Multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin.

Physiologically-based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site- and sex- population variability to predict local and systemic bioavailability. The present report outlines the structure and assumptions of the MPML MechDermA model and includes results from simulations comparing absorption at multiple body sites for two compounds, caffeine and benzoic acid, formulated as solutions. Finally, a model of the Feldene (piroxicam) topical gel, 0.5% was developed and assessed for its ability to predict both plasma and local skin concentrations when compared to in vivo PK data.

Establishment and validation of microsampling techniques in wild rodents for ecotoxicological research.

Compounds and products in the biocide and plant protection sector can only be registered after formal risk assessment to ensure safety for users and the environment. In bird and mammal risk assessment, this is routinely done using generic focal species as models, which are of particular exposure risk. Such a species is the common vole (Microtus arvalis) due to its high food intake relative to the low body weight. For wild species, biological samples, data and hence realistic exposure estimations are particularly difficult to obtain. In recent years, advances have been made in the techniques related to serial microsampling of laboratory mice and rats that allow for a reduction in sampling volumes. Similar progress in wild species sampling is missing. This study presents a proof of concept to dose wild rodents with relevant compounds and to draw serial, low volume blood samples suitable for state-of-the art toxicokinetic analyses. For the first time, the jugular vein of common voles was used to administer compounds (two frequently used fungicidal components). This procedure and the following microsampling of blood (2 × 10 µl six times within 24 hours) from the lateral tail vein did not affect body weight and mortality of voles. Samples were sufficient to detect dissipation patterns of the compounds from blood in toxicokinetic analysis. These results suggest that microsampling can be well translated from laboratory mice to wild rodent species and help to obtain realistic exposure estimates in wild rodents for ecotoxicological studies as well as to promote the 3R concept in studies with wild rodent species.

An overview of cardiac morphogenesis.

Accurate knowledge of normal cardiac development is essential for properly understanding the morphogenesis of congenital cardiac malformations that represent the most common congenital anomaly in newborns. The heart is the first organ to function during embryonic development and is fully formed at 8 weeks of gestation. Recent studies stemming from molecular genetics have allowed specification of the role of cellular precursors in the field of heart development. In this article we review the different steps of heart development, focusing on the processes of alignment and septation. We also show, as often as possible, the links between abnormalities of cardiac development and the main congenital heart defects. The development of animal models has permitted the unraveling of many mechanisms that potentially lead to cardiac malformations. A next step towards a better knowledge of cardiac development could be multiscale cardiac modelling.

Epithelial to mesenchymal transition-the roles of cell morphology, labile adhesion and junctional coupling.

Epithelial to mesenchymal transition (EMT) is a fundamental process during development and disease, including development of the heart valves and tumour metastases. An extended cellular Potts model was implemented to represent the behaviour emerging from autonomous cell morphology, labile adhesion, junctional coupling and cell motility. Computer simulations normally focus on these functional changes independently whereas this model facilitates exploration of the interplay between cell shape changes, adhesion and migration. The simulation model is fitted to an in vitro model of endocardial EMT, and agrees with the finding that Notch signalling increases cell-matrix adhesion in addition to modulating cell-cell adhesion.

Towards multiscale systems modeling of endocardial to mesenchymal transition.

Cell behavior during endocardial to mesenchymal transition (EMT) was simulated using the cellular Potts formalism in Compucell 3D. The processes of loss of endocardial cohesion and invasion into the extracellular matrix (ECM) were stimulated by changing surface energy parameters. The simulations match in vitro results which suggest that endocardial motility on the surface of collagen gel can be induced separately from 3D invasion of the gel, via Notch signaling in the absence of BMP2. A principle by which the rate of mitosis would regulate the monolayer was demonstrated; suggesting a route for Vascular Endothelial Growth Factor (VEGF) control of EMT. A conceptual model of the system of protein interactions during EMT was assembled from multiple studies. A route for subcellular models to be formalized as Systems Biology Markup Language (SBML) differential equations is indicated. Scale linking would be achieved through Compucell 3D periodically integrating the SBML models for each cell during a simulation run, and updating parameters for protein concentrations assigned to individual cells. The surface energy parameters for the cells would be recalculated at each step from their simulated protein concentrations. Such scale linking opens up the potential for complexity to be gradually introduced, while maintaining experimental validation.

Multiscale systems modeling of the tetralogy of Fallot.

This paper provides a first description of a multiscale systems modeling approach applied to the congenital birth defect known as the tetralogy of Fallot. The multiscale approach adopted owes a lot to the effort of the world-wide physiome consortium and the work of research groups within the European Union on the Virtual Physiological Human. Both a spatial scale and time scale are used to establish the systems boundaries of the application. The tetralogy of Fallot includes up to four simultaneously occurring anatomic abnormalities that underpin the defect. The use of finite state machines and cellular automata pave the way to understand the processes in time and space that contribute to the defect.