BioDMET: a physiologically based pharmacokinetic simulation tool for assessing proposed solutions to complex biological problems

We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter-species scaling. While developing a tool to aid imaging agent and drug development, we aimed at accelerating the acceptance and broad use of PBPK modeling by providing a free mechanistic PBPK software that is user friendly, easy to adapt to a wide range of problems even by non-programmers, provided with ready-to-use parameterized models and benchmarking data collected from the peer-reviewed literature

Characterization techniques for studying the properties of nanocarriers for systemic delivery

Nanocarriers have attracted a huge interest in the last decade as efficient drug delivery systems and diagnostic tools. They enable effective, targeted, controlled delivery of therapeutic molecules while lowering the side effects caused during the treatment. The physicochemical properties of nanoparticles determine their in vivo pharmacokinetics, biodistribution and tolerability. The most analyzed among these physicochemical properties are shape, size, surface charge and porosity and several techniques have been used to characterize these specific properties. These different techniques assess the particles under varying conditions, such as physical state, solvents etc. and as such probe, in addition to the particles themselves, artifacts due to sample preparation or environment during measurement. Here, we discuss the different methods to precisely evaluate these properties, including their advantages or disadvantages. In several cases, there are physical properties that can be evaluated by more than one technique. Different strengths and limitations of each technique complicate the choice of the most suitable method, while often a combinatorial characterization approach is needed

Modèles animaux d'ostéoporose post-ménopausique

International audienc

Preserved bone mass in ovariectomized rats treated with parathyroid-hormone-related peptide (1-34) and (107-111) fragments

International audienc

Masse osseuse préservée chez des rats ovariectomisés traités avec des fragments de peptides apparentés à l'hormone parathyroïdienne (1-34) et (107-111)

International audienceL'effet de fragments humains synthétiques de PTHrP (1-34) ou (107-111) sur la perte osseuse a été étudié chez le rat, un mois après une ovariectomie (OVX). Quatre groupes de rats âgés de 7 à 8 mois ont été traités quotidiennement par voie sous-cutanée pendant 13 jours avec de la PTHrP (1-34) ou (107-111) à la dose de 1 ou 3 nmol/100 g de poids corporel. Les rats OVX opérés de manière fictive (SHO) et témoins ont reçu le solvant seul. Dans nos conditions, à la dose la plus faible, ni les fragments (1-34) ni (107-111) n'ont eu d'effet significatif. Cependant, à la dose de 3 nmol/100 g par jour pendant 13 jours, les deux traitements ont significativement augmenté le poids sec fémoral, le poids des cendres, la teneur en Ca et la densitométrie du fémur. L'effet de la PTHrP (1-34) résultait principalement d'une augmentation de l'os cortical et trabéculaire (% de récupération : 98,25 et 105,23 %, respectivement). Pour le fragment PTHrP (107-111), un effet positif n'a été démontré que sur l'os cortical (récupération de 98,25%). Les résultats de cette étude démontrent que les fragments hPTHrP (1-34) et (107-111, ostéostatine) sont positifs pour l'os lorsqu'ils sont administrés à la dose de 3 nmol/100 g de poids corporel/j pendant 13 jours à des rats OVX adultes

Dihydrotestosterone prevents glucocorticoid-negative effects on fetal rat metatarsal bone in vitro

The access to electronic resources in French libraries and documentation services is increasing rapidly. The knowledge of usage statistics of online serials and databases becomes more and more important for need analysis and acquisition decisions. The article describes the recommendations of the project COUNTER which are de facto going to be an international norm for the production of these statistics