scholarly journals Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

2006 ◽  
Vol 34 (1) ◽  
pp. 81-90 ◽  
Author(s):  
Gary A. Gintant ◽  
Zhi Su ◽  
Ruth L. Martin ◽  
Bryan F. Cox
Keyword(s):  
Cardiac Electrophysiology ◽  
Critical Role ◽  
Drug Effects ◽  
Torsades De Pointes ◽  
Cardiac Repolarization ◽  
Surrogate Markers ◽  
Related Gene ◽  
Drug Induced ◽  
Herg Current

HERG (human-ether-a-go-go-related gene) encodes for a cardiac potassium channel that plays a critical role in defining ventricular repolarization. Noncardiovascular drugs associated with a rare but potentially lethal ventricular arrhythmia (Torsades de Pointes) have been linked to delayed cardiac repolarization and block of hERG current. This brief overview will discuss the role of hERG current in cardiac electrophysiology, its involvement in drug-induced delayed repolarization, and approaches used to define drug effects on hERG current. In addition, examples of hERG blocking drugs acting differently (i.e., overt and covert hERG blockade due to multichannel block) together with the utility and limitations of hERG assays as tools to predict the risk of delayed repolarization and proarrhythmia are discussed.

scholarly journals Role of High-Mobility Group Box-1 in Liver Pathogenesis

2019 ◽  
Vol 20 (21) ◽  
pp. 5314 ◽  
Author(s):  
Bilon Khambu ◽  
Shengmin Yan ◽  
Nazmul Huda ◽  
Xiao-Ming Yin
Keyword(s):  
Liver Disease ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Sterile Inflammation ◽  
Contributing Factors ◽  
Drug Induced ◽  
Ductular Reaction ◽  
Alcoholic Fatty Liver

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.

scholarly journals The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice

2019 ◽  
Vol 130 ◽  
pp. 104486 ◽  
Author(s):  
Da-li Tong ◽  
Rui-guo Chen ◽  
Yu-lan Lu ◽  
Wei-ke Li ◽  
Yue-fang Zhang ◽  
...  
Keyword(s):  
Social Behavior ◽  
Critical Role ◽  
Related Gene ◽  
Synaptic Development

Comparison of sensitivity of surrogate markers of drug-induced torsades de pointes in canine hearts

2004 ◽  
Vol 502 (1-2) ◽  
pp. 117-122 ◽  
Author(s):  
Katsuyoshi Chiba ◽  
Atsushi Sugiyama ◽  
Kiyoshi Takasuna ◽  
Keitaro Hashimoto
Keyword(s):  
Torsades De Pointes ◽  
Surrogate Markers ◽  
Drug Induced

Drug-induced torsades de pointes: The evolving role of pharmacogenetics

Heart Rhythm ◽  
2005 ◽  
Vol 2 (11) ◽  
pp. S30-S37 ◽  
Author(s):  
Patrick T. Fitzgerald ◽  
Michael J. Ackerman
Keyword(s):  
Torsades De Pointes ◽  
Drug Induced

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).

The Critical Role of Mitochondria in Drug-Induced Liver Injury

2017 ◽  
pp. 159-181 ◽  
Author(s):  
Carl W. Decker ◽  
Joseph G. Casian ◽  
Kim Tho Nguyen ◽  
Luke A. Horton ◽  
Madhuri P. Rao ◽  
...  
Keyword(s):  
Liver Injury ◽  
Critical Role ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals HEPATIC MANIFESTATIONS IN COVID-19: APPROACHES ON THE MECHANISMS, LIVER INJURIES AND DRUG INTERACTIONS

2021 ◽  
Vol 2 (6) ◽  
pp. e26442
Author(s):  
Débora Dantas Nucci Cerqueira ◽  
Giuliene Rocha de Medeiros ◽  
João Victor Cordeiro Farias ◽  
Penelopy Rodrigues de Macedo
Keyword(s):  
Liver Damage ◽  
Liver Enzymes ◽  
Gastrointestinal Symptoms ◽  
Drug Effects ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Liver Injuries ◽  
Severe Liver Damage ◽  
Qualitative Nature

The current pandemic caused by SARS-CoV-2 originated in the city of Wuhan, China with an outbreak of pneumonia. The reported symptoms were mostly respiratory, but mounting evidence began to indicate that COVID-19 could reach other organs and systems. Among the gastrointestinal symptoms, liver involvement appears to be more common, with changes in liver enzymes (ALT and AST) being the first sign. Therefore, the present study aims to evaluate and discuss the hepatic manifestations in COVID-19 as the infection, manifestations, and drug effects. The study was based on a literature review, of a qualitative nature and an exploratory type. The mechanism that SARS-CoV-2 uses to reach the liver is still uncertain, there are currently 3 hypotheses: ACE2 receptors in cholangiocytes, cytokine storm, and drug-induced liver injury, due to the increase in the indiscriminate use of hepatotoxic drugs without scientific comprovation, hydroxychloroquine can lead to fulminant hepatic failure and azithromycin potentiates these effects, the role of remdesivir on the liver are still uncertain. Liver damage in mild cases of COVID-19 can be transient, but doctors should monitor and be alert to any changes in liver enzymes. When severe liver damage occurs, liver protective drugs have usually been given to these patients. Thus, this review provides a review of hepatic impairment and the management of patients considering the main studies carried out to date.

scholarly journals Critical role of OX40 in drug‐induced acute liver injury

2020 ◽  
Vol 177 (14) ◽  
pp. 3183-3196
Author(s):  
Chunpan Zhang ◽  
Hua Jin ◽  
Yan Wang ◽  
Changying Li ◽  
Xinyan Zhao ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Critical Role ◽  
Drug Induced
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