CardiaC toxiCity herg
ثبت نشده
چکیده
One of the major reasons of drug withdrawal or drug label revision is the drug induced sudden cardiac death associated with a prolongation of the QT interval in the electrocardiogram (ECG). When the QT interval is prolonged, there is an increased risk of ventricular tachyarrhythmia, including the life threatening form torsade de pointes. The QT interval of the ECG is a measure of the duration of ventricular depolarization and repolarization. Although a direct link between QT interval prolongation and arrhythmogenesis is still unclear, QT prolongation is now the subject of increased regulatory review and is considered a significant risk factor for predicting human safety of new chemical entities. Although prolongation of QT can occur through modulation of several types of ion channels, inhibition of the delayed rectifier K+ current (IKr), which is conducted by human Ether-a-go-go Related Gene (hERG) potassium channel, is the most common mechanism responsible for drug-induced prolongation of QT interval in humans. Therefore, testing the interaction of a compound with the hERG potassium channel in heterologous expression systems is recommended by the International Conference on Harmonisation (ICH) 1 as one of the non-clinical testing methods for assessing the potential of a test compound to prolong QT interval. Cerep employs two technologies to evaluate the inhibitory effect of test compounds on hERG potassium channel: patch-clamp assay (automated patch-clamp and conventional patch-clamp) and binding assay.
منابع مشابه
Indexing molecules for their hERG liability.
The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vit...
متن کاملThe association between HERG gene expression and cardiac arrhythmia disease in children
We explored the possible link between the expression of HERG gene and cardiomyopathy in children. From April 2013 to April 2015, 73 children with cardiac arrhythmia who were treated were enrolled in the present study to serve as the observation group. At the same time, 76 normal individuals were also enrolled as the control group. HERG expression level in the observation group was compared with...
متن کاملA mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel
Mutations in HERG cause an inherited cardiac arrhythmia, long QT syndrome (LQT). To define the function of HERG, we expressed the protein in Xenopus oocytes. The biophysical properties of expressed HERG are nearly identical to the rapidly activating delayed rectifier K+ current (IKr) in cardiac myocytes. HERG current is K+ selective, declines with depolarizations above 0 mV, is activated by ext...
متن کاملAntidepressant-induced ubiquitination and degradation of the cardiac potassium channel hERG.
The most common cause for adverse cardiac events by antidepressants is acquired long QT syndrome (acLQTS), which produces electrocardiographic abnormalities that have been associated with syncope, torsade de pointes arrhythmias, and sudden cardiac death. acLQTS is often caused by direct block of the cardiac potassium current I(Kr)/hERG, which is crucial for terminal repolarization in human hear...
متن کاملRole of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG.
The human ether-a-gogo-related gene (hERG) encodes the alpha subunit of the cardiac potassium current IKr. Several mutations in hERG produce trafficking-deficient channels that may cause hereditary long-QT syndrome and sudden cardiac death. Although hERG currents have been studied extensively, little is known about the proteins involved in maturation and trafficking of hERG. Using immunoprecipi...
متن کاملEffects of 4-Aminopyridine on Cloned hERG Channels Expressed in Mammalian Cells
INTRODUCTION: Non-clinical evaluation of a medication's potential to induce cardiac toxicity is recommended by regulatory agencies. 4-Aminopyridine (fampridine) is a potassium channel blocker with the demonstrated ability to improve walking ability in patients with multiple sclerosis. We evaluated the in vitro effects of 4-aminopyridine on the human ether-à-go-go-related gene (hERG) channel cur...
متن کامل