scholarly journals Identification of Drug-Induced Multichannel Block and Proarrhythmic Risk in Humans Using Continuous T Vector Velocity Effect Profiles Derived From Surface Electrocardiograms

2020 ◽  
Vol 11 ◽  
Author(s):  
Werner Bystricky ◽  
Christoph Maier ◽  
Gary Gintant ◽  
Dennis Bergau ◽  
David Carter
Keyword(s):  
Drug Induced ◽  
Vector Velocity ◽  
Proarrhythmic Risk ◽  
Velocity Effect

Estimation of uncertainty in multi-level in silico models predicting biomarkers of drug-induced proarrhythmic risk

2021 ◽  
Vol 350 ◽  
pp. S64-S65
Author(s):  
K. Kopanska ◽  
J.C. Gómez-Tamayo ◽  
J. Llopis-Lorente ◽  
B.A. Trenor-Gomis ◽  
J. Sáiz ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Induced ◽  
Proarrhythmic Risk ◽  
Multi Level ◽  
In Silico Models ◽  
Estimation Of Uncertainty

scholarly journals Protocol-dependent differences in IC50 values measured in hERG assays occur in a predictable way and can be used to quantify state preference of drug binding

2019 ◽  
Author(s):  
William Lee ◽  
Monique J. Windley ◽  
Matthew D. Perry ◽  
Jamie I. Vandenberg ◽  
Adam P. Hill
Keyword(s):  
State Dependence ◽  
Drug Binding ◽  
Machine Learning Algorithms ◽  
Drug Induced ◽  
Preferential Binding ◽  
State Preference ◽  
Proarrhythmic Risk ◽  
Ic50 Values ◽  
Novel Method ◽  
Open Versus

AbstractCurrent guidelines around preclinical screening for drug-induced arrhythmias require the measurement of the potency of block of Kv11.1 channels as a surrogate for risk. A shortcoming of this approach is that the measured IC50 of Kv11.1 block varies widely depending on the voltage protocol used in electrophysiological assays. In this study, we aimed to investigate the factors that that contribute to these differences and to identify whether it is possible to make predictions about protocol-dependent block that might facilitate comparison of potencies measured using different assaysOur data demonstrate that state preferential binding, together with drug binding kinetics and trapping, is an important determinant of the protocol-dependence of Kv11.1 block. We show for the first time that differences in IC50 measured between protocols occurs in a predictable way, such that machine learning algorithms trained using a selection of simple voltage protocols can indeed predict protocol-dependent potency. Furthermore, we also show that a drug’s preference for binding to the open versus the inactivated state of Kv11.1 can also be inferred from differences in IC50 measured between protocols.Our work therefore identifies how state preferential drug binding is a major determinant of the protocol dependence of IC50 measured in preclinical Kv11.1 assays. It also provides a novel method for quantifying the state dependence of Kv11.1 drug binding that will facilitate the development of more complete models of drug binding to Kv11.1 and improve our understanding of proarrhythmic risk associated with compounds that block Kv11.1.

Evaluation of four in silico biomarkers for drug-induced proarrhythmic risk: COVID-19 off-label therapies case study

2021 ◽  
Vol 111 ◽  
pp. 107052
Author(s):  
Elisa Passini ◽  
Xin Zhou ◽  
Cristian Trovato ◽  
Annie Delaunois ◽  
Jean-Pierre Valentin ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Induced ◽  
Off Label ◽  
Proarrhythmic Risk

Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs

2020 ◽  
Vol 39 (6) ◽  
pp. 530-541 ◽  
Author(s):  
Emmanuel Boulay ◽  
Eric Troncy ◽  
Michael V. Accardi ◽  
Michael K. Pugsley ◽  
Anne-Marie Downey ◽  
...  
Keyword(s):  
Body Temperature ◽  
Qtc Interval ◽  
Pharmacological Effects ◽  
Beagle Dogs ◽  
Drug Induced ◽  
Pharmacological Characterization ◽  
Temperature Changes ◽  
Safety Studies ◽  
Proarrhythmic Risk ◽  
Ecg Leads

Introduction: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. Methods: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. Results: Covariate adjusted QT (slope −12.57 ms/°C) and JTpca (−14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. Conclusion: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.

scholarly journals In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk

2018 ◽  
Vol 58 (4) ◽  
pp. 867-878 ◽  
Author(s):  
Lucia Romero ◽  
Jordi Cano ◽  
Julio Gomis-Tena ◽  
Beatriz Trenor ◽  
Ferran Sanz ◽  
...  
Keyword(s):  
In Silico ◽  
Early Screening ◽  
Drug Induced ◽  
Proarrhythmic Risk

Early Development of Drug-Induced Hepatic Necrosis

1971 ◽  
Vol 29 ◽  
pp. 576-577
Author(s):  
F. G. Zaki ◽  
E. Detzi ◽  
C. H. Keysser
Keyword(s):  
Early Development ◽  
Hepatic Necrosis ◽  
Screening Tests ◽  
Dense Matrix ◽  
Sprague Dawley ◽  
Electron Microscopic ◽  
Drug Induced ◽  
Hepatocellular Damage ◽  
Sprague Dawley Rats ◽  
Microscopic Studies

This study represents the first in a series of investigations carried out to elucidate the mechanism(s) of early hepatocellular damage induced by drugs and other related compounds. During screening tests of CNS-active compounds in rats, it has been found that daily oral administration of one of these compounds at a dose level of 40 mg. per kg. of body weight induced diffuse massive hepatic necrosis within 7 weeks in Charles River Sprague Dawley rats of both sexes. Partial hepatectomy enhanced the development of this peculiar type of necrosis (3 weeks instead of 7) while treatment with phenobarbital prior to the administration of the drug delayed the appearance of necrosis but did not reduce its severity.Electron microscopic studies revealed that early development of this liver injury (2 days after the administration of the drug) appeared in the form of small dark osmiophilic vesicles located around the bile canaliculi of all hepatocytes (Fig. 1). These structures differed from the regular microbodies or the pericanalicular multivesicular bodies. They first appeared regularly rounded with electron dense matrix bound with a single membrane. After one week on the drug, these vesicles appeared vacuolated and resembled autophagosomes which soon developed whorls of concentric lamellae or cisterns characteristic of lysosomes (Fig. 2). These lysosomes were found, later on, scattered all over the hepatocytes.

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