A Critical Review of Adverse Effects to the Kidney: Mechanisms, Data Sources and In Silico Tools to Assist Prediction

Introduction: The kidney is a major target for toxicity elicited by pharmaceuticals and environmental pollutants. Standard testing which often does not investigate underlying mechanisms has proven not to be an adequate hazard assessment approach. As such, there is an opportunity for the application of computational approaches that utilise multi-scale data based on the Adverse Outcome Pathway (AOP) paradigm, coupled with an understanding of the chemistry underpinning the molecular initiating event (MIE) to provide a deep understanding of how structural fragments of molecules relate to specific mechanisms of nephrotoxicity. Aims covered: The aim of this investigation was to review the current scientific landscape related to computational methods, including mechanistic data, AOPs, publicly available knowledge bases and current in silico models, for the assessment of pharmaceuticals and other chemicals with regard to their potential to elicit nephrotoxicity. A list of over 250 nephrotoxicants enriched with, where possible, mechanistic and AOP-derived understanding was compiled. Expert opinion: Whilst little mechanistic evidence has been translated into AOPs, this review identified a number of data sources of in vitro, in vivo and human data that may assist in the development of in silico models which in turn may shed light on the inter-relationships between nephrotoxicity mechanisms

A critical review of adverse effects to the kidney: mechanisms, data sources and in silico tools to assist prediction

Introduction: The kidney is a major target for toxicity elicited by pharmaceuticals and environmental pollutants. Standard testing which often does not investigate underlying mechanisms has proven not to be an adequate hazard assessment approach. As such, there is an opportunity for the application of computational approaches that utilise multi-scale data based on the Adverse Outcome Pathway (AOP) paradigm, coupled with an understanding of the chemistry underpinning the molecular initiating event (MIE) to provide a deep understanding of how structural fragments of molecules relate to specific mechanisms of nephrotoxicity. The aim of this investigation was to review the current scientific landscape related to computational methods, including mechanistic data, AOPs, publicly available knowledge bases and current in silico models, for the assessment of pharmaceuticals and other chemicals with regard to their potential to elicit nephrotoxicity. A list of over 250 nephrotoxicants enriched with, where possible, mechanistic and AOP-derived understanding was compiled. Expert opinion: Whilst little mechanistic evidence has been translated into AOPs, this review identified a number of data sources of in vitro, in vivo and human data that may assist in the development of in silico models which in turn may shed light on the inter-relationships between nephrotoxicity mechanisms

Antioxidant and DPPH-Scavenging Activities of Compounds and Ethanolic Extract of the Leaf and Twigs of Caesalpinia bonduc L. Roxb.

Antioxidant effects of ethanolic extract of Caesalpinia bonduc and its isolated bioactive compounds were evaluated in vitro. The compounds included two new cassanediterpenes, 1α,7α-diacetoxy-5α,6β-dihydroxyl-cass-14(15)-epoxy-16,12-olide (1)and 12α-ethoxyl-1α,14β-diacetoxy-2α,5α-dihydroxyl cass-13(15)-en-16,12-olide(2); and others, bonducellin (3), 7,4’-dihydroxy-3,11-dehydrohomoisoflavanone (4), daucosterol (5), luteolin (6), quercetin-3-methyl ether (7) and kaempferol-3-O-α-L-rhamnopyranosyl-(1Ç2)-β-D-xylopyranoside (8). The antioxidant properties of the extract and compounds were assessed by the measurement of the total phenolic content, ascorbic acid content, total antioxidant capacity and 1-1-diphenyl-2-picryl hydrazyl (DPPH) and hydrogen peroxide radicals scavenging activities.Compounds 3, 6, 7 and ethanolic extract had DPPH scavenging activities with IC50 values of 186, 75, 17 and 102 μg/ml respectively when compared to vitamin C with 15 μg/ml. On the other hand, no significant results were obtained for hydrogen peroxide radical. In addition, compound 7 has the highest phenolic content of 0.81±0.01 mg/ml of gallic acid equivalent while compound 8 showed the highest total antioxidant capacity with 254.31±3.54 and 199.82±2.78 μg/ml gallic and ascorbic acid equivalent respectively. Compound 4 and ethanolic extract showed a high ascorbic acid content of 2.26±0.01 and 6.78±0.03 mg/ml respectively.The results obtained showed the antioxidant activity of the ethanolic extract of C. bonduc and deduced that this activity was mediated by its isolated bioactive compounds

Usability analysis of contending electronic health record systems

In this paper, we report measured usability of two leading EHR systems during procurement. A total of 18 users participated in paired-usability testing of three scenarios: ordering and managing medications by an outpatient physician, medicine administration by an inpatient nurse and scheduling of appointments by nursing staff. Data for audio, screen capture, satisfaction rating, task success and errors made was collected during testing. We found a clear difference between the systems for percentage of successfully completed tasks, two different satisfaction measures and perceived learnability when looking at the results over all scenarios. We conclude that usability should be evaluated during procurement and the difference in usability between systems could be revealed even with fewer measures than were used in our study. © 2019 American Psychological Association Inc. All rights reserved.Peer reviewe

Mind the developmental gap: Identifying adverse drug effects across childhood to evaluate biological mechanisms from growth and development

Adverse drug reactions are a leading cause of morbidity and mortality that costs billions of dollars for the healthcare system. In children, there is increased risk for adverse drug reactions with potentially lasting adverse effects into adulthood. The current pediatric drug safety landscape, including clinical trials, is limited as it rarely includes children and relies on extrapolation from adults. Children are not small adults but go through an evolutionarily conserved and physiologically dynamic process of growth and maturation. We hypothesize that adverse drug reactions manifest from the interaction between drug exposure and dynamic biological processes during child growth and development. While pediatric pharmacologists have studied and recognized this interaction, the evidence from these studies have focused on a few, well-known drug toxicities largely within animal models that have limited translation to children and their clinical care. Moreover, preclinical studies during drug development do not consider growth and maturation of children, which severely limits our knowledge of drug safety in this population. Post-marketing pediatric drug safety studies, on the other hand, leverage large amounts of observations to identify and characterize adverse drug events in the pediatric population after drugs enter the market. However, these observational studies have been limited to event surveillance and have not focused on evaluating why adverse drug events may manifest in children. We hypothesize that by developing statistical methodologies with prior knowledge of dynamic, shared information during development, we can improve the detection of adverse drug events in children. We further hypothesize that detecting adverse drug events in this way also improves the evaluation of dynamic biological and physiological processes during child growth and development. In chapter 1, we described the pediatric drug safety landscape, dynamic processes from pediatric developmental biology, and motivation for a large-scale and data-driven approach to study the interaction between drug treatment and child development. In chapter 2, using drug event reports collected by the Food and Drug Administration (FDA), we evaluated statistical models for identifying temporal trends of adverse effects across childhood. We found the generalized additive model (GAM), as compared to a popular disproportionality method, show improved detection performance especially of rare pediatric adverse drug events. In chapter 3, we applied covariate-adjusted drug-event GAMs in a systematic way to develop a resource of nearly half a million adverse drug event (ADE) risk estimates across child development stages. We showed that not only do significant ADEs through childhood recapitulate dynamic organ and system maturation, but we also provide granular, development-specific risk for known pediatric drug effects that were previously unknown. Importantly, this approach facilitated the evaluation of dynamic biological processes, such as drug-metabolizer gene expression levels across childhood, that we observed coincided with dynamic risk of adverse drug effects. In chapter 4, we performed several case studies showing population-level evidence for well-known pediatric adverse drug reactions using our generated resource. In addition, we developed an accessible web portal, the Pediatric Drug Safety portal (PDSportal), to retrieve from our resource the population-level evidence of user-specified adverse drug events in the pediatric population across child development stages. In conclusion, we summarize three key research directions in data-driven pediatric drug safety research: quantifying child vs. adult drug safety profiles, predicting pre-clinical drug toxicity across childhood, and detecting genetic susceptibility of pediatric adverse drug events. Our results demonstrate that developing pediatric drug safety methods directly for children using data-driven approaches improves both identification and evaluation of adverse drug events during the period of child growth and development

EPR Effect-Based Tumor Targeted Nanomedicine

I am honored to undertake the work for Guest Editor for this Special Issue of EPR Effect-Based Tumor Targeted Nanomedicine for the Journal of Personalized Medicine. It has already been 35 years since we published the concept of the EPR effect for the first time. The discovery of the new concept of EPR effect gave an impetus effect of growth momentum in nanomedicine, and numerous works are focused on tumor delivery, although the initial idea was based on vascular permeability in infection-induced inflamed tissue, where we discovered bradykinin in the key mediator of vascular permeability.I know, however, there are pros and cons to EPR effect. Cons stem either from a poor understanding of EPR effect, or somehow a biased view of the EPR effect, or from the tumor models being used, particularly in the clinical settings where vascular blood flow is so frequently obstructed. I hope scientists in the clinic, or basic researchers working on the tumor drug delivery, will join the forum of this Special Issue and express their data and opinions.The scope of this issue includes an in-depth understanding of the EPR effect, and issues associated with tumor microenvironment and also further exploitation of EPR effect in human cancer. In addition, new strategies for enhancement of the EPR effect using nanomedicine will be welcome, which is as important as the EPR effect itself. These papers cover not only cancer therapy, but also imaging techniques using nanofluorescent agents, including photodynamic therapy for inflammation, and boron neutron capture therapy