Tag: M.W=200-350

Niu, Wanjie published the artcileInvestigating the interaction between nifedipine- and ritonavir-containing antiviral regimens: A physiologically based pharmacokinetic/pharmacodynamic analysis, Name: Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is nifedipine ritonavir antiviral; drug-drug interaction; nifedipine; pharmacodynamics; physiologically-based pharmacokinetic; ritonavir.

Aims : Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Such patients are often concomitantly treated with antiviral and antihypertensive agents, including ritonavir and nifedipine. Since ritonavir is a strong inhibitor of CYP3A and nifedipine is mainly metabolized via CYP3A, the combination of ritonavir and nifedipine can potentially cause drug-drug interactions. This study provides guidance on nifedipine treatment during and after coadministration with ritonavir-containing regimens, using a physiol. based pharmacokinetic/pharmacodynamic (PBPK/PD) anal. Methods : The PBPK/PD models for 3 formations of nifedipine were developed based on the Simcyp nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release and controlled-release formulations in patients. Various nifedipine regimens were investigated when coadministered with or without ritonavir. Results : PBPK/PD models for 3 formulations of nifedipine were successfully established. The predicted maximum concentration (Cmax), area under plasma concentration-time curve (AUC), maximum reduction in SBP and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. Conclusion : Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.

British Journal of Clinical Pharmacology published new progress about Antiviral agents. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Name: Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Chen, Xin published the artcileGCN-BMP: Investigating graph representation learning for DDI prediction task, Formula: C17H18N2O6, the main research area is GCN BMP graph convolutional network; DDI; Graph representation learning; Interpretability; Robustness; Scalability.

One drug’s pharmacol. activity may be changed unexpectedly, owing to the concurrent administration of another drug. It is likely to cause unexpected drug-drug interactions (DDIs). Several machine learning approaches have been proposed to predict the occurrence of DDIs. However, existing approaches are almost dependent heavily on various drug-related features, which may incur noisy inductive bias. To alleviate this problem, we investigate the utilization of the end-to-end graph representation learning for the DDI prediction task. We establish a novel DDI prediction method named GCN-BMP (Graph Convolutional Network with Bond-aware Message Propagation) to conduct an accurate prediction for DDIs. Our experiments on two real-world datasets demonstrate that GCN-BMP can achieve higher performance compared to various baseline approaches. Moreover, in the light of the self-contained attention mechanism in our GCN-BMP, we could find the most vital local atoms that conform to domain knowledge with certain interpretability.

Methods (Amsterdam, Netherlands) published new progress about Drug interactions. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Jiang, Lin published the artcileCRISPR activation of endogenous genes reprograms fibroblasts into cardiovascular progenitor cells for myocardial infarction therapy, Formula: C17H18N2O6, the main research area is CRISPR fibroblast cardiovascular progenitor cell myocardial infarction therapy; CRISPR; cardiovascular progenitor cells; cell reprogramming; heart regeneration; myocardial infarction.

Fibroblasts can be reprogrammed into cardiovascular progenitor cells (CPCs) using transgenic approaches, although the underlying mechanism remains unclear. We determined whether activation of endogenous genes such as Gata4, Nkx2.5, and Tbx5 can rapidly establish autoregulatory loops and initiate CPC generation in adult extracardiac fibroblasts using a CRISPR activation system. The induced fibroblasts (>80%) showed phenotypic changes as indicated by an Nkx2.5 cardiac enhancer reporter. The progenitor characteristics were confirmed by colony formation and expression of cardiovascular genes. Cardiac sphere induction segregated the early and late reprogrammed cells that can generate functional cardiomyocytes and vascular cells in vitro. Therefore, they were termed CRISPR-induced CPCs (ciCPCs). Transcriptomic anal. showed that cell cycle and heart development pathways were important to accelerate CPC formation during the early reprogramming stage. The CRISPR system opened the silenced chromatin locus, thereby allowing transcriptional factors to access their own promoters and eventually forming a pos. feedback loop. The regenerative potential of ciCPCs was assessed after implantation in mouse myocardial infarction models. The engrafted ciCPCs differentiated into cardiovascular cells in vivo but also significantly improved contractile function and scar formation. In conclusion, multiplex gene activation was sufficient to drive CPC reprogramming, providing a new cell source for regenerative therapeutics.

Molecular Therapy published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Jaeger, Karoline Horgmo published the artcileImproved computational identification of drug response using optical measurements of human stem cell derived cardiomyocytes in microphysiological systems, Product Details of C17H18N2O6, the main research area is microphysiol system human stem cell optical measurement; cardiac action potential model; cardiac ion channel blockade; computational identification of drug response; computational inversion; computational maturation; human induced pluripotent stem cell derived cardiomyocytes; voltage sensitive dye.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells’ electrophysiol. properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodol. to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and Ca2+ transients made in stem cell derived cardiac microtissues. This methodol. quantifies ion channel changes through the inversion of data into a math. model, and maps this response to an adult phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation. Here, we utilize an updated action potential model to represent both hiPSC-CMs and adult cardiomyocytes, apply an IC50-based model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for anal. of dose escalation measurements using five drugs with known effects. The improved methodol. can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodol. is a step towards employing computational procedures to elucidate drug effects in adult cardiomyocytes for new drugs using stem cell-derived exptl. tissues.

Frontiers in Pharmacology published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Product Details of C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Zeng, Haoyu published the artcileResolving the reversed rate effect of calcium channel blockers on human-induced pluripotent stem cell-derived cardiomyocytes and the impact on in vitro cardiac safety evaluation, Synthetic Route of 21829-25-4, the main research area is calcium channel blocker pluripotent stem cell cardiomyocyte heart safety.

Calcium channel blockers (CCBs), such as diltiazem, nifedipine, and verapamil, cause tachycardia effects on several com. available human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), when tested in culture media provided by suppliers, rather than bradycardia effects, as seen in vivo. We found that in test conditions where Na+ current of hiPSC-CMs was reduced to certain threshold by either specific Na+ channel blocker tetrodotoxin (TTX), or by voltage-dependent inactivation using elevated extracellular potassium concentrations, CCBs produced bradycardia effects on hiPSC-CMs. However, elevated extracellular potassium concentrations or the presence of TTX did not change other pharmacol. responses of hiPSC-CMs, including CCBs’ effects on contraction intensity and duration; beating rate change by calcium channel opener FPL64176, HCN blocker ivabradine, and β-adrenergic agonist isoproterenol; and action potential duration prolongation by hERG channel blocker dofetilide. We concluded that action potentials of hiPSC-CMs, with regards to the CCB phenotype, were Na+ current driven. When Na+ channel availability was reduced to a critical level, their action potentials became Ca2+ current driven, and their responses to CCBs correlated well to those seen in vivo. Importantly, the corrected bradycardia effect of calcium channel block with our defined conditions will provide more reliable results in cardiac safety readouts of test compounds that integrate multiple effects including calcium channel inhibition.

Toxicological Sciences published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Synthetic Route of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Pfeiffer-Kaushik, Emily R. published the artcileElectrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms, Quality Control of 21829-25-4, the main research area is arrhythmia cardiomyocyte nifedipine mexiletine voltage sensitive optical sensor; Action potential; Cardiac electrophysiology; Comprehensive in vitro proarrhythmia assay (CiPA); ICH S7B; Methods; Safety pharmacology; Stem cell-derived cardiomyocyte; Torsades de pointes (TdP) arrhythmia; Voltage-sensitive optical sensors; hERG.

Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for preclin. cardiac electrophysiol. assays. Three com. and one academic laboratory completed a limited study of the effects of 8 blinded compounds on the electrophysiol. of 2 com. lines of human induced pluripotent stem-cell derived cardiomyocytes (hSC-CMs). Acquisition technologies included CMOS camera and photometry; fluorescent voltage sensors included di-4-ANEPPS, FluoVolt and genetically encoded QuasAr2. The exptl. protocol was standardized with respect to cell lines, plating and maintenance media, blinded compounds, and action potential parameters measured. Serum-free media was used to study the action of drugs, but the exact composition and the protocols for cell preparation and drug additions varied among sites. Baseline AP waveforms differed across platforms and between cell types. Despite these differences, the relative responses to four selective ion channel blockers (E-4031, nifedipine, mexiletine, and JNJ 303 blocking IKr, ICaL, INa, and IKs, resp.) were similar across all platforms and cell lines although the absolute changes differed. Similarly, four mixed ion channel blockers (flecainide, moxifloxacin, quinidine, and ranolazine) had comparable effects in all platforms. Differences in repolarization time course and response to drugs could be attributed to cell type and exptl. method differences such as composition of the assay media, stimulated vs. spontaneous activity, and single vs. cumulative compound addition In conclusion, VSOs represent a powerful and appropriate method to assess the electrophysiol. effects of drugs on iPSC-CMs for the evaluation of proarrhythmic risk. Protocol considerations and recommendations are provided toward standardizing conditions to reduce variability of baseline AP waveform characteristics and drug responses.

Journal of Pharmacological and Toxicological Methods published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Quality Control of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Goldfracht, Idit published the artcileGenerating ring-shaped engineered heart tissues from ventricular and atrial human pluripotent stem cell-derived cardiomyocytes, Quality Control of 21829-25-4, the main research area is pluripotent stem cell cardiomyocyte heart tissue engineering ventricle atria.

The functions of the heart are achieved through coordination of different cardiac cell subtypes (e.g., ventricular, atrial, conduction-tissue cardiomyocytes). Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer unique opportunities for cardiac research. Traditional studies using these cells focused on single-cells and utilized mixed cell populations. Our goal was to develop clin.-relevant engineered heart tissues (EHTs) comprised of chamber-specific hPSC-CMs. Here we show that such EHTs can be generated by directing hPSCs to differentiate into ventricular or atrial cardiomyocytes, and then embedding these cardiomyocytes in a collagen-hydrogel to create chamber-specific, ring-shaped, EHTs. The chamber-specific EHTs display distinct atrial vs. ventricular phenotypes as revealed by immunostaining, gene-expression, optical assessment of action-potentials and conduction velocity, pharmacol., and mech. force measurements. We also establish an atrial EHT-based arrhythmia model and confirm its usefulness by applying relevant pharmacol. interventions. Thus, our chamber-specific EHT models can be used for cardiac disease modeling, pathophysiol. studies and drug testing.

Nature Communications published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Quality Control of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Chang, Yun published the artcilehERG-deficient human embryonic stem cell-derived cardiomyocytes for modelling QT prolongation, Synthetic Route of 21829-25-4, the main research area is cardiomyocyte embryonic stem cell hERG QT prolongation; CRISPR/Cas9; Human ether-a-go-go-related gene; KCNH2; QT prolongation; hESCs.

Long-QT syndrome type 2 (LQT2) is a common malignant hereditary arrhythmia. Due to the lack of suitable animal and human models, the pathogenesis of LQT2 caused by human ether-a-go-go-related gene (hERG) deficiency is still unclear. In this study, we generated an hERG-deficient human cardiomyocyte (CM) model that simulates ′human homozygous hERG mutations′ to explore the underlying impact of hERG dysfunction and the genotype-phenotype relationship of hERG deficiency. The KCNH2 was knocked out in the human embryonic stem cell (hESC) H9 line using the CRISPR/Cas9 system. Using a chem. defined differentiation protocol, we obtained and verified hERG-deficient CMs. Subsequently, high-throughput microelectrode array (MEA) assays and drug interventions were performed to characterize the electrophysiol. signatures of hERG-deficient cell lines. Our results showed that KCNH2 knockout did not affect the pluripotency or differentiation efficiency of H9 cells. Using high-throughput MEA assays, we found that the elec. field potential duration and action potential duration of hERG-deficient CMs were significantly longer than those of normal CMs. The hERG-deficient lines also exhibited irregular rhythm and some early afterdepolarisations. Moreover, we used the hERG-deficient human CM model to evaluate the potency of agents (nifedipine and magnesium chloride) that may ameliorate the phenotype. We established an hERG-deficient human CM model that exhibited QT prolongation, irregular rhythm and sensitivity to other ion channel blockers.

Stem Cell Research & Therapy published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Synthetic Route of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Kernik, Divya C. published the artcileA computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources, Application In Synthesis of 21829-25-4, the main research area is Pluripotent stem cell cardiomyocyte electrophysiol; computer modelling; iPSC-CMs; variability.

A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in exptl. data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole-cell model of iPSC-CMs composed of simple model components comprising ion channel models with single exponential voltage-dependent gating variable rate constants, parameterized to fit exptl. iPSC-CM data for all major ionic currents. By optimizing ionic current model parameters to multiple exptl. datasets, we incorporate exptl.-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs. This approach links mol. mechanisms to known cellular-level iPSC-CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyze the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacol. interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

Journal of Physiology (Oxford, United Kingdom) published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Application In Synthesis of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Hayes, Heather B. published the artcileNovel method for action potential measurements from intact cardiac monolayers with multiwell microelectrode array technology, COA of Formula: C17H18N2O6, the main research area is cardiac monolayer action potential multiwell microelectrode array.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biol. and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphol. of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphol. changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphol. from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.

Scientific Reports published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, COA of Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem