Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”

Unsupervised Learning of Reflexive and Action-Based Affordances to Model Adaptive Navigational Behavior

Here we introduce a cognitive model capable to model a variety of behavioral domains and apply it to a navigational task. We used place cells as sensory representation, such that the cells’ place fields divided the environment into discrete states. The robot learns knowledge of the environment by memorizing the sensory outcome of its motor actions. This is composed of a central process, learning the probability of state-to-state transitions by motor actions and a distal processing routine, learning the extent to which these state-to-state transitions are caused by sensory-driven reflex behavior (obstacle avoidance). Navigational decision making integrates central and distal learned environmental knowledge to select an action that leads to a goal state. Differentiating distal and central processing increases the behavioral accuracy of the selected actions and the ability of behavioral adaptation to a changed environment. We propose that the system can canonically be expanded to model other behaviors, using alternative definitions of states and actions. The emphasis of this paper is to test this general cognitive model on a robot in a real-world environment

Gastrointestinale Stromatumoren:eigene Beobachtungen an fünfzehn Fällen mit Literaturstudie zu Risikostratifizierung und aktuellen Therapieprinzipien

Die seltenen und teils noch unerforschten gastrointestinalen Stromatumoren (GIST) sind die häufigsten mesenchymalen Tumoren des GI-Traktes. Wir vergleichen unser Patientenkollektiv mit der Literatur. Risikostratifizierung und aktuelle Therapieoptionen werden anhand der Literatur beleuchtet. GIST treten meist bei etwa fünfzigjährigen, männlichen Patienten in Magen oder Dünndarm auf, metastasieren v.a. in Leber und Peritoneum und sind meist von spindelzelliger Histologie. GIST exprimieren fast immer CD 117 und Vimentin, seltener auch CD34, sm-Aktin und S100, Desmin normalerweise nicht. Vermutlich sind GIST immer potentiell maligne. Risikofaktoren für schlechte Prognose werden erläutert. In der Tumorgenese spielen mutierte Tyrosinkinasen wie CD 117 und PDGFRA eine Rolle. Therapiert wird hauptsächlich operativ oder chemotherapeutisch mit dem Tyrosinkinasehemmer Imatinib. Zur weiteren Therapieoptimierung sollte eine Behandlung von GIST nur im Rahmen von Studien erfolgen

Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: A European survey

Objective To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting. Methods A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology. Results Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I i

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures