Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Solubility can be the absorption limiting factor for drug candidates and is therefore a very important input parameter for oral exposure prediction of compounds with limited solubility. Biorelevant media of the fasted and fed state have been published for humans, as well as for dogs in the fasted state. In a drug discovery environment, rodents are the most common animal model to assess the oral exposure of drug candidates. In this study a rat simulated intestinal fluid (rSIF) is proposed as a more physiologically relevant media to describe drug solubility in rats. Equilibrium solubility in this medium was tested as input parameter for physiologically-based pharmacokinetics (PBPK) simulations of oral pharmacokinetics in the rat. Simulations were compared to those obtained using other solubility values as input parameters, like buffer at pH 6.8, human simulated intestinal fluid and a comprehensive dissolution assay based on rSIF. Our study on nine different compounds demonstrates that the incorporation of rSIF equilibrium solubility values into PBPK models of oral drug exposure can significantly improve the reliability of simulations in rats for doses up to 300 mg/kg compared to other media. The comprehensive dissolution assay may help to improve further simulation outcome, but the greater experimental effort as compared to equilibrium solubility may limit its use in a drug discovery environment. Overall, PBPK simulations based on solubility in the proposed rSIF medium can improve prioritizing compounds in drug discovery as well as planning dose escalation studies, e.g. during toxicological investigations

Innate Killing of Leishmania donovani by Macrophages of the Splenic Marginal Zone Requires IRF-7

Highly phagocytic macrophages line the marginal zone (MZ) of the spleen and the lymph node subcapsular sinus. Although these macrophages have been attributed with a variety of functions, including the uptake and clearance of blood and lymph-borne pathogens, little is known about the effector mechanisms they employ after pathogen uptake. Here, we have combined gene expression profiling and RNAi using a stromal macrophage cell line with in situ analysis of the leishmanicidal activity of marginal zone macrophages (MZM) and marginal metallophilic macrophages (MMM) in wild type and gene targeted mice. Our data demonstrate a critical role for interferon regulatory factor-7 (IRF-7) in regulating the killing of intracellular Leishmania donovani by these specialised splenic macrophage sub-populations. This study, therefore, identifies a new role for IRF-7 as a regulator of innate microbicidal activity against this, and perhaps other, non-viral intracellular pathogens. This study also highlights the importance of selecting appropriate macrophage populations when studying pathogen interactions with this functionally diverse lineage of cells

CESAR experiment: sodium boiling during transient overpower

International audienceIn the framework of nuclear revival under the constraint of global warming and in the context of the emergence of new small modular reactor concepts, sodium cooled fast breeders seem to be a good candidate for maximizing the energy yield of the fuel and burning actinides. In the case of rapid reactivity insertion, characterizing transient sodium boiling is essential, as it can lead to dry out and rupture of fuel pins, but also as it has an impact on core reactivity. As sodium is a metal with a low Prandtl number, its boiling behavior is different from that of water. In order to provide insights and data on boiling of sodium during transient overpower, past experimental results obtained in the frame of the CESAR program (Caracterisation de l’Ebullition du Sodium en Accident de Réactivité) performed at CEA Grenoble in the 70th are described and main learnings are given. The CESAR test loop and experimental procedure are described, and results of seven transient tests with different inlet flow rates, temperatures, pressures and transient powers are described and interpreted on the basis of a comparison with single-phase simulations. The phenomenon of sodium superheat at boiling onset is studied. These data, which are rare in the literature, can be used to validate simulation tools

Modélisation avancée de la polydispersion en taille des écoulements bouillants

Un programme de Recherche et Développement dans le domaine de l'Accident de Perte du Réfrigérant Primaire, sur un Réacteur à Eau sous Pression, est en cours à l'Institut de Radioprotection et de Sûreté Nucléaire. Lors de ce transitoire accidentel, l'ébullition du fluide sur la paroi des crayons conduit au dénoyage du coeur du réacteur. L'étude présentée est orientée sur le développement de modèles permettant la simulation CFD de la topologie locale d'un écoulement bouillant. En effet, les observations expérimentales ont permis de mettre en évidence une polydispersion en taille : statistiquement et localement, la population de bulles se caractérise par un large spectre de taille. Or, les forces gouvernant l'hydrodynamique locale d'une bulle dependent fortement de sa taille. Cette taille détermine également la surface d'échange avec le liquide et donc les différents transferts entre phases. Ces observations soulignent la nécessité de prendre en compte cette polydispersion en taille au sein d'une description moyennée de l'écoulement. Ainsi, un modèle de population de bulles a été développé, basé sur des équations de transport des densités de moments statistiques de la fonction de distribution en taille de la population de bulles. Dans ce papier, on décrit les termes sources traduisant les différentes contributions à l'évolution des diamètres des bulles. Ce modèle, intégré dans le code NEPTUNE_CFD, a été testé sur des resultants d'expérience d'écoulements bouillants obtenus sur l'installation DEBORA. Les simulations réalisées constituent une validation du modèle ainsi qu'une étude de sa convergence en maillage et de l'impact de certains phénomènes sur la topologie de l'écoulement

Modelling of the expansion phase of Sodium fast reactor severe accident

International audienceImproving safety is one of the current objective of the fourth generation of sodium fast reactors (SFR). In order to achieve this requirement and increase safety margins, developments are carried out to take into account severe accidents as soon as the pre-conceptual phase. In this context,fast-running and parametric tools are used in addition to mechanistic tools for parametric studies and probabilistic margin evaluations.This paper is dedicated to MOREINa (Model Of vapouR Expansion and fuel coolant Interaction in sodium fast Reactor), a new parametric tool modelling expansion phase transients. During a severe accident in SFR integrating a low void worth core (non energetic primary phase), a meltdown of the core may occur and form a molten material pool in the vessel. After a secondary power excursion in the molten material pool, the expansion phase implies the self-vaporization of superheated materials and their expansion toward the sodium located in the upper plenum, abovethe core. Fuel Coolant Interaction (FCI) will be possible during this phase when the unvaporized overheated molten materials are mixed with the coolant, implying a huge transfer of energy from the superheated materials to the coolant ; vaporizing this latter. The mechanical energy releasedby the two aforementionned phenomena is evaluated during this phase in order to assess the potential damage on the vessel. Thus, MOREINa integrates a new expansion phase model quantifying the mechanical energy induced by this severe accident phase in order to study its consequences on the reactor vessel walls.The modelling implemented in MOREINa, based on dimensional analysis and different balanceequations, is able to simulate:- fuel and steel vaporisations;- the creation of a vapour bubble with or without fission gases inside- the expansion of the molten materials due to the pressure difference between the saturatedpressure of the molten materials and the cover gas located above the sodium, at the top of the vessel;- the integration of the molten material droplet into the bubble vapour owing to Rayleigh-Taylor instabilities at the vapour-liquid interface;- the fuel coolant interaction (FCI) if the expansion leads the molten materials to contact the coolant.First, the safety context of the expansion phase study is introduced. The new parametric tool MOREINa is then presented with its main models. Validations of MOREINa against a validated tool and on available test cases are carried-out and, finally, a parametric study is presented and analyzed

Physico-statistical approach to assess the core damage variability due to a total instantaneous blockage of SFR fuel sub-assembly

International audienceWithin the framework of the generation IV Sodium Fast Reactors (SFR) R&D program of CEA (French commissariat a l'energie atomique et aux energies alternatives), the safety in case of accidents is assessed. These accidental scenarios involve very complex transient phenomena. To get round the difficulty of modelling them, only Sounding' (most damaging) accidental conditions have been up to now studied for the safety demonstration. These transients are simulated with very complex multi-physical codes (such as SIMMER) which nevertheless include some adjusted and not well known parameters and require a long CPU (process) time preventing their direct use for uncertainty propagation and sensitivity studies, especially in case of a high number of uncertain input parameters. To cope with these constraints, a new physico-statistical approach is followed in parallel by the CEA. This approach involves the fast-running description of extended accident sequences coupling analytical models for the main physical phenomena in combination with advanced statistical analysis techniques. The efficiency of the methodology for the reactor safety analysis is demonstrated here for one type of accident - the Total Instantaneous Blockage (TIB) - which involves an extended range of complex physical phenomena. From the establishment of the physical models describing the TIB phenomenology, 27 uncertain input parameters and their associated probability distributions are identified. A propagation of these input parameter uncertainties is performed via a Monte-Carlo sampling, providing probability distribution of TIB outputs. A quantification of safety margins is also deduced

Evaluation du transfert radiatif dans un cœur de Réacteur à Eau Pressurisée (REP) lors de la phase de re-noyage d’un Accident de Perte de Réfrigérant Primaire (APRP)

National audienceDes études basées sur l’utilisation de la CFD ont été menée s dans le contexte de la phase de renoyage d’un Accident de Perte de Réfrigérant Primaire (APRP) d’une centrale nucléaire. Le logiciel Neptune_CFD permet de simuler des écoulements diphasiques avec transfert de masses et d’énergie. Le transfert radiatif entre les crayons du cœur du réacteur nucléaire et le milieu environnant, formé de vapeur et de gouttelettes, a notamment été étudié à l’aide d’une méthode IDA, dérivée de l’approximation P1. Ces études ont permis de montrer que, dans les configurations étudiées, le transfert radiatif contribue à hauteur d’environ 20% aux transferts de masse et d’ énergie

Evaluation du transfert radiatif dans un cœur de Réacteur à Eau Pressurisée (REP) lors de la phase de re-noyage d’un Accident de Perte de Réfrigérant Primaire (APRP)

National audienceDes études basées sur l’utilisation de la CFD ont été menée s dans le contexte de la phase de renoyage d’un Accident de Perte de Réfrigérant Primaire (APRP) d’une centrale nucléaire. Le logiciel Neptune_CFD permet de simuler des écoulements diphasiques avec transfert de masses et d’énergie. Le transfert radiatif entre les crayons du cœur du réacteur nucléaire et le milieu environnant, formé de vapeur et de gouttelettes, a notamment été étudié à l’aide d’une méthode IDA, dérivée de l’approximation P1. Ces études ont permis de montrer que, dans les configurations étudiées, le transfert radiatif contribue à hauteur d’environ 20% aux transferts de masse et d’ énergie