GPS for QSP: A Summary of the ACoP6 Symposium on Quantitative Systems Pharmacology and a Stage for Near-Term Efforts in the Field

Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics.[1] As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal

The altered expression of α1 and β3 subunits of the gamma-aminobutyric acid A receptor is related to the hepatitis C virus infection

The modulation of the gamma-aminobutyric acid type A (GABA A) receptors activity was observed in several chronic hepatitis failures, including hepatitis C. The expression of GABA A receptor subunits α1 and β3 was detected in peripheral blood mononuclear cells (PBMCs) originated from healthy donors. The aim of the study was to evaluate if GABA A α1 and β3 expression can also be observed in PBMCs from chronic hepatitis C (CHC) patients and to evaluate a possible association between their expression and the course of hepatitis C virus (HCV) infection. GABA A α1- and β3-specific mRNAs presence and a protein expression in PBMCs from healthy donors and CHC patients were screened by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. In patients, HCV RNA was determined in sera and PBMCs. It was shown that GABA A α1 and β3 expression was significantly different in PBMCs from CHC patients and healthy donors. In comparison to healthy donors, CHC patients were found to present an increase in the expression of GABA A α1 subunit and a decrease in the expression of β3 subunit in their PBMCs. The modulation of α1 and β3 GABA A receptors subunits expression in PBMCs may be associated with ongoing or past HCV infection

Urinary extracellular vesicles: A position paper by the Urine Task Force of the International Society for Extracellular Vesicles

Urine is commonly used for clinical diagnosis and biomedical research. The discovery of extracellular vesicles (EV) in urine opened a new fast-growing scientific field. In the last decade urinary extracellular vesicles (uEVs) were shown to mirror molecular processes as well as physiological and pathological conditions in kidney, urothelial and prostate tissue. Therefore, several methods to isolate and characterize uEVs have been developed. However, methodological aspects of EV separation and analysis, including normalization of results, need further optimization and standardization to foster scientific advances in uEV research and a subsequent successful translation into clinical practice. This position paper is written by the Urine Task Force of the Rigor and Standardization Subcommittee of ISEV consisting of nephrologists, urologists, cardiologists and biologists with active experience in uEV research. Our aim is to present the state of the art and identify challenges and gaps in current uEV-based analyses for clinical applications. Finally, recommendations for improved rigor, reproducibility and interoperability in uEV research are provided in order to facilitate advances in the field

A geometrical approach to the PKPD modelling of inhaled bronchodilators

The present work introduces a new method to model the pharmacokinetics and pharmacodynamics (PKPD) of an inhaled dose of bronchodilator. This method provides an alternative approach to classic compartmental representations or computational fluid dynamics. A five compartment lung model comprising the upper airways, bronchial tree mucosa, bronchial muscles, alveoli and plasma has been modified to take into account anatomical, geometrical features such as bronchial branching and smooth muscle distribution. Many anatomical and physiological features of the bronchial tree depend, as a first approximation, on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which work together in determining the local response to the inhaled dose; integrating these local responses over the whole bronchial tree allows an approximation of total broncodilator response, particularly with respect to airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part substitutes a simplified geometrical and functional description of the bronchial tree for the typical PD models of effect, leading to the direct computation of the approximate FEV1. In the present work the construction of the model is detailed, and literature data are used to derive the anatomical approximations used. Simulation of two asthmatic subjects is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and effect of an inhaled dose of bronchodilator. The relevance of formulation diffusivity on therapeutic efficacy is discussed and conclusions regarding the applicability of the model in interpreting single-subject and population experiments are drawn