--- title: | Toxicology description: Toxicology | --- [![Cyprotex | The Leading ADME-Tox Specialist](https://news.cyprotex.com/hs-fs/hubfs/cyprotex%20logo.png?width=224&height=62&name=cyprotex%20logo.png "Cyprotex | The Leading ADME-Tox Specialist")](https://www.cyprotex.com/) # Science Pool ## [Improved Predictive Power in Cardiac Risk Assessment](https://news.cyprotex.com/sciencepool/improved-predictive-power-in-cardiotox) Posted by [Cyprotex](https://news.cyprotex.com/sciencepool/author/cyprotex) on Dec 21, 2023 3:09:38 PM Cardiotoxicity is one of the most reported adverse effects that leads to pre-clinical and clinical drug failure. To tackle this, the International Conference of Harmonization (ICH) S7B guideline in 2005, proposed a non-clinical assessment of new drug entities using *in vitro *electrophysiology studies (typically hERG ion channel) and *in vivo* telemetry in animal models. Although these are very sensitive approaches, they may have also led to unwarranted drug attrition of many potentially valuable therapeutics due to the low specificity nature of the assays. More recently, the Comprehensive *in vitro *Proarrhythmia Assay (CiPA) initiative was proposed by experts in the field and was established to move safety pharmacology towards *in silico *and *in vitro* approaches utilising new and emerging technologies such as stem-cell-derived cardiomyocytes. Building on this new safety paradigm, colleagues from Evotec and Cyprotex have worked collaboratively to develop a non-clinical model using cutting-edge techniques with improved predictive power to de-risk cardiotoxicity in early drug discovery. We have presented the output of this work in a research article titled **“*In-depth mechanistic analysis including high-throughput RNA sequencing in the prediction of functional and structural cardiotoxicants using hiPSC cardiomyocytes”**** *published in* *a recent edition of Expert Opinion on Drug Metabolism and Toxicology. In this article, we describe the use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an *in vitro* model system together with three high-throughput technologies incorporating structural assays (high-content imaging, HCI), functional assays (Ca2+ transience, CaT) and high-throughput RNA-sequencing (ScreenSeq) for the pre-clinical risk assessment of novel compounds. The transcriptional responses of hiPSC-CMs to 24 h treatment with 33 cardiotoxicants (12 structural cardiotoxicants, 14 functional cardiotoxicants, 7 structural/functional cardiotoxicants) and 9 non-cardiotoxicants of mixed therapeutic indications were investigated and compound-induced differential gene expression (DEG) was calculated in comparison with vehicle treated controls. Likewise, the hiPSC-CMs responses to six structural readouts (cell count, cellular ATP, mitochondrial mass, mitochondrial membrane potential, calcium content, DNA structure and nuclear size) and four functional readouts (amplitude, frequency, peak width and decay time) were analysed. In summary, hiPSC-CMs recapitulated expected structural and functional toxicity mechanisms, validating their use as *in vitro* model system to detect and characterize modes of toxicity. ScreenSeq identified several molecular mechanisms of toxicity such as alterations in cardiac pathways, genotoxicity, ER stress and mitochondrial toxicity. Together, HCI, CaT and ScreenSeq provided the best cardiotoxicity prediction metrics (10x Cmax: 100% specificity, 82% sensitivity, 86% accuracy; 25x Cmax: 89% specificity, 91% sensi-tivity, 90% accuracy). This study not only provides invaluable cardiotoxic mechanistic information of the drugs tested, but it also demonstrates the potential of this mechanism-driven risk assessment approach in predicting drug-induced cardiotoxicity in hiPSC-CMs. [Read the paper.](https://www.tandfonline.com/doi/full/10.1080/17425255.2023.2273378) Read more about our [Cardiotox Screen](https://www.cyprotex.com/toxicology/cardiotoxicity/cardiotoxscreen) assay consisting of both a functional assay (examining the mechanical function of the cardiomyocytes) and a structural assay (assessing morphological changes and loss of viability). In addition, discover more about our transcriptomics offerings [here](https://www.cyprotex.com/toxicology/customised-toxicology/transcriptomics-services). Find out more: [Contact Us](mailto:enquiries@cyprotex.com) 0 Comments [Click here to read/write comments](https://news.cyprotex.com/sciencepool/improved-predictive-power-in-cardiotox#comments-listing) Tags: [Toxicology](https://news.cyprotex.com/sciencepool/tag/toxicology), [Articles & Whitepapers](https://news.cyprotex.com/sciencepool/tag/articles-whitepapers), [Blog](https://news.cyprotex.com/sciencepool/tag/blog), [Toxicology & Safety](https://news.cyprotex.com/sciencepool/tag/toxicology-safety) ## [Understanding the Mechanism behind Pilocarpine Neurotoxicity](https://news.cyprotex.com/sciencepool/pilocarpine-mea-multiple-neuronal-cell-types-sps2018) Posted by [Evotec](https://news.cyprotex.com/sciencepool/author/evotec) on Feb 12, 2021 5:18:48 PM Pilocarpine is a muscarinic cholinergic agonist which is used as an epilepsy model in rats.  In this presentation, we evaluate: - the seizurogenic response of pilocarpine *in vitro* in different neuronal models including rat cortical neurons, rat hippocampal neurons and a human iPSC-derived co-culture model - the importance of maturation of the cells (DIV) - the use of MEA for the sensitive detection of firing, bursting and synchrony of the cells View the presentation to learn more! [LEARN MORE](https://news.cyprotex.com/hubfs/Sciencepool/Presentations/Cyprotex%20presentations/pilocarpine-mea-evaluation-multiple-neuronal-cell-types-sps2018.pdf)       0 Comments [Click here to read/write comments](https://news.cyprotex.com/sciencepool/pilocarpine-mea-multiple-neuronal-cell-types-sps2018#comments-listing) Tags: [Toxicology](https://news.cyprotex.com/sciencepool/tag/toxicology), [Presentations](https://news.cyprotex.com/sciencepool/tag/presentations) ## [Using In Vitro 3D Cell-Based Models to Detect Tissue Specific Toxicity](https://news.cyprotex.com/sciencepool/in-vitro-3d-toxicology-cell-models-dmg2017) Posted by [Evotec](https://news.cyprotex.com/sciencepool/author/evotec) on Feb 12, 2021 5:08:55 PM Human-derived 3D cell-based models are more representative of *in vivo* cellular physiology and have improved longevity *in vitro*.   In this presentation, we focus on: - causes of drug failure in drug development - the advances in high content screening - developments in 3D cell-based models including organ-specific cellular models - the prediction of tissue specific toxicities such as hepatotoxicity (DILI), cardiotoxicity, nephrotoxicity and neurotoxicity View the presentation to learn more! [LEARN MORE](https://news.cyprotex.com/hubfs/Sciencepool/Presentations/Cyprotex%20presentations/in-vitro-3d-toxicology-models-DMG2017.pdf)       0 Comments [Click here to read/write comments](https://news.cyprotex.com/sciencepool/in-vitro-3d-toxicology-cell-models-dmg2017#comments-listing) Tags: [Toxicology](https://news.cyprotex.com/sciencepool/tag/toxicology), [Presentations](https://news.cyprotex.com/sciencepool/tag/presentations) ## [Mitobiogenesis - A Key Mechanism in Drug-Induced Toxicity](https://news.cyprotex.com/sciencepool/high-throughput-hcs-mitobiogenesis-sot2019) Posted by [Evotec](https://news.cyprotex.com/sciencepool/author/evotec) on Feb 12, 2021 5:06:09 PM Mitobiogenesis (or mitochondrial biogenesis) is defined as the growth and division of pre-existing mitochondria. Drug-induced perturbations in this process can result in mitochondrial dysfunction or toxicity.  In this presentation, we focus on: - mechanisms involved in mitochondrial toxicity including drug-induced mitobiogenesis - the development of a high throughput high content imaging assay for detecting drug-induced effects on mitobiogenesis - validation of the assay using known drugs which inhibit mitochondrial DNA and protein synthesis (e.g., antibiotics, anti-viral and anticancer drugs) as well as some non-mitochondrial toxicants. View the presentation to learn more! [LEARN MORE](https://news.cyprotex.com/hubfs/Sciencepool/Presentations/Cyprotex%20presentations/high-throughput-HCS-mitobiogenesis-assay-sot2019.pdf)       0 Comments [Click here to read/write comments](https://news.cyprotex.com/sciencepool/high-throughput-hcs-mitobiogenesis-sot2019#comments-listing) Tags: [Toxicology](https://news.cyprotex.com/sciencepool/tag/toxicology), [Presentations](https://news.cyprotex.com/sciencepool/tag/presentations) ## [The Importance of 3D Neuronal Microtissues for Safety Testing](https://news.cyprotex.com/sciencepool/characterisation-3d-neuronal-microtissues-ivts2017) Posted by [Evotec](https://news.cyprotex.com/sciencepool/author/evotec) on Feb 12, 2021 5:03:16 PM The brain is a complex organ. Find out more about the use of *in vitro* 3D co-culture brain microtissues for predicting human CNS liability. In this presentation, we focus on: - a background to drug-induced brain neurotoxicity - the importance of astrocytes and their function - the use of brain 3D co-cultured microtissues - neurotransmitter pathway development over time - high content screening (HCS) of brain microtissues and validation data View the presentation to learn more! [LEARN MORE](https://news.cyprotex.com/hubfs/Sciencepool/Presentations/Cyprotex%20presentations/development-and-characterisation-3d-neuronal-microtissues-ivts2017.pdf)       0 Comments [Click here to read/write comments](https://news.cyprotex.com/sciencepool/characterisation-3d-neuronal-microtissues-ivts2017#comments-listing) Tags: [Toxicology](https://news.cyprotex.com/sciencepool/tag/toxicology), [Presentations](https://news.cyprotex.com/sciencepool/tag/presentations) ## [Detecting Cardiotoxicity of Chronically Exposed Drugs using MEA](https://news.cyprotex.com/sciencepool/cardiac-liability-prediction-chronic-exposure-ipsc-mea-sot2019) Posted by [Evotec](https://news.cyprotex.com/sciencepool/author/evotec) on Feb 12, 2021 4:03:33 PM Cardiotoxicity is a key cause of late stage attrition in drug development. iPSC-derived cardiomyocytes remain viable for more than 2 weeks on MEA plates. As MEA measures electrical activity without addition of any reagents, the cells can be exposed and monitored over extended time periods. In this presentation, we focus on: - a background to MEA - design of the assay for detecting cardiotoxicity following chronic exposure to drugs - case studies for cardiotoxic drugs with different mechanisms (hERG traffickers, multichannel blockers, specific ion channel effects) View the presentation to learn more! [LEARN MORE](https://news.cyprotex.com/hubfs/Sciencepool/Presentations/Cyprotex%20presentations/cardiac-safety-prediction-chronic-exposure-ipsc-mea-sot2019.pdf)       0 Comments [Click here to read/write comments](https://news.cyprotex.com/sciencepool/cardiac-liability-prediction-chronic-exposure-ipsc-mea-sot2019#comments-listing) Tags: [Toxicology](https://news.cyprotex.com/sciencepool/tag/toxicology), [Presentations](https://news.cyprotex.com/sciencepool/tag/presentations) [All posts](https://news.cyprotex.com/sciencepool/all)