LES TOMBES EN BLOCS MEGALITHIQUES ET EN MACONNERIE DE PIERRES SECHES. DANS LE LEVANT ET LA PENINSULE ARABIQUE AUX IVE ET IIIE MILLENAIRES AVANT J.-C.

PARIS1-BU Pierre Mendès-France (751132102) / SudocSudocFranceF

Les tombes en blocs mégalithiques et en maçonnerie de pierres sèches dans le Levant et la Péninsule arabique aux IVe et IIIe millénaires avant J.-C.

Les tombes en blocs mégalithiques et en maçonnerie de pierres sèches se distribuent dans le Levant et la Péninsule arabique aux Ive et I~ millénaires avant J.-C. Parmi de nombreux types de tombes, l'analyse morphologique a fait apparaître trois grands ensembles de monuments funéraires: dolmens, tombes circulaires hautes, tumuli à ciste. Ces monuments se distribuent géographiquement dans des zones de pâturage, le plus souvent liées à un milieu semi-aride. Les nécropoles de dolmens couvrent principalement la Syrie du sud et la Jordanie .du nord, celles des tumuli à ciste sont concentrées dans le Néguev, alors que celles des tombes circulaires hautes se disséminent sur un vaste territoire qui s'étend du Sinaï au Yémen. Contrairement à ceux des zones côtières du Levant, les modes funéraires des marges arides du Ive au me millénaire étaient relativement mal connus. Ce travail réuni un corpus de plus de 10 000 tombes, qui, outre la connaissance des traditions architecturales funéraires de ces régions, a permis de distinguer les multiples facettes socio-économiques des sociétés qui ont utilisé, pendant 1500 ans un mode funéraire unique. En effet, la fin du IVe et le IIIe millénaire apparaissent être des moments clefs de formation et d'expérimentation des systèmes pastoraux d'une manière analogue aux premières formes élaborées au même moment dans les systèmes urbains. La relation entre les deux phénomènes est, dans certaines régions, assez proche. En effet certains groupes de pasteurs paraissent avoir expérimentés sans suite des formes architecturales et proto-urbaines et d'autres ont adoptés un mode de vie nomade pour lequel nous ne possédons que très peu de vestiges. L' etude des différents modes de vie pratiqués montre que l' architecture funéraire mégalithique au Proche et Moyen-Orient a essentiellement été adoptée pour délimiter un territoire et affirmer une identité culturelle; lorsque ces besoins n'ont plus été nécessaires, elle a périclité.PARIS1-BU Pierre Mendès-France (751132102) / SudocSudocFranceF

Pharmacokinetic similarity of biologics: analysis using nonlinear mixed-effects modeling.

International audienceOur objective was to show, using two examples, that a pharmacokinetic (PK) similarity analysis can be performed using nonlinear mixed-effects models (NLMEM). We used two studies that compared different biosimilars: a three-way crossover trial with somatropin and a parallel-group trial with epoetin-α. For both data sets, the results of NLMEM-based analysis were compared with those of noncompartmental analysis (NCA). For the latter analysis, we performed an NLMEM-based equivalence Wald test on secondary parameters of the model: the area under the curve and the maximal concentration. Somatropin PK was described by a one-compartment model and epoetin-α PK by a two-compartment model with linear and Michaelis-Menten elimination. For both studies, similarity of PK was demonstrated by means of both NCA and NLMEM, and both methods led to similar results. Therefore, for establishing similarity, PK data can be analyzed by either of the methods. NCA is an easier approach because it does not require data modeling; however, NLMEM leads to a better understanding of the underlying biological system

Pharmacometrics – Opportunity for Reducing Disease Burden in the Developing World

Pharmacometricians are virtually non-existent in Africa and the developing world. The unrelenting burden of neglected infectious diseases, which are often treated using medicines with narrow effectiveness – safety dose windows, and the growing prevalence of non-communicable diseases represents a significant burden for the patients while affording an opportunity for advancing science. Pharmacometrics is (still) an emerging discipline in the developed world which struggles to integrate into the established ways of conducting drug discovery and development. In Africa, the science and infrastructure is being built without a legacy system representing opportunity amid a need to better define and/or optimize dosing in local populations, or patients with co-morbidities. This paper outlines the business case for pharmacometricians to re-direct their expertise to focus on the disease burden affecting the developing world

Incorporating Physiological and Biochemical Mechanisms into Pharmacokinetic-Pharmacodynamic Models: A Conceptual Framework

The aim of this conceptual framework paper is to contribute to the further development of the modelling of effects of drugs or toxic agents by an approach which is based on the underlying physiology and pathology of the biological processes. In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g. a clinical trial and (2b) to obtain the most relevant parameters, (3) to test hypotheses and (4) to make predictions within the boundaries of experimental conditions, e.g. range of doses tested (interpolation) and out of the boundaries of the experimental conditions, e.g. to extrapolate from animal data to the situation in man. Describing the drug/xenobiotic-target interaction and the chain of biological events following the interaction is the first step to build a biologically based model. This is an approach to represent the underlying biological mechanisms in qualitative and also quantitative terms thus being inherently connected in many aspects to systems biology. As the systems biology models may contain variables in the order of hundreds connected with differential equations, it is obvious that it is in most cases not possible to assign values to the variables resulting from experimental data. Reduction techniques may be used to create a manageable model which, however, captures the biologically meaningful events in qualitative and quantitative terms. Until now, some success has been obtained by applying empirical pharmacokinetic/pharmacodynamic models which describe direct and indirect relationships between the xenobiotic molecule and the effect, including tolerance. Some of the models may have physiological components built in the structure of the model and use parameter estimates from published data. In recent years, some progress toward semi-mechanistic models has been made, examples being chemotherapy-induced myelosuppression and glucose-endogenous insulin-antidiabetic drug interactions. We see a way forward by employing approaches to bridge the gap between systems biology and physiologically based kinetic and dynamic models. To be useful for decision making, the 'bridging' model should have a well founded mechanistic basis, but being reduced to the extent that its parameters can be deduced from experimental data, however capturing the biological/clinical essential details so that meaningful predictions and extrapolations can be made

Modelling and simulation in the development and use of anti-cancer agents: An underused tool?

To help identify the role of modelling and simulation in the development of anti-cancer agents, their main advantages and the obstacles to their rational use, an expert meeting was organized by COST B15. This manuscript presents a synthesis of views expressed at that meeting and indicates future directions. The manuscript also shows some examples where modelling and simulation have proven to be of relevant value in the drug development process for anti-cancer agents. © 2005 Springer Science+Business Media, Inc