Effects Of Drugs In Humans Research Articles

The Role of Quality Assurance in Clinical Trials: Safeguarding Data Integrity and Compliance.

Clinical trials, which investigate the effects of drugs in humans, aim to determine safety and efficacy while identifying adverse reactions. Data consistency and subject safety are crucial factors that determine the quality of clinical trials, necessitating overall quality management. There is a growing emphasis on implementing quality systems during the planning stages of clinical trials. Regulatory frameworks have evolved to ensure patient protection and data reliability, underscoring the need for systematic quality management in health research. A clinical trial quality management plan (CTQMP) is essential to describe the tools and methods used to ensure study quality. Globalization has led to an increase in conducting clinical trials in developing nations, presenting challenges due to procedural and ethical disparities. To manage these complexities, outsourcing trial management has become common. Adherence to good clinical practice (GCP) principles, as defined by the International Conference on Harmonization (ICH), is critical for safeguarding participant rights and ensuring credible data. Quality by design (QbD) and quality risk management are now central to clinical trial management, as advocated by the FDA. Technological advancements and robust protocols further enhance trial processes. Effective QA activities, including monitoring and data management, are vital for maintaining compliance, participant safety, and data integrity, highlighting the indispensable role of QA in clinical trial success.

Efficacy of Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles in Ameliorating Cisplatin Nephrotoxicity, as Modeled Using Three-Dimensional, Gravity-Driven, Two-Layer Tubule-on-a-Chip (3D-MOTIVE Chip).

Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to have a therapeutic effect on nephrotoxicity. As animal models require significant time and resources to evaluate drug effects, there is a need for a new experimental technique that can accurately predict drug effects in humans. We evaluated the therapeutic effect of MSC-derived EVs in cisplatin nephrotoxicity using a three-dimensional, gravity-driven, two-layer tubule-on-a-chip (3D-MOTIVE chip). In the 3D-MOTIVE chip, 10 μM cisplatin decreased the number of attached cells compared to the vehicle. Conversely, annexin V and reactive oxygen species (ROS) were increased. Cell viability was increased 2.8-fold and 2.5-fold after treatment with EVs at 4 and 8 µg/mL, respectively, compared to the cisplatin-induced nephrotoxicity group. Cell attachment was increased 2.25-fold by treatment with 4 µg/mL EVs and 2.02-fold by 8 µg/mL EVs. Annexin V and ROS levels were decreased compared to those in the cisplatin-induced nephrotoxicity group. There were no significant differences in annexin V and ROS levels according to EV concentration. In sum, we created a cisplatin-induced nephrotoxicity model on a 3D-MOTIVE chip and found that MSC-derived EVs could restore cell viability. Thus, MSC-derived EVs may have the potential to ameliorate cisplatin-induced nephrotoxicity.

Acute and Chronic Pulmonary Side Effects of Drugs in Humans

Complications caused by the inhalation of microbial agents or their products, as well as inhaled toxic particles present in the space air of the surrounding environment lead to acute or chronic inflammation in the lung and other deep respiratory tissues. This can be the source of metastatic spread of inflammation in other organs. It becomes more dangerous, especially when these agents can disrupt the common regulatory defense system in the lungs. In the state of balance and health of the environment and avoiding exposure to hazardous inhalation agents, the respiratory system has the power to regulate inflammation.

Microfluidic nanodevices for drug sensing and screening applications

The outbreak of pandemics (e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 in 2019), influenza A viruses (H1N1 in 2009), etc.), and worldwide spike in the aging population have created unprecedented urgency for developing new drugs to improve disease treatment. As a result, extensive efforts have been made to design novel techniques for efficient drug monitoring and screening, which form the backbone of drug development. Compared to traditional techniques, microfluidics-based platforms have emerged as promising alternatives for high-throughput drug screening due to their inherent miniaturization characteristics, low sample consumption, integration, and compatibility with diverse analytical strategies. Moreover, the microfluidic-based models utilizing human cells to produce in-vitro biomimetics of the human body pave new ways to predict more accurate drug effects in humans. This review provides a comprehensive summary of different microfluidics-based drug sensing and screening strategies and briefly discusses their advantages. Most importantly, an in-depth outlook of the commonly used detection techniques integrated with microfluidic chips for highly sensitive drug screening is provided. Then, the influence of critical parameters such as sensing materials and microfluidic platform geometries on screening performance is summarized. This review also outlines the recent applications of microfluidic approaches for screening therapeutic and illicit drugs. Moreover, the current challenges and the future perspective of this research field is elaborately highlighted, which we believe will contribute immensely towards significant achievements in all aspects of drug development.

Comparison of bromazepam and ibuprofen influence on tooth pulp-evoked potentials in humans

Introduction/Objective. Somatosensory evoked potentials are a neurophysiological tool for testing the effects of drugs in humans and animals. The aim of this study was to estimate the way that bromazepam and ibuprofen had on tooth pulp-evoked potentials (TPEPs) after non-painful stimuli, as well as to detect possible differences in this activity. Methods. Sixty young healthy subjects were included in the study. They were arranged into three groups: ibuprofen, bromazepam, and placebo. To record TPEPs response, dental pulp were electrically stimulated through intact enamel with non-painful stimuli. For stimulation and registration we used Xltek Protektor 32 system, software EPWorks, version 5.0 (Natus Medical Incorporated, Oakville, ON, Canada). The experiment consisted of two testing sessions. Five recordings were performed in each session. The first test session was before, and the second was 45 minutes after administration of a single dose of the ibuprofen (400 mg), bromazepam (1.5 mg) or placebo. Results. The results of the present study exhibit that both ibuprofen and bromazepam significantly increased all the latencies; ibuprofen decreased amplitudes of all the waves except the first one (p < 0.05), and bromazepam decreased amplitudes of all the waves except the first one (p < 0.05); placebo did not modified TPEPs waves (p > 0.05). Additionally, there were no significant differences in influence on TPEPs between bromazepam and ibuprofen (p > 0.05). Conclusion. Our study showed that both bromazepam and ibuprofen had the same influence on TPEPs after non-painful stimuli. That indicates that anxiolytic dose of bromazepam affects neurotransmission in the same manner as non-opioid analgesics ibuprofen.

Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Three-dimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-a-go-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca2+ levels or myocardial Ca2+ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 μM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.

Imaging Fast-Acting Drug Effects in Humans Using 1H-MRS.

Proton magnetic spectroscopy (1H-MRS) is a noninvasive imaging technique that allows for the quantification of neurometabolic compounds at millimolar concentrations in the living human brain. This technique has been most often used to assess long-term changes in human brain metabolism in psychiatric disorders, pharmacological treatment, chronic drug use, and alcohol dependence. In contrast, the capacity of 1H-MRS to evaluate the biochemical changes in the minutes to hours following drug consumption, which contribute to fast-acting drug-induced changes in perception, mood, cognition, and behavior, is largely unexplored. This Viewpoint highlights the utility of 1H-MRS imaging for revealing neural mechanisms of rapid drug action in the human brain, with implications for phasic, in vivo changes in biosynthetic and catabolic pathways after drug exposure. Drawing from examples of psychostimulant drug effects, neuromodulatory input and drug-induced mood, we present strategies to optimize 1H-MRS for noninvasively imaging fast-acting drug effects and other rapid phenomena within the living human brain. These approaches could provide powerful tools for both basic research and drug development.

Assessment of Drug-Induced Toxicity Biomarkers in the Brain Microphysiological System (MPS) Using Targeted and Untargeted Molecular Profiling.

Early assessment of adverse drug effects in humans is critical to avoid long-lasting harm. However, current approaches for early detection of adverse effects still lack predictive and organ-specific biomarkers to evaluate undesired responses in humans. Microphysiological systems (MPSs) are in vitro representations of human tissues and provide organ-specific translational insights for physiological processes. In this study, a brain MPS was utilized to assess molecular signatures of neurotoxic and non-neurotoxic compounds using targeted and untargeted molecular approaches. The brain MPS comprising of human embryonic stem (ES) cell-derived neural progenitor cells seeded on three-dimensional (3D), chemically defined, polyethylene glycol hydrogels was treated with the neurotoxic drug, bortezomib and the non-neurotoxic drug, tamoxifen over 14-days. Possible toxic effects were monitored with human N-acetylaspartic acid (NAA) kinetics, which correlates the neuronal function/health and DJ-1/PARK7, an oxidative stress biomarker. Changes in NAA levels were observed as early as 2-days post-bortezomib treatment, while onset detection of oxidative stress (DJ-1) was delayed until 4-days post-treatment. Separately, the untargeted extracellular metabolomics approach revealed distinct fingerprints 2-days post-bortezomib treatment as perturbations in cysteine and glycerophospholipid metabolic pathways. These results suggest accumulation of reactive oxygen species associated with oxidative stress, and disruption of membrane structure and integrity. The NAA response was strongly correlated with changes in a subset of the detected metabolites at the same time point 2-days post-treatment. Moreover, these metabolite changes correlated strongly with DJ-1 levels measured at the later time point (4-days post-treatment). This suggests that early cellular metabolic dysfunction leads to later DJ-1 leakage and cell death, and that early measurement of this subset of metabolites could predict the later occurrence of cell death. While the approach demonstrated here provides an individual case study for proof of concept, we suggest that this approach can be extended for preclinical toxicity screening and biomarker discovery studies.

Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

ABSTRACTBackground: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.

Semi-implicit Non-conforming Finite-Element Schemes for Cardiac Electrophysiology: A Framework for Mesh-Coarsening Heart Simulations.

The field of computational cardiology has steadily progressed toward reliable and accurate simulations of the heart, showing great potential in clinical applications such as the optimization of cardiac interventions and the study of pro-arrhythmic effects of drugs in humans, among others. However, the computational effort demanded by in-silico studies of the heart remains challenging, highlighting the need of novel numerical methods that can improve the efficiency of simulations while targeting an acceptable accuracy. In this work, we propose a semi-implicit non-conforming finite-element scheme (SINCFES) suitable for cardiac electrophysiology simulations. The accuracy and efficiency of the proposed scheme are assessed by means of numerical simulations of the electrical excitation and propagation in regular and biventricular geometries. We show that the SINCFES allows for coarse-mesh simulations that reduce the computation time when compared to fine-mesh models while delivering wavefront shapes and conduction velocities that are more accurate than those predicted by traditional finite-element formulations based on the same coarse mesh, thus improving the accuracy-efficiency trade-off of cardiac simulations.

Systematic review of drug effects in humans and models with surfactant-processing disease.

Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky-Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations.We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent.This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients.

Drug Discrimination: Historical Origins, Important Concepts, and Principles.

Research on the stimulus properties of drugs began with studies on state dependent learning during the first half of the twentieth century. From that research, an entirely new approach evolved called drug discrimination. Animals (including humans) could discriminate the presence or absence of a drug; once learned, the drug could serve as a discriminative stimulus, signaling the availability or nonavailability of reinforcement. Early drug discrimination research involved the use of a T-maze task, which evolved in the 1970s into a two-lever operant drug discrimination task that is still used today. A number of important concepts and principles of drug discrimination are discussed. (1) The discriminative stimulus properties of drugs are believed in large part to reflect the subjective effects of drugs. While it has been impossible to directly measure subjective effects in nonhuman animals, drug discrimination studies in human subjects have generally supported the belief that discriminative stimulus properties of drugs in nonhuman animals correlate highly with subjective effects of drugs in humans. In addition to the ability of the drug discrimination procedure to measure the subjective effects of drugs, it has a number of other strengths that help make it a valuable preclinical assay. (2) Drug discrimination can be used for classification of drugs based on shared discriminative stimulus properties. (3) The phenomena of tolerance and cross-tolerance can be studied with drug discrimination. (4) Discriminative stimulus properties of drugs typically have been found to be stereospecific, if a drug is comprised of enantiomers. (5) Discriminative stimulus properties of drugs reflect specific CNS activity at neurotransmitter receptors. (6) Both human and nonhuman subjects display individual differences in their sensitivity to discriminative stimuli and drugs. (7) The drug discrimination procedure has been used extensively as a preclinical assay in drug development. This chapter is the first in the volume The Behavioural Neuroscience of Drug Discrimination, which includes chapters concerning the discriminative stimulus properties of various classes of psychoactive drugs as well as sections on the applications and approaches for using this procedure.

Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges.

Traditional cell culture and animal models utilized for preclinical drug screening have led to high attrition rates of drug candidates in clinical trials due to their low predictive power for human response. Alternative models using human cells to build in vitro biomimetics of the human body with physiologically relevant organ-organ interactions hold great potential to act as "human surrogates" and provide more accurate prediction of drug effects in humans. This review is a comprehensive investigation into the development of tissue-engineered human cell-based microscale multiorgan models, or multiorgan microphysiological systems for drug testing. The evolution from traditional models to macro- and microscale multiorgan systems is discussed in regards to the rationale for recent global efforts in multiorgan microphysiological systems. Current advances in integrating cell culture and on-chip analytical technologies, as well as proof-of-concept applications for these multiorgan microsystems are discussed. Major challenges for the field, such as reproducibility and physiological relevance, are discussed with comparisons of the strengths and weaknesses of various systems to solve these challenges. Conclusions focus on the current development stage of multiorgan microphysiological systems and new trends in the field.

The effects of human drugs in Corbicula fluminea. Assessment of neurotoxicity, inflammation, gametogenic activity, and energy status

The constant release of pharmaceuticals products to aquatic environment even at low concentrations (ng L−1 to µg L−1) could lead to unknown chronic effects to non-target organisms. The aim of this study was to evaluate neurotoxic responses, inflammation, gametogenic activity and energy status on the fresh water clam C. fluminea after exposure to different concentrations of caffeine (CAF), ibuprofen (IBU), carbamazepine (CBZ), novobiocin (NOV) and tamoxifen (TMX) for 21 days under laboratory conditions. During the assay, water was spiked every two days with CAF (0; 0.1; 5; 15; 50µgL−1), IBU (0; 0.1; 5; 10; 50µgL−1), CBZ, NOV, and TMX (0.1, 1, 10, 50µgL−1). After the exposure period, dopamine levels (DOP), monoamine oxidase activity (MAO), arachidonic acid cyclooxygenase activity (COX), vitellogenin-like proteins (VTG), mitochondrial electron transport (MET), total lipids (TLP), and energy expenditure (MET/TLP) were determined in gonad tissues, and acetyl cholinesterase activity (AChE) was determined in digestive gland tissues. Results showed a concentration-dependence response on biomarkers tested, except for MAO. Environmental concentrations of pharmaceuticals induced significant changes (p < 0.05) in the neurotoxic responses analyzed (CAF, CBZ and NOV increased DOP levels and CBZ inhibited AChE activity), inflammation (CAF induced COX), and energy status (MET and TLP increased after exposure to CBZ, NOV and TMX). Responses of clams were related to the mechanism of action (MoA) of pharmaceuticals. Biomarkers applied and the model organism C. fluminea constituted a suitable tool for environmental risk assessment of pharmaceutical in aquatic environment.

Characterizing QT interval prolongation in early clinical development: a case study with methadone.

Recently, we have shown how pharmacokinetic–pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug‐specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of ≥5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug‐specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical.

Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721).

Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans.

Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the Salvia divinorum plant, which has been used for hallucinogenic effects. Previous research on salvinorin A pharmacokinetics likely underestimated plasma levels typically resulting from the doses administered due to inefficient vaporization and not collecting samples during peak drug effects. Six healthy adults inhaled a single high dose of vaporized salvinorin A (n = 4, 21 mcg/kg; n = 2, 18 mcg/kg). Participant- and monitor-rated effects were assessed every 2 min for 60 min post-inhalation. Blood samples were collected at 13 time points up to 90 min post-inhalation. Drug levels peaked at 2 min and then rapidly decreased. Drug levels were significantly, positively correlated with participant and monitor drug effect ratings. Significant elevations in prolactin were observed beginning 5 min post-inhalation and peaking at 15 min post-inhalation. Cortisol showed inconsistent increases across participants. Hormonal responses were not well correlated with drug levels. This is the first study to demonstrate a direct relationship between changes in plasma levels of salvinorin A and drug effects in humans. The results confirm the efficacy of an inhalation technique for salvinorin A.

Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs.

Drug-discrimination procedures empirically evaluate the control that internal drug states have over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs in vivo. As a result, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This chapter provides a basic overview of human drug-discrimination procedures and reviews the extant literature concerning the use of these procedures to elucidate the underlying neuropharmacological mechanisms of commonly abused illicit drugs (i.e., stimulants, opioids, and cannabis) in humans. This chapter is not intended to review every available study that used drug-discrimination procedures in humans. Instead, when possible, exemplary studies that used a stimulant, opioid, or Δ9-tetrahydrocannabinol (the primary psychoactive constituent of cannabis) to assess the discriminative-stimulus effects of drugs in humans are reviewed for illustrative purposes. We conclude by commenting on the current state and future of human drug-discrimination research.

Large animal models of atherosclerosis--new tools for persistent problems in cardiovascular medicine.

Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk stratification and monitoring of drug effects in humans. Efficient large animal models of atherosclerosis may help tackle these problems. Recent years have seen tremendous advances in gene-editing tools for large animals. This has made it possible to create gene-modified minipigs that develop atherosclerosis with many similarities to humans in terms of predilection for lesion sites and histopathology. Together with existing porcine models of atherosclerosis that are based on spontaneous mutations or severe diabetes, such models open new avenues for translational research in atherosclerosis. In this review, we discuss the merits of different animal models of atherosclerosis and give examples of important research problems where porcine models could prove pivotal for progress.

Morphological and functional characterization of human induced pluripotent stem cell-derived neurons (iCell Neurons) in defined culture systems.

Pre-clinical testing of drug candidates in animal models is expensive, time-consuming, and often fails to predict drug effects in humans. Industry and academia alike are working to build human-based in vitro test beds and advanced high throughput screening systems to improve the translation of preclinical results to human drug trials. Human neurons derived from induced pluripotent stems cells (hiPSCs) are readily available for use within these test-beds and high throughput screens, but there remains a need to robustly evaluate cellular behavior prior to their incorporation in such systems. This study reports on the characterization of one source of commercially available hiPSC-derived neurons, iCell(®) Neurons, for their long-term viability and functional performance to assess their suitability for integration within advanced in vitro platforms. The purity, morphology, survival, identity, and functional maturation of the cells utilizing different culture substrates and medium combinations were evaluated over 28 days in vitro (DIV). Patch-clamp electrophysiological data demonstrated increased capacity for repetitive firing of action potentials across all culture conditions. Significant differences in cellular maturity, morphology, and functional performance were observed in the different conditions, highlighting the importance of evaluating different surface types and growth medium compositions for application in specific in vitro protocols.