Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals

The physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite—nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology. The cardiac effect with regard to QT and RR interval lengths was assessed. The Emax model to describe the relationship between amitriptyline concentration and heart rate (RR) length was proposed. The developed PBPK model was used to mimic 29 clinical trials and 19 cases of amitriptyline intoxication. Three clinical trials and 18 cases were simulated with the use of PBPK-QSTS approach, confirming lack of cardiotoxic effect of amitriptyline in therapeutic doses and the increase in heart rate along with potential for arrhythmia development in case of amitriptyline overdose. The results of our study support the validity and feasibility of the PBPK-QSTS modeling development for personalized medicine.     

Flanker task with equiprobable congruent and incongruent conditions does not elicit the conflict N2

In many published studies, various modifications of the flanker task have been used. Regardless of the flanker task version, the conflict N2 component has been consistently reported and interpreted as evidence for the resolution of conflict introduced by incongruent flankers. However, ERP studies that used the most basic flanker task (i.e., a version with equiprobable congruent and incongruent conditions in which only congruency between the target and flankers is manipulated) have not provided compelling evidence for the conflict N2 component. We report the results of a large‐sample ERP study employing a basic flanker task that allowed us to revisit the mechanism underlying the resolution of conflict introduced by incongruent flankers. In the behavioral data, we observed the classic effect of congruency. In the ERP data, we found three conflict‐sensitive components: (a) an early frontal component, presumably corresponding to P2, (b) P300 for congruent trials, followed by (c) P300 for incongruent trials. We did not find evidence for the conflict N2 component. Based on a review of literature, we propose that the conflict N2 component observed in a basic flanker task might be a frontal aspect of the P300 component. Given previous attempts to attribute the functional role of the ERP components, the absence of the conflict N2 in the basic flanker task suggests that response inhibition may not be crucial for the resolution of conflict induced by incongruent flankers. Instead, the P2 component appears to indicate that selective attention might play an important role in resolving the flanker conflict.     

The role of the alternative pathway of complement activation in glomerular diseases

The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called ‘thick-over.’ A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.     

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd.     

Health literacy and public health: A systematic review and integration of definitions and models

Background  

Health literacy concerns the knowledge and competences of persons to meet the complex demands of health in modern society. Although its importance is increasingly recognised, there is no consensus about the definition of health literacy or about its conceptual dimensions, which limits the possibilities for measurement and comparison. The aim of the study is to review definitions and models on health literacy to develop an integrated definition and conceptual model capturing the most comprehensive evidence-based dimensions of health literacy.     

Cobalt-based Catalysts for Ammonia Decomposition

An effect of promoters such as calcium, aluminium, and potassium oxides and also addition of chromium and manganese on the structure of cobalt catalysts was examined. Studies of the catalytic ammonia decomposition over the cobalt catalysts are presented. The studies of the ammonia decomposition were carried out for various ammonia-hydrogen mixtures in which ammonia concentration varied in the range from 10% to 100%. Co(0) catalyst, promoted by oxides of aluminium, calcium, and potassium, showed the highest activity in the ammonia decomposition reaction. Contrary to expectations, it was found that chromium and manganese addition into the catalysts decreased their activity.     

Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization

BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina. METHODS: Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide. RESULTS: The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide. CONCLUSIONS: NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.