Discussion: Adding quantitative information about prodrug conversion

in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion (ADME) selleck screening library properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood. Also in a prospective compound selection process, this integrative approach can improve decision making on prodrug candidates by putting relative differences in prodrug conversion of a large number of candidates into the perspective of their human PK profile, before conducting any in vivo experiments. (C) 2012 Elsevier Inc. All rights reserved.”
“Asthma PRIMA-1MET in vivo is a disease of the airways in which several cytokines such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF alpha) play a major role in the development and progression of inflammation, airway hyperresponsiveness, mucus production, and airway remodeling.

The conventional anti-inflammatory therapies, represented by inhaled corticosteroids and antileukotrienes, are not always able to provide optimal disease control and it is therefore hoped that cytokine antagonists could achieve this goal in such situations. Anticytokine therapies have been tested in preclinical studies and some have entered

clinical trials. Anti-IL-4 therapies have been tested in animal models of allergy-related asthma, but because of unclear efficacy their development was discontinued. However, IL-4/IL-13 dual antagonists and IL-13-specific blocking agents are more promising, Alvocidib as they exhibit more sustained anti-inflammatory effects. IL-5 antagonists have been found to be of limited efficacy in clinical studies but might be useful in conditions characterized by severe hypereosinophilia, and in which asthma is one of the disease manifestations. Unlike other chronic inflammatory conditions, such as rheumatoid arthritis, the use of anti-TNF alpha therapies in asthma might be limited by the unfavorable risk/benefit ratio associated with long-term

use. The identification of so-called asthma TNF alpha phenotypes and perhaps the use of a less aggressive treatment regimen might address this important aspect. Other cytokine antagonists (for example for IL-9 or IL-25) are currently being evaluated in the asthma setting, and could open new therapeutic perspectives based on their efficacy and safety.”
“Stress myocardial perfusion scintigraphy imaging (SMPSI) has important applications for evaluating coronary disease and ventricular function. Studies consistently focus on the left ventricle (LV), with no normal right ventricle (RV) data available. This study sought to evaluate the feasibility of RV perfusion with technetium (Tc-99m) sestamibi using a low radiotracer dose for children free of coronary artery (CA) anomalies and to determine its normal pattern.