scholarly journals Comparison of Electrocardiographic Biomarkers for Differentiating Drug‐Induced Single vs. Multiple Cardiac Ion Channel Block

2019 ◽  
Vol 12 (3) ◽  
pp. 257-266 ◽  
Author(s):  
Marina Brockway ◽  
Jay W. Mason ◽  
Brian P. Brockway
Keyword(s):  
Ion Channel ◽  
Channel Block ◽  
Drug Induced

scholarly journals Comparison of Two Highly Automated ECG Algorithms for Detection of Drug-Induced Cardiac Ion Channel Block

2017 ◽  
Vol 104 (2) ◽  
pp. 356-363 ◽  
Author(s):  
Marina Brockway ◽  
Anthony A. Fossa ◽  
Jay W. Mason
Keyword(s):  
Ion Channel ◽  
Channel Block ◽  
Drug Induced

scholarly journals Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the Ci PA Phase I ECG Biomarker Validation Study

2019 ◽  
Vol 105 (4) ◽  
pp. 943-953 ◽  
Author(s):  
Jose Vicente ◽  
Robbert Zusterzeel ◽  
Lars Johannesen ◽  
Roberto Ochoa‐Jimenez ◽  
Jay W. Mason ◽  
...  
Keyword(s):  
Phase I ◽  
Ion Channel ◽  
Study Design ◽  
Validation Study ◽  
Randomized Study ◽  
Channel Block ◽  
Biomarker Validation

scholarly journals Kv1.4 channel block by quinidine: evidence for a drug‐induced allosteric effect

2003 ◽  
Vol 546 (2) ◽  
pp. 387-401 ◽  
Author(s):  
Shimin Wang ◽  
Michael J. Morales ◽  
Yu‐Jie Qu ◽  
Glenna C. L. Bett ◽  
Harold C. Strauss ◽  
...  
Keyword(s):  
Channel Block ◽  
Allosteric Effect ◽  
Drug Induced

scholarly journals Understanding the cellular mode of action of vernakalant using a computational model: answers and new questions

2015 ◽  
Vol 1 (1) ◽  
pp. 418-422 ◽  
Author(s):  
Axel Loewe ◽  
Yan Xu ◽  
Eberhard P. Scholz ◽  
Olaf Dössel ◽  
Gunnar Seemann
Keyword(s):  
Mode Of Action ◽  
In Silico ◽  
Antiarrhythmic Agent ◽  
Current Knowledge ◽  
Tissue Level ◽  
System Level ◽  
Channel Block ◽  
Dose Frequency ◽  
Drug Induced ◽  
Level Data

AbstractVernakalant is a new antiarrhythmic agent for the treatment of atrial fibrillation. While it has proven to be effective in a large share of patients in clinical studies, its underlying mode of action is not fully understood. In this work, we aim to link experimental data from the subcellular, tissue, and system level using an in-silico approach. A Hill’s equation-based drug model was extended to cover the frequency dependence of sodium channel block. Two model variants were investigated: M1 based on subcellular data and M2 based on tissue level data. 6 action potential (AP) markers were evaluated regarding their dose, frequency and substrate dependence. M1 comprising potassium, sodium, and calcium channel block reproduced the reported prolongation of the refractory period. M2 not including the effects on potassium channels reproduced reported AP morphology changes on the other hand. The experimentally observed increase of ERP accompanied by a shortening of APD90 was not reproduced. Thus, explanations for the drug-induced changes are provided while none of the models can explain the effects in their entirety. These results foster the understanding of vernakalant’s cellular mode of action and point out relevant gaps in our current knowledge to be addressed in future in-silico and experimental research on this aspiring antiarrhythmic agent.

scholarly journals Arrhythmic hazard map for a 3D whole-ventricle model under multiple ion channel block

2018 ◽  
Vol 175 (17) ◽  
pp. 3435-3452 ◽  
Author(s):  
Jun-ichi Okada ◽  
Takashi Yoshinaga ◽  
Junko Kurokawa ◽  
Takumi Washio ◽  
Tetsushi Furukawa ◽  
...  
Keyword(s):  
Ion Channel ◽  
Hazard Map ◽  
Channel Block

scholarly journals Beta-Adrenergic Receptor Stimulation Limits the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

2020 ◽  
Author(s):  
Henry Sutanto ◽  
Jordi Heijman
Keyword(s):  
Ion Channel ◽  
Cardiac Electrophysiology ◽  
Drug Effects ◽  
Individual Variability ◽  
Sympathetic Stimulation ◽  
Adrenergic Stimulation ◽  
Drug Induced ◽  
Early Afterdepolarizations ◽  
Beta Adrenergic ◽  
Channel Function

Background: The antimalarial drug chloroquine and antimicrobial drug azithromycin have received significant attention during the current COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection), and may influence the electrophysiological effects of chloroquine and azithromycin. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of chloroquine and azithromycin using a detailed in silico model of ventricular electrophysiology. Methods: Concentration-dependent chloroquine and azithromycin-induced alterations in ion-channel function were incorporated into the Heijman canine ventricular cardiomyocyte model. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 592 models accommodating inter-individual variability. Sympathetic stimulation was simulated by an increase in pacing rate and experimentally validated isoproterenol-induced changes in ion-channel function. Results: At 1 Hz pacing, therapeutic doses of chloroquine and azithromycin (5 and 20 µM, respectively) individually prolonged AP duration (APD) by 33% and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 µM isoproterenol corrected the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of 0.1-1 µM isoproterenol. Conclusion: Sympathetic stimulation limits chloroquine- and azithromycin-induced proarrhythmia by reducing their APD-prolonging effect, suggesting the importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).

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