The acute gastroenteritis (AGE), a frequent pathology of the young child, is responsible for a medical socioeconomic burden in industrialized countries. A simple, effective and little expensive treatment exists, the oral rehydration solution (ORS). The use of the ORS by parents and caregivers is rather low. The drug package leaflet is an easy-to-access information tool. Existing drug package leaflet of ORS contains incomplete or contradictory informations, source of confusion for users, slowing down their use of the ORS. The objective of our work was to propose a drug package leaflet for ORS, validated by healthcare professionals and tested from the point of view of the legibility and the understanding of the users. We developed a drug package leaflet based on the current recommendations. We then collected the opinion of 11 healthcare professionals among general practitioners, pediatricians and pharmacists via online iterative questionnaires according to the Delphi technique. Then we tested the obtained drug package leaflet from the point of view of the legibility and the understanding with 20 users among parents and grandparents through the conduct of individual interviews. This test came out positive with the obtaining of drug package leaflet containing readable and understandable informations for the users and in agreement with the recommendations. The diffusion of this drug package leaflet to the users could improve their knowledge on the ORS, favor its spontaneous and early use and so decrease the failures of treatment by ORS, complications and hospitalizations in case of GEA of the young child.; La gastroentérite aigue (GEA) est une pathologie fréquente du jeune enfant responsable d’un fardeau médico-socio-économique dans les pays industrialisés. Un traitement simple, efficace et peu couteux existe, le soluté de réhydratation orale (SRO). L’usage du SRO par les parents et aidants s’occupant de jeunes enfants (usagers) est assez faible. La notice des médicaments est un outil d’information facilement accessible. Les notices de SRO existantes sont porteuses d’informations incomplètes ou contradictoires, source de confusion pour les usagers freinant leur utilisation. L’objectif de notre travail était de proposer une notice pour accompagner les SRO, validée par des professionnels de santé et testée sur le plan de la lisibilité et de la compréhension auprès des usagers. Nous avons élaboré une notice en se basant sur les recommandations actuelles. Nous avons ensuite recueilli l’avis sur cette notice de 11 professionnels de santé composés de médecins généralistes, pédiatres et pharmaciens d’officine via des questionnaires en ligne itératifs selon la technique Delphi. Puis nous avons testé la notice obtenue sur le plan de la lisibilité et de la compréhension auprès de 20 usagers composés de parents et grand-parents par la conduite d’entretiens individuels. Ce test a été positif avec l’obtention d’une notice contenant des informations en accord avec les recommandations, lisible et compréhensible pour les usagers. La diffusion de cette notice auprès des usagers pourrait améliorer leur connaissance sur le SRO, favoriser son usage spontané et précoce et ainsi diminuer les échecs de traitement par SRO, complications et hospitalisations en cas de GEA du jeune enfant.

Background The use of probiotics to improve anti-microbial defence, such as for influenza infections, is increasingly recommended. However, no data are available on the effect of probiotics on flu-associated secondary bacterial infections. There is strong evidence of a spatiotemporal association between influenza virus infection and invasive Neisseria meningitidis. We thus investigated the effect of feeding mice Lactobacillus paracasei CNCM I-1518 in a mouse model of sequential influenza-meningococcal infection. Methods We intranasally infected BALB/c mice with a strain of influenza A virus (IAV) H3N2 that was first adapted to mice. Seven days later, a secondary bacterial infection was induced by intranasal administration of bioluminescent N. meningitidis. During the experiment, mice orally received either L. paracasei CNCM I-1518 or PBS as a control. The effect of L. paracasei administration on secondary bacterial infection by N. meningitidis was evaluated. Results Oral consumption of L. paracasei CNCM I-1518 reduced the weight loss of infected mice and lowered the bioluminescent signal of infecting meningococci. This improvement was associated with higher recruitment of inflammatory myeloid cells, such as interstitial monocytes and dendritic cells, to the lungs. Conclusions Our data highlight the role of the gut-lung axis. L. paracasei CNCM I-1518 may boost the defence against IAV infection and secondary bacterial infection, which should be further studied and validated in clinical trials. Electronic supplementary material The online version of this article (10.1186/s12879-018-3086-9) contains supplementary material, which is available to authorized users.

International audience; PurposePosaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration–toxicity relationship of posaconazole tablets in patients with haematological malignancies.MethodsSixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC–MS/MS. The rates of ADR by quartile of C min were compared.ResultsEighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1–3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different.ConclusionsPosaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.

Aims: \ud \ud Thrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF-rEF) and documented coronary artery disease.\ud Methods: \ud \ud This is an international prospective, multicentre, randomized, double-blind, placebo-controlled, event-driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide ≥200 pg/mL or N-terminal pro–B-type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all-cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria.\ud Conclusion: \ud \ud COMMANDER HF is the first prospective study of a target-specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF-rEF patient population with coronary artery disease.

International audience; INTRODUCTION:The increasing prescription of oral anticancer therapies has significantly changed inpatient care to outpatient care. This transformation requires an excellent coordination between different professionals to ensure healthcare channel security.METHOD:We performed a prospective study in 18 French cancer centers from March to April 2016. The aim of this study was to identify resources deployed to support patients receiving oral anticancer therapies and to assess pharmacist's involvement.RESULTS:More than half of the centers have developed patient education program and/or practice pharmaceutical consultations. In total, 54.5% have deployed an oral anticancer drugs program and the pharmacist is involved in multidisciplinary teams. In total, 44.4% of the centers have developed hospital-to-community coordination actions but all of them highlight the time-consuming character of those programs.DISCUSSION:Administrative burdens are seriously hindering patient education program's development. Multidisciplinary consultations can offer an attractive alternative because of easy implementation modalities. Finally, hospital-to-community coordination actions seem hard to implement and require harmonization of communication practices, and need more technical and financial means.

Recent estimates on global morbidity and mortality caused by Leptospirosis point to one million cases and almost 60,000 deaths a year worldwide, especially in resource poor countries. We analyzed how a commensal probiotic immunomodulator, Lactobacillus plantarum, affects Leptospira interrogans pathogenesis in a murine model of sub-lethal leptospirosis. We found that repeated oral pre-treatment of mice with live L. plantarum restored body weight to normal levels in mice infected with L. interrogans. Pre-treatment did not prevent L. interrogans access to the kidney but it affected the inflammatory response and it reduced histopathological signs of disease. Analysis of the immune cell profiles in lymphoid tissues of mice pre-treated with L. plantarum showed increased numbers of B cells as well as naïve and memory CD4+ helper T cell populations in uninfected mice that shifted towards increased numbers of effector CD4+ helper T in infected mice. CD8+ cytotoxic T cell profiles in pre-treated uninfected and infected mice mirrored the switch observed for CD4+ except that CD8+ memory T cells were not affected. In addition, pre-treatment led to increased populations of monocytes in lymphoid tissues of uninfected mice and to increased populations of macrophages in the same tissues of infected mice. Immunohistochemistry of kidney sections of pre-treated infected mice showed an enrichment of neutrophils and macrophages and a reduction of total leucocytes and T cells. Our results suggest that complex myeloid and T cell responses orchestrate the deployment of monocytes and other cells from lymphoid tissue and the recruitment of neutrophils and macrophages to the kidney, and that, the presence of these cells in the target organ may be associated with reductions in pathogenesis observed in infected mice treated with L. plantarum., Author summary Leptospirosis is an emerging neglected zoonotic disease with worldwide distribution that affects nearly all vertebrates and causes infection in ~1 million people on a yearly basis. Effective cross-protective vaccines are not available and antibiotic treatment is only effective if used early in the course of infection. In this study we describe how repeated oral treatment of mice with a commonly used probiotic, Lactobacillus plantarum, did not completely prevent colonization of the kidney by Leptospira interrogans but it did reduce signs and symptoms of leptospirosis. We also analyzed a number of immune cell types in spleen, lymph nodes and kidney after treatment and found that complex responses orchestrate the deployment of phagocytes to the kidney in infected mice. Our results suggest that pre-treatment with L. plantarum modulates systemic immune responses in a beneficial way in a mammalian host later exposed to L. interrogans infection.

International audience; The treatment duration of acute uncomplicated pyelonephritis (AUP) is still under debate. As shortening treatment duration could be a means to reduce antimicrobial resistance, we aimed to establish whether 5 days of antibiotic treatment is non-inferior to 10 days in patients with AUP. We performed an open-label prospective randomized trial comparing 5 days to 10 days of fluoroquinolone treatment for AUP. The inclusion criteria were: female patients aged ≥18 years with clinical signs of urinary tract infection, fever >38 °C, and positive urinalysis. Patients were randomized to either 5 or 10 days of fluoroquinolone treatment. Outcome was cure at day 10 and day 30 after the end of treatment. One hundred patients were randomized and 12 were excluded after randomization. The mean ± standard deviation (SD) age was 31.8 ± 11 years old and the mean ± SD temperature was 38.6 ± 0.7 °C. The main bacterium involved was Escherichia coli (n = 86; 97.7%) and 3 (3.4%) patients had a positive blood culture. In the post-hoc analysis, clinical cure 10 days after the end of the treatment was 28/30 (93.3%) in the 5-day arm and 36/38 (94.7%) in the 10-day arm (p = 1.00). At day 30, the clinical cure rate was 23/23 (100%) in the 5-day arm and 20/20 (100%) in the 10-day arm (p = 1.00). The microbiological cure rate was 20/23 (87.0%) in the 5-day arm and 16/20 (80.0%) in the 10-day arm (p = 1.00). The efficacy of 5 days of fluoroquinolone treatment does not seem different from 10 days of treatment for AUP.

International audience; BACKGROUND A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety. METHODS Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report. RESULTS An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic. CONCLUSIONS An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown.

International audience; PURPOSE:Results of previous studies assessing the risk of bleeding associated with prescription of antiplatelet (AP) and/or oral anticoagulant (AC) therapy to hemodialysis patients are conflicting. Our purpose was to describe practices for prescription of AP and AC in hemodialysis patients in the Lorraine region, and to assess their effect on the risk of major bleeding events.METHODS:All adults with chronic kidney disease who began a first renal replacement therapy by hemodialysis in 2009 or 2010 in one of the 12 dialysis centers in Lorraine were included in the Thrombosis and Hemorrhage in HemoDialysis patients (T2HD) study and followed up until 30 June 2013. The association of each treatment (AP, AC, AP + AC) with the risk of major bleeding was estimated by three Cox proportional hazard models with an inverse probability of treatment weighting on a propensity score, considering the untreated patients as the reference.RESULTS:Among 502 patients included, 227 (45.2%) received an AP, 68 (13.5%) an AC, 81 (16.1%) a combination AP + AC, and 126 (25.1%) were untreated. As compared with untreated patients, those given AP (HR 5.52, 95% CI [3.11-9.80]), AC (HR: 4.15, 95% CI: [3.46-4.99]), and AP + AC (HR: 5.59, 95% CI [2.62-11.91]) were at greater risk of major bleeding events.CONCLUSIONS:The risk of major bleeding is higher in patients receiving an oral AC compared with untreated patients and those receiving an AP agent. A combination of the two drugs does not seem to increase the risk.

International audience; Yersinia pestis, the agent of plague, is among the deadliest bacterial pathogens affecting humans, and is a potential biological weapon. Because antibiotic resistant strains of Yersinia pestis have been observed or could be engineered for evil use, vaccination against plague might become the only means to reduce mortality. Although plague is re-emerging in many countries, a vaccine with worldwide license is currently lacking. The vaccine strategy described here is based on an oral vaccination with an attenuated strain of Yersinia pseudotuberculosis. Indeed, this species is genetically almost identical to Y. pestis, but has a much lower pathogenicity and a higher genomic stability. Gradual modifications of the wild-type Yersinia pseudotuberculosis strain IP32953 were performed to generate a safe and immunogenic vaccine. Genes coding for three essential virulence factors were deleted from this strain. To increase cross-species immunogenicity, an F1-encapsulated Y. pseudotuberculosis strain was then generated. For this, the Y. pestis caf operon, which encodes F1, was inserted first on a plasmid, and subsequently into the chromosome. The successive steps achieved to reach maximal vaccine potential are described, and how each step affected bacterial virulence and the development of a protective immune response is discussed. The final version of the vaccine, named VTnF1, provides a highly efficient and long-lasting protection against both bubonic and pneumonic plague after a single oral vaccine dose. Since a Y. pestis strain deprived of F1 exist or could be engineered, we also analyzed the protection conferred by the vaccine against such strain and found that it also confers full protection against the two forms of plague. Thus, the properties of VTnF1 makes it one of the most efficient candidate vaccine for mass vaccination in tropical endemic areas as well as for populations exposed to bioterrorism.

International audience; ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Crassocephalum bauchiense have long been used in traditional Cameroonian medicine for the treatment of epilepsy, pain, inflammatory disorders, arthritis and intestinal pain. AIM OF THE STUDY: In this study, we attempted to identify the possible antinociceptive action of the aqueous extract and the alkaloid fraction prepared from the leaves of Crassocephalum baucheiense. MATERIALS AND METHODS: Using acetic acid induced abdominal constrictions, formalin-, capsaisin- and glutamate-induced nociception, and hot plate assay procedures, the antinociceptive effects of the aqueous extract and the alkaloid fraction was assessed after oral administration in mice. Morphine sulfate was used as reference analgesic agent. Mice were submitted to the rota-rod task and open-field test in order to assess any non-specific muscle-relaxant or sedative effects of the extracts of Crassocephalum bauchiense. Male and female Swiss mice were used to assess acute toxicity of these extracts. RESULTS: The aqueous extract and the alkaloid fraction of Crassocephalum bauchiense produced a significant antinociceptive effects in the acetic acid, formalin, glutamate, capsaicin and hot plate tests. These antinociceptive effects of Crassocephalum bauchiense were significantly attenuated by pretreatment with naloxone. The extracts of Crassocephalum bauchiense did not alter the locomotion of animals in the open-field or rotarod tests, which suggest a lack of a central depressant effect. The animals did not exhibit any acute toxicity to the aqueous extract and the alkaloid fraction, so it was not possible to calculate the LD(50). CONCLUSION: The results confirm the popular use of Crassocephalum bauchiense as an antinociceptive, and contribute to the pharmacological knowledge of this species because it was shown that the aqueous extract and the alkaloid fraction of Crassocephalum bauchiense produced dose related antinociception in models of chemical and thermal nociception through mechanisms that involve an interaction with opioidergic pathway.

While Crimean-Congo hemorrhagic fever (CCHF) has a high mortality rate in humans, the associated virus (CCHFV) does not induce clinical symptoms in animals, but animals play an important role in disease transmission to humans. Our aim in this study was to examine the immunogenicity of the CCHFV glycoprotein when expressed in the root and leaf of transgenic plants via hairy roots and stable transformation of tobacco plants, respectively. After confirmatory analyses of transgenic plant lines and quantification of the expressed glycoprotein, mice were either fed with the transgenic leaves or roots, fed the transgenic plant material and injected subcutaneously with the plant-made CCHFV glycoprotein (fed/boosted), vaccinated with an attenuated CCHF vaccine (positive control), or received no treatment (negative control). All immunized groups had a consistent rise in anti-glycoprotein IgG and IgA antibodies in their serum and feces, respectively. The mice in the fed/boosted group showed a significant rise in specific IgG antibodies after a single boost. Our results imply that oral immunization of animals with edible materials from transgenic plants is feasible, and further assessments are under way. In addition, while the study of CCHF is challenging, our protocol should be further used to study CCHFV infection in the knockout mouse model and virus neutralization assays in biosafety level 4 laboratories.

Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to fed antigens. However, the molecular mechanism mediating oral tolerance remains unclear. In this study, we examined the role of the B7 family members of costimulatory molecules in the establishment of oral tolerance. Deficiencies of B7-H1 and B7-DC abrogated the oral tolerance, accompanied by enhanced antigen-specific CD4+ T-cell response and IgG1 production. Mesenteric lymph node (MLN) dendritic cells (DCs) displayed higher levels of B7-H1 and B7-DC than systemic DCs, whereas they showed similar levels of CD80, CD86, and B7-H2. MLN DCs enhanced the antigen-specific generation of CD4+Foxp3+ inducible regulatory T cells (iTregs) from CD4+Foxp3− T cells rather than CD4+ effector T cells (Teff) relative to systemic DCs, owing to the dominant expression of B7-H1 and B7-DC. Furthermore, the antigen-specific conversion of CD4+Foxp3− T cells into CD4+Foxp3+ iTregs occurred in MLNs greater than in peripheral organs during oral tolerance under steady-state conditions, and such conversion required B7-H1 and B7-DC more than other B7 family members, whereas it was severely impaired under inflammatory conditions. In conclusion, our findings suggest that B7-H1 and B7-DC expressed on MLN DCs are essential for establishing oral tolerance through the de novo generation of antigen-specific CD4+Foxp3+ iTregs.

International audience; BACKGROUND: Mitotane (o,p'-DDD) is considered to be the drug of choice in the treatment of nonresectable and metastasized adrenocortical carcinoma. However, mitotane has poor solubility in the gastrointestinal tract and very low bioavailability. Consequently, to achieve therapeutic plasma level, high cumulative doses (4-6 g/day) of mitotane were usually used during 3-5 months. To shorten this equilibration time and reduce gastrointestinal side effects, a self-microemulsifying drug delivery system (SMEDDS) of mitotane has been developed. METHOD: First time, the solubility of mitotane was determined in various oils and surfactants; then, the influence of oils, surfactants, and cosurfactants on the formation of SMEDDS was investigated by constructing ternary phase diagrams. SMEDDS was characterized by morphological observations and droplet size measurements. Intestinal drug permeation of SMEDDS of mitotane (3 mM) was assessed in an Ussing-type apparatus and the bioavailability was determined in a rabbit model. RESULTS: The optimum formulation consisted of a mixture of Capryol, Tween, and Cremophor EL (33:33:33). The formulation was found to pass through the intestinal barrier much faster than a solution of mitotane (14.85 +/- 0.8 versus 3.03 +/- 0.2 micromol/cm(2)). Moreover, after oral administration in rabbits, the relative bioavailability was 3.4, compared with that of the conventional form (Lysodren). CONCLUSION: This SMEDDS can now be considered as a very good candidate to optimize the administration of mitotane.

International audience; The anti-inflammatory effects of CI-1044 and of the other selective PDE4 inhibitors rolipram and cilomilast were investigated in Brown-Norway (BN) rats, against lipopolysaccharide-induced tumor necrosis factor alpha (TNFalpha) production in whole blood and antigen-induced lung eosinophilia. In vitro, CI-1044 inhibited TNFalpha production with an IC(50) of 0.31 microm being equipotent to Cilomilast (IC(50) = 0.26 microm) and rolipram (IC(50) = 0.11 microm). Given orally, CI-1044 inhibited ex vivo TNFalpha production with an ED(50) value of 0.4 mg/kg after single administration, whereas rolipram (ED(50) = 1.4 mg/kg) and cilomilast (ED(50) = 1.6 mg/kg) were less potent. In the same ex vivo setting, but given repeatedly, CI-1044 led to an ED(50) of 0.5 mg/kg corresponding to a plasma concentration of 82.6 ng/mL (0.22 microm). In vivo, CI-1044 prevented TNFalpha release with an ED(50) of 1 mg/kg p.o. and inhibited ovalbumin-induced lung eosinophilia following single or repeated oral administration with an ED(50) of 3.25 and 4.8 mg/kg p.o., respectively, suggesting the absence of pharmacological tolerance. CI-1044 in this model was equipotent to rolipram (81% inhibition at 10 mg/kg) but better than cilomilast (25% inhibition at 10 mg/kg). Finally, CI-1044 (10 mg/kg) inhibited inflammatory cell recruitment with a long duration of action (up to 8 h) and was still active when given post-challenge. Our data show that CI-1044 is an orally active PDE4 inhibitor that may be used as an anti-inflammatory therapy in lung inflammatory diseases.

International audience; INTRODUCTION: Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients. METHODS: Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule. RESULTS: Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose (r = 0.88, P < 0.0001). The mean difference between observed and predicted dose was not clinically significant: -0.1 +/- 1.1 mg. CONCLUSION: In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.

International audience; CMV reactivation is frequently observed in acute flares of ulcerative colitis (UC), particularly those which do not respond to intravenous steroids. Several recent series have suggested that, in most cases, CMV reactivation does not lead to severe complications and resolves spontaneously with the UC flare and discontinuation of immunosuppression. In the present paper, we describe two patients with active UC who developed a severe systemic CMV infection during a treatment with an oral microemulsion form of cyclosporine. This is of concern, particularly in a context of increasing use of immunosuppressive drugs in UC. We propose a prophylactic and curative approach to decrease morbidity related to CMV infection in active UC.

Background. Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection. Methods. An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/ kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment. Results. A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n = 48 ) were observed only with the 3 monotherapy regimens. Conclusion. A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.

Background No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably. Methodology/Principal Findings The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1—Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis. Significance VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration., Author Summary Yersinia pestis, the agent of plague, is among the deadliest infectious agents affecting humans. Injected in the skin by infected fleas, Y. pestis causes bubonic plague, which occasionally evolves into the very lethal and contagious pneumonic plague. Y. pestis is also a dangerous potential bioweapon but no plague vaccine is available. The current study describes the development of a vaccine highly efficient against plague in both its bubonic and pneumonic forms. The strategy consists of a live, avirulent, genetically modified Yersinia pseudotuberculosis that produces the capsule antigen of Y. pestis, named F1. The goal was to propose a vaccine that would be both easy to produce rapidly in large amounts with high quality, and easy to administer to individuals via a single oral dose. The VTnF1 strain described fulfills these demands. The immune response generated is long-lasting, involving both antibodies and memory cells directed against F1 and other antigens. We conclude that VTnF1 is a very promising candidate vaccine against plague.

International audience; Enrofloxacin and marbofloxacin are two veterinary fluoroquinolones used to treat severe bacterial infections in horses. A repeated measures study has been designed to compare their pharmacokinetic parameters, to investigate their bioavailability and to estimate their absorbed fraction and first-pass effect by using plasma, urinary and metabolite data collected from five healthy mares. Clearance and V(d(ss)) were greater for enrofloxacin (mean +/- SD = 6.34 +/- 1.5 mL/min/kg and 2.32 +/- 0.32 L/kg, respectively) than for marbofloxacin (4.62 +/- 0.67 mL/min/kg and 1.6 +/- 0.25 L/kg, respectively). Variance of the AUC(0-inf) of marbofloxacin was lower than that for enrofloxacin, with, respectively, a CV = 15% and 26% intravenously and a CV = 31% and 55% after oral administration. Mean oral bioavailability was not significantly different between marbofloxacin (59%) and enrofloxacin (55%). The mean percentage of the dose eliminated unchanged in urine was significantly higher for marbofloxacin (39.7%) than that for enrofloxacin (3.4%). Absorbed fraction and first-pass effect were only determinable for enrofloxacin, whereas the percentage of the dose absorbed in the portal circulation was estimated to be 78% and the fraction not extracted during the first pass through the liver was 65%. Consequently, the moderate observed bioavailability of enrofloxacin appears to be mainly caused by hepatic first-pass effect.

International audience; The aim of the present study was to examine modifications of anti-tumor activity and toxicity of paclitaxel (PLX) when given p.o. after recombinant interleukin-2 (rIL-2) to Lewis lung carcinoma-bearing mice. PLX was given orally to mice at the dose of 15 mg/kg on day 8 and 30 mg/kg on day 15, either alone or after 16.5 microg of rIL-2 given i.p. twice a day either 1 or 3 days before. The anti-tumor activity was higher and PLX hematological toxicity not increased if orally administered PLX was given after a 3-day rIL-2 pre-treatment rather than if given alone. Lung metastasis was significantly lower and s.c. tumors were smaller in the PLX+rIL-2 group than in the PLX or rIL-2 or non-treated groups. In addition, a decrease in lung P-glycoprotein expression (investigated by Western blot analysis) was observed 1 h after the last administration of rIL-2 on day 7.

International audience; OBJECTIVE: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients. METHODS: A single dose (25-45 mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24 hr. Using NONMEM, oteracil and CDHP were analyzed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations. RESULTS: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes.

Contains fulltext : 133902.pdf (Publisher’s version ) (Open Access) RATIONALE: To prevent or combat infection, increasing the effectiveness of the immune response is highly desirable, especially in case of compromised immune system function. However, immunostimulatory therapies are scarce, expensive, and often have unwanted side-effects. beta-glucans have been shown to exert immunostimulatory effects in vitro and in vivo in experimental animal models. Oral beta-glucan is inexpensive and well-tolerated, and therefore may represent a promising immunostimulatory compound for human use. METHODS: We performed a randomized open-label intervention pilot-study in 15 healthy male volunteers. Subjects were randomized to either the beta -glucan (n = 10) or the control group (n = 5). Subjects in the beta-glucan group ingested beta-glucan 1000 mg once daily for 7 days. Blood was sampled at various time-points to determine beta-glucan serum levels, perform ex vivo stimulation of leukocytes, and analyze microbicidal activity. RESULTS: beta-glucan was barely detectable in serum of volunteers at all time-points. Furthermore, neither cytokine production nor microbicidal activity of leukocytes were affected by orally administered beta-glucan. CONCLUSION: The present study does not support the use of oral beta-glucan to enhance innate immune responses in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01727895.

International audience; Rabies is responsible for 50,000 deaths per year worldwide. Mainland France has been officially freed from rabies in non-flying animals since 2001.; We wanted to provide an update on the French situation, using published data, and describe possible options since official guidelines are lacking.; Post-exposure prophylaxis (PEP) (early and careful cleaning and dressing of the wound, vaccination, and in case of high-risk exposure, injection of specific anti-rabies immunoglobulins) is known to be efficient except in rare cases. It is recommended after grade II contact (+specific immunoglobulins in immunodepressed patients), or grade III contact (vaccination+immunoglobulins).; Mainland France being rabies-free, 3 options may be considered in case of bite by a dog or a cat that cannot be monitored in France: (a) consider the risk of rabies as null, so no PEP should be administrated, whatever the severity of bites; (b) consider there is a weak but lethal risk, so the international recommendations should be applied, using immunoglobulins in some cases; (c) consider that the risk is extremely low but cannot be excluded, and that the patient should be vaccinated to be protected, but without adding immunoglobulins (whether in case of grade II or III bites).; There are no national guidelines for rabies in France, and so the physician managing the patient is the one who will decide to treat or not.

International audience; Postmenopausal hormone therapy (HT), which consists of exogenous estrogens with or without combined progestogens, remains the most effective treatment of climacteric symptoms. Depending on its characteristics, it may nevertheless increase the risk of venous thromboembolism, and its effects on hemostasis have been studied for several decades. The aim of this review was to summarize current knowledge on the effects of HT on hemostasis, taking into account the route of estrogen administration, the daily dose and chemical structure of estrogens, and the pharmacologic class of progestogens. Data from randomized controlled trials that included a control group (either placebo or no treatment) were selected, and analysis was conducted on different generations of biomarkers. Overall, studies showed a hemostasis imbalance among oral estrogen users with a decrease in coagulation inhibitors and an increase in markers of activation coagulation, leading to global enhanced thrombin generation. By contrast, transdermal estrogen use was associated with less change in hemostasis variables and did not activate coagulation and fibrinolysis. No clear difference in HT effects on hemostasis was highlighted between daily doses of estrogens, between estrogen compounds, and between pharmacologic classes of progestogens. Changes in hemostasis are in accordance with clinical results showing an increased thrombotic risk with oral--but not transdermal--estrogen use.

International audience; We evaluated a dog owner, participation-based, bait delivery system for the oral immunization of dogs against rabies. In a field study in a semirural area of northern Tunisia, dog owners were asked to come to temporary bait delivery sites. A total of 314 baits were given to 178 dog owners in four sites. The experimental baits used consisted of a freeze-dried core unit containing sulfadimethoxine (SDM) as a biological marker and an aromatized paraffin envelope. No vaccine was used. Preliminary tests had shown that by using a rapid commercial card test, positive SDM serum levels were detected in more than 95% of dogs up to two days after bait ingestion. During the two days following bait delivery, we visited more than 95% of all households in the study area and took blood samples from as many owned dogs as possible. Unconsumed baits were recovered and human contacts with the bait matrix were recorded. The campaign required 7.6 person-min per bait and 13.5 person-min per dog owner for providing baits, gloves, and instructions. The estimated average cost effectiveness ratio per dog accepting a bait was 1.7 US dollars. From the indications given by the dog owners and the results of the SDM test, it was concluded that 85-90% of the owned dogs in the study area had consumed a bait at least partially. Of 314 baits delivered, 78.7% were fully consumed by dogs and 4.1% were recovered during the household survey. The remaining baits (17.2%) that were not recovered were either not consumed or only partially consumed by the target dogs (3.7 baits per 100 inhabitants). These baits probably remained within the highly populated areas and were potentially accessible to other domestic animals and other nontarget species, including humans. Twenty-five unprotected human contacts with baits were recorded (1.7% of all inhabitants). Our study has demonstrated the potential of dog owner based bait delivery. This technique is simple and efficient, particularly if the human population is accustomed to mass immunization in defined centers. Before applying this method on a large scale with live vaccine loaded baits, further studies should focus on minimizing the number of human contacts with the vaccine bait, systematizing contact identification and establishing structures in ensuring proper treatment if exposure to vaccine should occur.

International audience; BACKGROUND: The clinically appropriate duration of thromboprophylaxis in hospitalized patients with acute medical illnesses is unknown. In this multicenter, randomized, double-blind trial, we evaluated the efficacy and safety of oral rivaroxaban administered for an extended period, as compared with subcutaneous enoxaparin administered for a standard period, followed by placebo. METHODS: We randomly assigned patients 40 years of age or older who were hospitalized for an acute medical illness to receive subcutaneous enoxaparin, 40 mg once daily, for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral rivaroxaban, 10 mg once daily, for 35±4 days. The primary efficacy outcomes were the composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 (noninferiority test) and up to day 35 (superiority test). The principal safety outcome was the composite of major or clinically relevant nonmajor bleeding. RESULTS: A total of 8101 patients underwent randomization. A primary efficacy outcome event occurred in 78 of 2938 patients (2.7%) receiving rivaroxaban and 82 of 2993 patients (2.7%) receiving enoxaparin at day 10 (relative risk with rivaroxaban, 0.97; 95% confidence interval [CI], 0.71 to 1.31; P=0.003 for noninferiority) and in 131 of 2967 patients (4.4%) who received rivaroxaban and 175 of 3057 patients (5.7%) who received enoxaparin followed by placebo at day 35 (relative risk, 0.77; 95% CI, 0.62 to 0.96; P=0.02). A principal safety outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group and 49 of 4001 patients (1.2%) in the enoxaparin group at day 10 (P

International audience; AIMS: A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for fludrocortisone. Since there continues to be disagreement about the utility of fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and fludrocortisone (50 μg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose-response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. METHODS: This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 × 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then fludrocortisone 50 μg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 μg kg(-1) min(-1)), each dose being infused during 5 min. RESULTS: Both fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (fludrocortisone × hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. CONCLUSIONS: Single administrations of fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo-aldosteronism. These similar effects of hydrocortisone and fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading.

International audience; BACKGROUND: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. RESULTS: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P

International audience

International audience; The purpose of this study was to identify clinician characteristics associated with higher prescription rates of long-acting injectable (LAI) antipsychotics, as well as the sources that influence medical decision-making regarding the treatment of schizophrenia. We surveyed 202 psychiatrists during six regional French conferences (Bordeaux, Lyon, Marseille, Nice, Paris, and Strasbourg). Data on the characteristics of practice, prescription rates of antipsychotic, and information sources about their clinical decisions were collected. Most psychiatrists used second-generation antipsychotics (SGAs), and preferentially an oral formulation, in the treatment of schizophrenia. LAI SGAs were prescribed to 30.4% of schizophrenic patients. The duration and type of practice did not influence the class or formulation of antipsychotics used. The clinicians following the higher percentage of schizophrenic patients were associated with a higher use of LAI antipsychotics and a lower use of oral SGAs. Personal experience, government regulatory approval, and guidelines for the treatment of schizophrenia were the three main contributing factors guiding clinicians' decision-making regarding the treatment of schizophrenia. The more clinicians follow schizophrenic patients, the more they use LAI antipsychotics. The development of specialized programs with top specialists should lead to better use of LAI antipsychotics in the treatment of schizophrenia.

International audience; Although being a primary objective in the management of type 2 diabetes, optimal glycaemic control is difficult to achieve and usually not maintained over time. Type 2 diabetes is a complex pathology, comprising altered insulin sensitivity and impaired insulin secretion. Recent advances in the understanding of the physiological functions of incretins and their degrading enzyme dipeptidyl-peptidase (DPP)-4 have led to the 'discovery' of a new class of oral anti-diabetic drugs. Several DPP-4 inhibitors (or gliptins) with different chemical structures are now available. These agents inhibit the degradation of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and hence potentiate glucose-dependent insulin secretion. DPP-4 inhibitors inhibit DPP-4 activity by almost 100% in vitro, maintaining a ≥ 80% inhibition throughout the treatment period in vivo, thus prolonging GLP-1 half-life, and significantly reducing HbA1c generally by -0.7 to 0.8% as well as fasting and post-prandial glycaemia. They are well-tolerated with no weight gain and few adverse effects, and, of particular interest, no increase in hypoglycaemic episodes. Although different by their chemical structure and pharmacokinetic properties, the DPP4 inhibitors currently available have proven similar glucose lowering efficacy.

International audience; Although being a primary objective in the management of type 2 diabetes, optimal glycaemic control is difficult to achieve and usually not maintained over time. Type 2 diabetes is a complex pathology, comprising altered insulin sensitivity and impaired insulin secretion. Recent advances in the understanding of the physiological functions of incretins and their degrading enzyme dipeptidyl-peptidase (DPP)-4 have led to the 'discovery' of a new class of oral anti-diabetic drugs. Several DPP-4 inhibitors (or gliptins) with different chemical structures are now available. These agents inhibit the degradation of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and hence potentiate glucose-dependent insulin secretion. DPP-4 inhibitors inhibit DPP-4 activity by almost 100% in vitro, maintaining a ≥ 80% inhibition throughout the treatment period in vivo, thus prolonging GLP-1 half-life, and significantly reducing HbA1c generally by -0.7 to 0.8% as well as fasting and post-prandial glycaemia. They are well-tolerated with no weight gain and few adverse effects, and, of particular interest, no increase in hypoglycaemic episodes. Although different by their chemical structure and pharmacokinetic properties, the DPP4 inhibitors currently available have proven similar glucose lowering efficacy.

International audience; Although being a primary objective in the management of type 2 diabetes, optimal glycaemic control is difficult to achieve and usually not maintained over time. Type 2 diabetes is a complex pathology, comprising altered insulin sensitivity and impaired insulin secretion. Recent advances in the understanding of the physiological functions of incretins and their degrading enzyme dipeptidyl-peptidase (DPP)-4 have led to the 'discovery' of a new class of oral anti-diabetic drugs. Several DPP-4 inhibitors (or gliptins) with different chemical structures are now available. These agents inhibit the degradation of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and hence potentiate glucose-dependent insulin secretion. DPP-4 inhibitors inhibit DPP-4 activity by almost 100% in vitro, maintaining a ≥ 80% inhibition throughout the treatment period in vivo, thus prolonging GLP-1 half-life, and significantly reducing HbA1c generally by -0.7 to 0.8% as well as fasting and post-prandial glycaemia. They are well-tolerated with no weight gain and few adverse effects, and, of particular interest, no increase in hypoglycaemic episodes. Although different by their chemical structure and pharmacokinetic properties, the DPP4 inhibitors currently available have proven similar glucose lowering efficacy.

International audience; PURPOSE: Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics. METHODS: We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000. RESULTS: Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases. CONCLUSIONS: Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment.

International audience; BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

International audience; BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P

International audience; INTRODUCTION: Inflammation is one of the main mechanisms common to all forms of dry eye. Since polyunsaturated acids are known to show biological anti-inflammatory properties, the aim of this study was to evaluate the efficacy of dietary n-6 and n-3 fatty acids in patients suffering from ocular dryness. PATIENTS AND METHODS: One hundred and eighty-one patients diagnosed with bilateral moderate dry eye who were already treated with lachrymal substitutes were randomized in a double-blind international study to receive placebo or Nutrilarm(®) capsules (combination of omega-3 and omega-6), twice a day for 6 months. In all subjects, dryness feeling, overall subjective comfort, and ocular symptoms (burning, stinging, sandy and/or gritty sensation, light sensitivity, reflex tearing, and ocular fatigue) were evaluated at each visit. Furthermore, fluorescein tests (break-uptime and Oxford scheme) and lissamine green test were performed at each visit. The Schirmer test was performed at inclusion and after 6 months of treatment. RESULTS: After 6 months of supplementation with Nutrilarm(®), both the BUT scores and ocular fatigue were significantly improved when compared with placebo (P=0.036 and P=0.044, respectively). There was a trend in favor of Nutrilarm(®) in terms of the efficacy evaluated by the investigator (P=0.061). Fewer patients experienced a feeling of severe dryness with Nutrilarm(®) compared with placebo after 6 months of treatment (2.5 and 9.3%, respectively), but the difference was not statistically significant. CONCLUSION: Oral administration of a double supplementation dietary n-6 and n-3 fatty acids present an additional therapeutic advantage in patients suffering from ocular dryness who were already treated with lachrymal substitutes.

WOS:000296332000008; International audience; PURPOSE: To determine whether oral supplementation with omega-3 and omega-6 fatty acids can reduce conjunctival epithelium expression of the inflammatory marker human leucocyte antigen-DR (HLA-DR) in patients with dry eye syndrome (DES). METHODS: This 3-month, double-masked, parallel-group, controlled study was conducted in nine centres, in France and Italy. Eligible adult patients with mild to moderate DES were randomized to receive a placebo containing medium-chain triglycerides or treatment supplement containing omega-3 and omega-6 fatty acids, vitamins and zinc. Treatment regimen was three capsules daily. Impression cytology (IC) was performed at baseline and at month 3 to assess the percentage of cells expressing HLA-DR and to evaluate fluorescence intensity, an alternate measure of HLA-DR. Dry eye symptoms and objective signs were also evaluated. Analyses were performed on the full analysis set (FAS) and per-protocol set (PPS). RESULTS: In total, 138 patients were randomized; 121 patients with available IC were included in the FAS, and of these, 106 patients had no major protocol deviations (PPS). In the PPS, there was a significant reduction in the percentage of HLA-DR-positive cells in the fatty acids group (p = 0.021). Expression of HLA-DR as measured by fluorescence intensity quantification was also significantly reduced in the fatty acids group [FAS (p = 0.041); PPS (p = 0.017)]. No significant difference was found for the signs and symptoms, but there was a tendency for improvement in patients receiving the fatty acids treatment. CONCLUSION: This study demonstrates that supplementation with omega-3 and omega-6 fatty acids can reduce expression of HLA-DR conjunctival inflammatory marker and may help improve DES symptoms.

Background During the last decade, oral bisphosphonates (BP) became the most widely prescribed pharmacologic class for post-menopausal osteoporosis. However, many surveys revealed the important issue of poor persistence with those drugs resulting in a failure of treatment to reduce fracture risk sufficiently. Using a published Markov model, this study analyses the economic impact of non-persistence with bisphosphonates in the context of the introduction of generics in France. Methods Direct costs of vertebral, hip and wrist fracture were assessed and included in an existing 10-year Markov model developed to analyse consequences of non-persistence. Three alternatives of comparison were set: no treatment, real-world persistence, and ideal persistence. Simulated patients' characteristics matched those from a French observational study and the real-world adherence alternative employed persistence data from published database analysis. The risk of fracture of menopausal women and the risk reduction associated with the drugs were based on results reported in clinical trials. Incremental cost-effectiveness ratios (ICERs) were calculated first between real-world adherence and no treatment alternatives, and second between ideal and real-world persistence alternatives. The cost of non-persistence was defined as the difference between total cost of ideal and real-world persistence alternatives. Results Within fractured women population, mean costs of 10-year management of fracture were significantly different between the three alternatives with €7,239 (± €4,783), €6,711 (± €4,410) and €6,134 (± €3,945) in the no-treatment, the real-world and ideal persistence alternatives, respectively (p < 0.0001). Cost-effectiveness ratio for real-world treatment persistence compared with no-treatment alternative was found dominant and as well, alternative of ideal persistence dominated the former. Each ten percentage point of persistence gain amounted to €58 per patient, and extrapolation resulted in a global annual cost of non-persistence of over €30 million to the French health care system, with a substantial transfer from hospital to pharmacy budgets. Conclusion Within term, improving persistence with oral bisphosphonates should be economically dominant on levels currently known in real-world. Given this potential savings, ambitious adherence-enhancing interventions should be considered in osteoporotic patients.

International audience; Nicotine dependence is linked to single nucleotide polymorphisms in the CHRNB4-CHRNA3-CHRNA5 gene cluster encoding the a3b4a5 nicotinic acetyl-choline receptor (nAChR). Here we show that the b4 subunit is rate limiting for receptor activity, and that current increase by b4 is maximally competed by one of the most frequent variants associated with tobacco usage (D398N in a5). We identify a b4-specific residue (S435), mapping to the intracellular vestibule of the a3b4a5 receptor in close proximity to a5 D398N, that is essential for its ability to increase currents. Transgenic mice with targeted overexpres-sion of Chrnb4 to endogenous sites display a strong aversion to nicotine that can be reversed by viral-mediated expression of the a5 D398N variant in the medial habenula (MHb). Thus, this study both provides insights into a3b4a5 receptor-mediated mechanisms contributing to nicotine consumption, and identifies the MHb as a critical element in the circuitry controlling nicotine-dependent phenotypes.

International audience; Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng * h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng * h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.