The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co-formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries.</p> <p>Methods</p> <p>Pharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal) within a larger Public Private partnership (the FACT project), set up by WHO/TDR, Médecins Sans Frontières and the Drugs for Neglected Disease initiative (DND<it>i</it>).</p> <p>Results</p> <p>The main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long-term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DND<it>i</it>.</p> <p>Conclusions</p> <p>Collaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the development process, and no intellectual property right was claimed. This approach resulted in a rapid technology transfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO pre-qualification of the fixed-dose co-formulation together with DND<it>i</it>. The bi-layered tablet is made available under the names of Coarsucam^®and Artesunate amodiaquine Winthrop^®, Sanofi-Aventis. The issue related to the difficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of applied research is discussed.</p

Differential Function of Lip Residues in the Mechanism and Biology of an Anthrax Hemophore

To replicate in mammalian hosts, bacterial pathogens must acquire iron. The majority of iron is coordinated to the protoporphyrin ring of heme, which is further bound to hemoglobin. Pathogenic bacteria utilize secreted hemophores to acquire heme from heme sources such as hemoglobin. Bacillus anthracis, the causative agent of anthrax disease, secretes two hemophores, IsdX1 and IsdX2, to acquire heme from host hemoglobin and enhance bacterial replication in iron-starved environments. Both proteins contain NEAr-iron Transporter (NEAT) domains, a conserved protein module that functions in heme acquisition in Gram-positive pathogens. Here, we report the structure of IsdX1, the first of a Gram-positive hemophore, with and without bound heme. Overall, IsdX1 forms an immunoglobin-like fold that contains, similar to other NEAT proteins, a 310-helix near the heme-binding site. Because the mechanistic function of this helix in NEAT proteins is not yet defined, we focused on the contribution of this region to hemophore and NEAT protein activity, both biochemically and biologically in cultured cells. Site-directed mutagenesis of amino acids in and adjacent to the helix identified residues important for heme and hemoglobin association, with some mutations affecting both properties and other mutations affecting only heme stabilization. IsdX1 with mutations that reduced the ability to associate with hemoglobin and bind heme failed to restore the growth of a hemophore-deficient strain of B. anthracis on hemoglobin as the sole iron source. These data indicate that not only is the 310-helix important for NEAT protein biology, but also that the processes of hemoglobin and heme binding can be both separate as well as coupled, the latter function being necessary for maximal heme-scavenging activity. These studies enhance our understanding of NEAT domain and hemophore function and set the stage for structure-based inhibitor design to block NEAT domain interaction with upstream ligands

French Roadmap for complex Systems 2008-2009

This second issue of the French Complex Systems Roadmap is the outcome of the Entretiens de Cargese 2008, an interdisciplinary brainstorming session organized over one week in 2008, jointly by RNSC, ISC-PIF and IXXI. It capitalizes on the first roadmap and gathers contributions of more than 70 scientists from major French institutions. The aim of this roadmap is to foster the coordination of the complex systems community on focused topics and questions, as well as to present contributions and challenges in the complex systems sciences and complexity science to the public, political and industrial spheres

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Contribution à la caractérisation des épilepsies canines et à son utilisation en tant que modèle des épilepsies humaines

LYON1-BU Santé (693882101) / SudocTOULOUSE-EN Vétérinaire (315552301) / SudocSudocFranceF

Intérêt pronostique des métalloprotéases sériques et synoviales dans la polyarthrite rhumatoïde

La polyarthrite rhumatoïde entraîne une destruction articulaire parfois très précoce. Les métalloprotéases et leurs inhibiteurs interviennent dans la protéolyse matricielle. Nous avons de façon prospective, initialement et à un an, recueilli des données cliniques, biologiques et radiologiques concernant 23 patients porteurs de polyarthrite rhumatoïde ou non (26) présentant un épanchement articulaire. Nous avons apprécié la progression de la destruction articulaire selon le score de Sharp et nous l'avons corrélé aux différents paramètres étudiés. Les taux synoviaux de MMP-8, MMP-9 et ß-glucuronidase sont corrélés au nombre de polynucléaires neutrophiles, et l'aggravation du score de Sharp sur une année est liée positivement à la présence de MMP-8 et de ß-glucuronidase dans le liquide synovial. Ces résultats soulignent le fait que la destruction articulaire est liée à la présence de polynucléaires neutrophiles synoviaux activés comme en témoignent les marqueurs de dégranulation. entraîne une destruction articulaire parfois très précoce. Les métalloprotéases et leurs inhibiteurs interviennent dans la protéolyse matricielle. Nous avons de façon prospective, initialement et à un an, recueilli des données cliniques, biologiques et radiologiques concernant 23 patients porteurs de polyarthrite rhumatoïde ou non (26) présentant un épanchement articulaire. Nous avons apprécié la progression de la destruction articulaire selon le score de Sharp et nous l'avons corrélé aux différents paramètres étudiés. Les taux synoviaux de MMP-8, MMP-9 et ß-glucuronidase sont corrélés au nombre de polynucléaires neutrophiles, et l'aggravation du score de Sharp sur une année est liée positivement à la présence de MMP-8 et de ß-glucuronidase dans le liquide synovial. Ces résultats soulignent le fait que la destruction articulaire est liée à la présence de polynucléaires neutrophiles synoviaux activés comme en témoignent les marqueurs de dégranulation.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Introduction

L’Irlande, dont les historiens s’attachent à faire ressortir le caractère patriarcal n’a pas, malgré tout, totalement oblitéré le souvenir de ses citoyennes qui, en dépit des pressions, ont su manifester leur volonté d’exister, de combattre pour un statut et pour un rôle à part entière dans cette société irlandaise qui se constitue à partir du XIXe siècle. Atypiques dans les années formatrices, (cf. article de Maurice Goldring) féministes et nationalistes ont fait école, pour donner aux femme..

Utilisation potentielle de l'acide alpha-lipoïque dans le traitement de la neuropathie diabétique

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

L'implication des vitamines B6, B9, B12 et de l'homocystéine dans les Défauts de Fermeture du Tube Neural (à propos d'une étude cas témoins)

LYON1-BU Santé (693882101) / SudocSudocFranceF