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Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). Methods Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. Results We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 μM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. Conclusion We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.

Protein-protein interactions (PPIs) constitute many potential therapeutic targets for the discovery of new drugs. Given their specificity, PPIs are more challenging to target than other ligands. Thus, finding the best screening process can be difficult. Moreover, PPIs often have no direct accessible activity readout. Therefore, it can be unclear which test to choose for the screening of small molecules targeting PPIs. Given that noncellular assays are the most suitable both as first screening assays and for high-throughput screening (HTS), here we focus on noncellular screening assays. For each assay, we discuss the principles and advantages/drawbacks and provide a recent example. We also highlight the crucial parameters to take into account to select the most suitable assays to screen PPI modulators.

Drug-drug interactions are sometimes considered to be detrimental and responsible for adverse effects. In some cases, however, some are stakeholders of the efficiency of the treatment and this combinatorial strategy is exploited by some drug associations, including levodopa (L-Dopa) and dopadecarboxylase inhibitors, β-lactam antibiotics and clavulanic acid, 5-fluorouracil (5-FU) and folinic acid, and penicillin and probenecid. More recently, some drug-drug combinations have been integrated in modern drug design strategies, aiming to enhance the efficiency of already marketed drugs with new compounds acting not only as synergistic associations, but also as real boosters of activity. In this review, we provide an update of examples of such strategies, with a special focus on microbiology and oncology.

Objectives Drug repositioning, that is, the use of a drug in an indication other than the one for which it was initially marketed, is a growing trend. Its origins lie mainly in the attrition experienced in recent years in the field of new drug discovery. Key findings Despite some regulatory and economic challenges, drug repositioning offers many advantages, and a number of recent successes have confirmed both its public health benefits and its commercial value. The first examples of successful drug repositioning mainly came about through serendipity like acetylsalicylic acid, thalidomide, sildenafil or dimethylfumarate. Conclusion The history of great-repositioned drugs has given some solutions to various pathologies. Serendipity is not yet useful to find repositioning drugs. Drug repositioning is of growing interest. Nowadays, a more rational approach to the identification of drug candidates for repositioning is possible, especially using data mining.

International audience; Background A significant number of clinical pharmacy services have shown to improve in-hospital medication safety and patient outcome. Prescription review and pharmacist interventions are a fundamental part of hospital clinical pharmacy activities. In a context of restricted financial resources, proving the economic and clinical impact of this activity seems necessary. Objective The aim of this study was to assess the clinical impact on patient outcomes and economic benefit of prescription review by pharmacists. Setting 1624-bed tertiary French university teaching hospital. Method Prospective single center study evaluating prescriptions for which a pharmacist intervention was issued over a 6-month period. The clinical impact of every pharmacist intervention was evaluated by a multidisciplinary experts committee. Economic benefit was evaluated from the public health care system spending standpoint. Main outcome measures Number of avoided hospitalization days and associated public health care system cost-avoidance. Results Prescription review and interventions by pharmacists prevented 73 intensive care unit hospitalization days, 74 continuous monitoring unit hospitalization days and 66 days of conventional hospitalization. €252,294.00 in public health expenditure were thus prevented. For every Euro invested in the prescription review activity, €5.09 of public health spending were potentially saved. Conclusion Our study shows that prescription review and clinical pharmacists' interventions had an impact on clinical outcomes which translated into prevented hospitalization days. Prescription optimization through pharmacist interventions allows significant health care cost savings which makes this service highly efficient

Memories of Near-Death Experiences (NDEs) most often are recounted as emotionally positive events. At present, no satisfactory explanatory model exists to fully account for the rich phenomenology of NDEs following a severe acute brain injury. The particular population of patients with locked-in syndrome (LIS) provides a unique opportunity to study NDEs following infratentorial brain lesions. We here retrospectively characterized the content of NDEs in 8 patients with LIS caused by an acute brainstem lesion (i.e., “LIS NDEs”) and 23 NDE experiencers after coma with supratentorial lesions (i.e., “classical NDEs”). Compared to “classical NDEs”, “LIS NDEs” less frequently experienced a feeling of peacefulness or well-being. It could be hypothesized that NDEs containing less positive emotions might have a specific neuroanatomical substrate related to impaired pontine/paralimbic connectivity or alternatively might be related to the emotional distress caused by the presence of conscious awareness in a paralyzed body.

International audience; Herein we describe the drug design steps developed to increase the radical scavenging and β-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease

International audience; This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation

Background: Near death experiences (NDEs) are increasingly being reported as a clearly identifiable physiological and psychological reality of clinical significance. However, the definition and causes of the phenomenon as well as the identification of NDE experiencers is still a matter of debate. To date, the most widely used standardized tool to identify and characterize NDEs in research is the Greyson NDE scale. Using this scale, retrospective and prospective studies have been trying to estimate their incidence in various populations but few studies have attempted to associate the experiences' intensity and content to etiology. Methods: This retrospective investigation assessed the intensity and the most frequently recounted features of self-reported NDEs after a non-life-threatening event (i.e., “NDE-like” experience) or after a pathological coma (i.e., “real NDE”) and according to the etiology of the acute brain insult. We also compared our retrospectively acquired data in anoxic coma with historical data from the published literature on prospective post-anoxic studies using the Greyson NDE scale. Results: From our 190 reports who met the criteria for NDE (i.e., Greyson NDE scale total score >7/32), intensity (i.e., Greyson NDE scale total score) and content (i.e., Greyson NDE scale features) did not differ between “NDE-like” (n = 50) and “real NDE” (n = 140) groups, nor within the “real NDE” group depending on the cause of coma (anoxic/traumatic/other). The most frequently reported feature was peacefulness (89–93%). Only 2 patients (1%) recounted a negative experience. The overall NDE core features' frequencies were higher in our retrospective anoxic cohort when compared to historical published prospective data. Conclusions: It appears that “real NDEs” after coma of different etiologies are similar to “NDE-like” experiences occurring after non-life threatening events. Subjects reporting NDEs retrospectively tend to have experienced a different content compared to the prospective experiencers.

Performing Jefford’s cyclization of ethyl 2-pyrrol-1-ylcyclohex-2-ene-1-carboxylate (5) using boron tribromide in refluxing dichloromethane led to a trans–cis bromopyrrolohydrindolone 7 whose debromination in alkaline medium afforded a highly strained cyclopenta[1,3]cyclopropa[1,2-b]pyrrolizin-8-one 6. Compound 7 and two of its diastereoisomers were synthesized in order to better understand this unusual reaction and more generally the reactivity of these systems.

The letter and the Fabric - The letter is a double symbol in its representation and in its language. The ambiguity of forms and meanings expresses this duality between the signified and its signifier. The duplication of the letter is not merely ornamental. Doubling or redoubling the letter gives more intensity to its symbolic import. The signification of the letters derives from the moral, didactic, religious, cosmological or mantic properties they were endowed with. The letter whose form is as if « inhabited » expresses a mystery of presence. The mystery is also contained in the name which the letter identifies but which cannot be designated : « Amour » (love) is at the heart of the letters, the « âme » (soul) of the cipher., La lettre et l'étoffe - La lettre est un symbole double dans sa représentation et son langage. Les équivoques de formes et de sens expriment cette dualité entre le signifiant et son signifié. La duplication de la lettre est plus qu'un simple souci d'ornementation. En redoublant ou dédoublant la lettre, cette duplication ajoute une charge symbolique. Le signifié des lettres procède d'une sédimentation d'emploi utilisant leurs propriétés morales, didactiques, christiques, cosmologiques et manti- ques. La lettre dont la forme est comme « habitée » exprime un mystère de la présence. Ce mystère est aussi celui du nom que la lettre identifie et qu'on ne peut pourtant nommer. L'Amour est au cœur des lettres, l'âme du chiffre., Jourdan Jean-Pierre. La lettre et l'étoffe. Étude sur les lettres dans le dispositif vestimentaire à la fin du Moyen Âge. In: Médiévales, n°29, 1995. L'étoffe et le vêtement, sous la direction de Michel Pastoureau . pp. 23-46.

For a long time the Pas was regarded as a mere part of the chivalric combat, as a ritual of parade and as a dramatisation having the childish fantasy of a fairy tale; the Emprise being the expression of the mentality of a former age which could only survive in Burgundy supported by heroic literature. This historiographic conception, influenced by the work of . Huizinga and . Rychner, seems to underestimate the symbolical significance of these combat rituals whose dramatisation is meaningful. This paper tries to show how the careful choice of place and setting determines the meaning of the combat as part of a ritual of alliance and stresses its political significance. Adding or substituting new links of a contractual nature to the feudal links which became-less binding and more uncertain as a result of wars, the Pas paves the way to subjection and to make it more acceptable, transforming it into a bound of Love.

The Bulletin of Laws is an essential source of the history of salaries in the public office in the 19 th century. The close study of dispositions and the examination of the numerical data that this study provides allow us to conclude a few major points for the period of 1789-1814. The Revolution established a new definition of remunerations around the principle of their nationalization. The approach to the subject of salaries is not made any easier due to their diversed forms and their internal complexity. In other respects, the scale of remuneration is, above all else, reproductive of urban hierarchies. If the idea of personal class is not ignored, the rules of retribution are more inclined to penalize absenteism than to recompensate merit and in a wider scope, the mediocrity of the majority of remunerations dominates. For most civil servants, the revolutionalry period was particularly difficult., Résumé : Le Bulletin des Lois apparaît comme l'une des sources essentielles d'une histoire des traitements dans la fonction publique au XIXe siècle. Pour la période 1789-1814, l'étude attentive des dispositions et des nombreuses données chiffrées qu'il fournit permet de dégager quelques points majeurs. La Révolution a consacré une nouvelle définition des rémunérations autour du principe de leur nationalisation. L'approche des traitements n'en est pas pour autant aisée en raison de leur diversité de forme et de leur complexité interne. Par ailleurs, l'échelle des rémunérations est avant tout reproductrice des hiérarchies citadines. Si l'idée de classe personnelle n'est pas ignorée, les règles de rétribution sont plus enclines à pénaliser l'absentéisme qu'à récompenser le mérite. Dans le cadre d'un éventail extrêmement ouvert domine la médiocrité du plus grand nombre des rémunérations. Pour la plupart des employés de l'administration, la période révolutionnaire fut particulièrement difficile., Jourdan J.-P. Pour une histoire des traitements des fonctionnaires de l'Administration au XIXe siècle : l'apport du Bulletin des Lois à travers les années 1789-1814. In: Histoire, économie et société, 1991, 10ᵉ année, n°2. pp. 227-244.

With the increase of life expectancy, age-related macular degeneration has become a major public health problem to which the community pharmacist is able to provide solutions. In this thesis, a survey was conducted giving us an overview of the amount of information available to patients with an exudative form of AMD. In turn we could channel what role the pharmacist has in the treatment process. Thus, we will be discussing his role in disease prevention and detection as well as how he can help with care and support for patients with AMD.; Avec l’augmentation de l’espérance de vie, la dégénérescence maculaire liée à l’âge est devenue un problème majeur de santé publique auquel le pharmacien d’officine est capable d’apporter des solutions. Dans ce travail, la réalisation d’un questionnaire a permis de faire un état des lieux sur le niveau d’information des patients atteints par une forme exsudative de DMLA dans le but de dégager les principaux axes de réflexion concernant la place du pharmacien d’officine dans le parcours de soin. Ainsi, il sera question de son rôle dans la prévention et le dépistage de la maladie mais également dans la prise en charge et l’accompagnement du patient atteint de DMLA.

Since their commercialization in 1963, benzodiazepines have been widely prescribed. Having many uses (anxiolytic, hypnotic, muscle relaxant and antiseizure drug), a large proportion of the population have consumed it during their lifetime. But their undesirable effects, such as dependence, paradoxical reactions or anterograde amnesia, led to an important misuse of these molecules. In this thesis, we will confront the use of benzodiazepines in France and Vietnam, in relation to the mentality and the philosophy of the populations.; Depuis leur arrivée sur le marché en 1963, les benzodiazépines ont largement été prescrites. Possédant de nombreuses utilisations (anxiolytique, hypnotique, myorelaxante et anti-convulsivante), une large proportion de la population en ont consommé durant leur vie. Mais leurs effets indésirables, tels que la dépendance, les réactions paradoxales ou encore l’amnésie antérograde, ont conduit à un mésusage important de ces molécules. Dans cette thèse, nous confronterons l’utilisation des benzodiazépines en France et au Vietnam, en relation avec la mentalité et la philosophie des populations étudiées.