A5090359959- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Neuroscience and Neural Engineering
- Receptor Mechanisms and Signaling
- ECG Monitoring and Analysis
- Tissue Engineering and Regenerative Medicine
- 3D Printing in Biomedical Research
- Cardiac pacing and defibrillation studies
- Electrochemical Analysis and Applications
- Click Chemistry and Applications
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Cardiovascular Function and Risk Factors
- Synthesis and Catalytic Reactions
- Viral Infections and Immunology Research
- Chemical Synthesis and Analysis
- Chemical Reactions and Isotopes
- Electrostatic Discharge in Electronics
- Fluorine in Organic Chemistry
- Cardiac Imaging and Diagnostics
- Chemotherapy-induced cardiotoxicity and mitigation
- Advanced Battery Technologies Research
- Neuroscience and Neuropharmacology Research
- Electrospun Nanofibers in Biomedical Applications
- Biosimilars and Bioanalytical Methods
Roche (Switzerland)
2016-2025
SRI International
2015
Three-dimensional in vitro cell systems are a promising alternative to animals study cardiac biology and disease. We have generated three-dimensional models of the human heart ("cardiac spheroids", CSs) by co-culturing primary or iPSC-derived cardiomyocytes, endothelial cells fibroblasts at ratios approximating those present vivo. The cellular organisation, extracellular matrix microvascular network mimic tissue. These spheroids been employed investigate dose-limiting cardiotoxicity common...
Ring the changes: Introduction of an oxetane ring results in remarkably improved physico- and biochemical properties underlying scaffold. The confers enhanced solubility, reduces metabolic degredation, lipophilicity, amphiphilicity, modulates basicity a nearby amine group.
Major depressive disorder (MDD) is a serious public health burden and leading cause of disability. Its pharmacotherapy currently limited to modulators monoamine neurotransmitters second-generation antipsychotics. Recently, glutamatergic approaches for the treatment MDD have increasingly received attention, preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors antidepressant-like properties. Basimglurant...
This white paper presents principles for validating proarrhythmia risk prediction models regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food Drug Administration–sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate progress in development new cardiac safety paradigm, Comprehensive Vitro Proarrhythmia Assay (CiPA). opinions regarding these reflect collective views...
Predicting how pharmaceuticals may affect heart rhythm is a crucial step in drug development and requires deep understanding of compound's action on ion channels. In vitro hERG channel current recordings are an important evaluating the proarrhythmic potential small molecules now routinely performed using automated high-throughput patch-clamp platforms. These machines can execute traditional voltage-clamp protocols aimed at specific gating processes, but array needed to fully characterize...
Abstract Automated patch clamp (APC) instruments enable efficient evaluation of electrophysiologic effects drugs on human cardiac currents in heterologous expression systems. Differences experimental protocols, instruments, and dissimilar site procedures affect the variability IC 50 values characterizing drug block potency. This impacts utility APC platforms for assessing a drug’s safety margin. We determined data from multiple sites that measured blocking potency 12 blinded (with different...
Ion channel behavior can depend strongly on temperature, with faster kinetics at physiological temperatures leading to considerable changes in currents relative room temperature. These temperature-dependent voltage-dependent ion (rates of opening, closing, inactivating, and recovery) are commonly represented Q10 coefficients or an Eyring relationship. In this article, we assess the validity these representations by characterizing multiple temperatures. We focus human Ether-à-go-go-Related...
hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and lack statistical quantification experimental variability. Since the new cardiac paradigm being discussed International Council for Harmonisation promotes tighter integration nonclinical clinical data risk assessment, more systematic approach estimate needed. A cross-industry study was...
Currentin vivoandin vitromodels fail to accurately recapitulate the human heart microenvironment for biomedical applications. This study explores use of cardiac spheroids (CSs) biofabricate advancedin heart. CSs were created from myocytes, fibroblasts and endothelial cells (ECs), mixed within optimal alginate/gelatin hydrogels then bioprinted on a microelectrode plate drug testing. Bioprinted maintained their structure viability at least 30 d after printing. Vascular growth factor (VEGF)...
3 Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications 4 in disease modelling, therapy, drug screening and personalised medicine. Computational 5 models can be used to interpret experimental findings iPSC-CMs, provide mechanistic insights, 6 translate these adult cardiomyocyte (CM) electrophysiology. However, different 7 lines display expression of ion channels, pumps receptors, show differences 8 In this exploratory study, we use a mathematical model based...
Abstract During drug development, candidate compounds are extensively tested for proar-rhythmic risk and in particular of Torsade de Pointes (TdP), as indicated by prolongation the QT interval. Drugs that inhibit rapid delayed rectifier K + current (I Kr ) can prolong action potential duration (APD) thereby interval, so routinely rejected. However, simultaneous inhibition L-type Ca 2+ CaL mitigate effect I inhibition, including both effects improve test specificity. Mathematical models (AP)...
<ns3:p>Background L-type calcium channels (LCCs) are macro-molecular complexes that conduct I<ns3:sub>CaL</ns3:sub> and involved in several critical functions cardiac, skeletal, neuronal, smooth muscle, endocrine cells. In common with other ionic they can be studied by isolating overexpressing a cell line, the current through them measured using patch-clamp experiments. However, LCC recordings known to contaminated attenuation of current, as ‘rundown’. Previous work has shown increased...
Ein Ring ändert alles: Das Einführen eines Oxetanrings führt zu erheblich verbesserten physiko- und biochemischen Eigenschaften des zugrunde liegenden Gerüsts. Der Oxetanring erhöht die Löslichkeit, verringert den metabolischen Abbau, Lipophilie Amphiphilie moduliert Basizität einer benachbarten Aminogruppe.
The Patchliner® temperature-controlled automated patch clamp system was evaluated for testing drug effects on potassium currents through human ether-à-go-go related gene (hERG) channels expressed in Chinese hamster ovary cells at 35-37°C. IC(50) values a set of reference drugs were compared with those obtained using the conventional voltage technique. results showed good correlation between data and electrophysiology. Based these results, Patchliner(®) represents an innovative...
Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment cancers and autoimmune diseases such asthma, rheumatoid arthritis, systemic lupus erythematous. We report structure-guided optimization pyridazine amide inhibitors. Early representatives this scaffold were highly potent selective but mutagenic in an Ames assay. An approach that led to successful identification nonmutagenic examples, well further compounds with reduced cardiovascular liabilities...
Reduction of the rapid delayed rectifier potassium current ( I Kr ) via drug binding to human Ether-à-go-go-Related Gene (hERG) channel is a well recognised mechanism that can contribute an increased risk Torsades de Pointes. Mathematical models have been created replicate effects blockers, such as reducing ionic conductance channel. Here, we study impact including state-dependent in mathematical model hERG when translating inhibition action potential changes. We show difference predictions...