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hERG test-preclinical cardiac safety evaluation

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Cardiac safety evaluation is an important factor that must be investigated before various new drugs enter clinical trials, and it is also one of the most important and difficult links in the early clinical research of innovative drugs. In recent years, some drugs that have been put into clinical use have received extensive attention from drug safety management departments and drug companies because of their potential cardiotoxicity. Medicilon, as a one-stop comprehensive medical R&D outsourcing service CRO company, has an experienced team of experts that can provide multi-level preclinical cardiac safety evaluation services from cells to whole animals.
Efficiently predict the reliability of drugs in early cardiac safety pharmacology, which is particularly important for reducing potential adverse reactions in clinical research. At present, China can provide a one-stop medical research and development that meets GLP standards and can be used for IND applications including cardiac safety evaluation There are not many service companies. Medicilon is one of them. The service details are as follows:

In vitro safety pharmacology study

Clarifying the non-target adverse reactions (ADR) of the compound and the adverse reactions caused by the uneven reaction of the target will help the compound avoid potential adverse reactions through subsequent in vivo experiments.
◆Research on the mechanism of lead compounds;
◆Detect the influence of compounds on hERG ion channels, and provide comprehensive evaluation of its cardiac safety in various stages of drug screening and development;
◆ Detection at the cell level.

In vivo safety pharmacology research

◆The non-invasive telemetry system observes the ECG and hemodynamic changes of the whole animal, and can continuously monitor the effect of drugs on the cardiovascular system.

Advantages of Medicilon’s preclinical cardiac safety evaluation

◆High cost performance, short research period, fast project start;
◆The expert team has very rich project experience and can provide constructive solutions;
◆As a one-stop medical R&D outsourcing service company, early provision of cardiotoxicity evaluation information will help Medicilon screen out candidate compounds with higher cardiac safety coefficients through a complete set of technical methods such as chemistry, efficacy, pharmacokinetics and preparations.

Drug safety evaluation is an extremely important step in the drug development process. As some non-cardiovascular drugs have been found to induce acquired QT prolonged syndrome (LQTS), leading to severe arrhythmia and withdrawing from the market, The safety of drugs to the heart has received more extensive attention. The QT interval of the heart refers to the period from the beginning of the QRS complex to the end of the T wave, including the process of ventricular depolarization and repolarization. QT interval extension is receiving more and more attention and is considered a new drug One of the key indicators of safety evaluation. In cardiomyocytes, the potassium channel encoded by human Ether-a-go-go Related Gene (hERG) mediates a delayed rectifier potassium current (IKr), and IKr inhibition is the most important mechanism for drugs to cause QT interval prolongation. Because of its special molecular structure, hERG can be inhibited by compounds with diverse structures. At present, detecting the effect of compounds on hERG potassium channels is a key step in preclinical evaluation of the cardiac safety of compounds, and it is also a necessary data for new drug approval required by the FDA.

Introduction to hERG

The hERG gene was originally isolated and identified from the human hippocampal cDNA library by Warmke et al in 1994, and it has homology with the Drosophila EAG gene. The hERG gene is located on human chromosome 7 (7q35~q36), is about 55kb, has 16 exons, and encodes 1159 amino acid residues. It is expressed in human body tissues such as myocardium, brain, liver, spleen, etc., and the highest expression is in myocardial tissue. Recent studies have shown that hERG genes are expressed in many tumor cell lines. The α subunit of hERG gene encoding Ikr and the β subunit minK-related protein encoded by minK together form Ikr. The hERG potassium ion channel consists of 4 identical α subunits to form a tetramer, and the intermediate type forms an ion channel. Since the protein encoded by the hERG gene has the structure of a voltage-gated channel protein, it includes 6 transmembrane α-helix fragments (S1~S6), the P loop between S5 and S6, the carboxyl terminal (C terminal) and the amino terminal ( N end) (Figure 2). In 1995, Sanguinetti et al. used the channel for transfecting hERG gene to express hERG protein on cells for the first time, and its biological characteristics were almost the same as those of encoding Ikr. The hERG gene plays an important role in physiological processes. The potassium ion channel it expresses has inward rectification properties. Inward Ikr is open at all phases of the action potential of cardiomyocytes, and conducts during the repolarization and resting potential phases of action potential 3 maximum. It shows obvious inward current when it is hyperpolarized, and outward current when it is slightly depolarized, thereby maintaining the stability of the resting potential. The hERG potassium channel is activated rapidly when the action potential is depolarized to about -30mV, and continues to the end of the 3-phase action potential. Therefore, the hHERG potassium channel can regulate the early arrival of excitatory impulses from the sinus node or allogeneic excitatory impulses from the myocardial sinus node and effectively inhibit the spread of premature contractions.

hERG detection method

We can use three technical methods to test the effect of compounds on hERG potassium channels, namely, Automated Patch-Clamp, Conventional Patch-Clamp and FluxORTM Thallium Assay.

A, B, C hERG potassium channel
A, B, C hERG potassium channel-mediated IKr inhibition leads to prolongation of the action potential duration and QT interval of cardiomyocytes

Automatic patch clamp technology (hERG Qpatch assay)

The traditional patch clamp technology is adsorbed on the cell surface through a special glass tube to form a high-impedance gigaohm seal, which can accurately record the changes in current mediated by ion channels. It is considered the “gold standard” for studying ion channels. The technical requirements for operators are relatively high, and the throughput is low, which cannot meet the current large demand for hERG toxicity evaluation in drug development. The Qpatch16X produced by the Danish Sophion company introduced into the workstation uses a glass chip similar to the traditional patch clamp, which can form a gigaohm seal, and achieves high-throughput detection under the premise of accurate measurement, and can simultaneously detect 16 at a time cell.

Automatic patch clamp technology (hERG Qpatch assay)
Automatic patch clamp technology (hERG Qpatch assay)

Traditional patch-clamp technique (hERG manual patch-clamp asssay)

Conventional Patch-Clamp is the most important technical method for the study of ion channels. It is recognized as the “gold standard” for ion channel research and the most accurate experimental method for measuring ion channels. It is suitable for studying compounds and ion channels. The mechanism of action can also be used for the toxicity evaluation of candidate drugs and the structure optimization of lead compounds in the new drug application process.

Cisapride inhibits hERG potassium current current graph and hERG peak current versus time
Cisapride inhibits hERG potassium current current graph and hERG peak current versus time
Cisapride inhibits the dose response curve of hERG
Cisapride inhibits the dose response curve of hERG potassium current.

FluxORTM Thallium Assay Thallium assay

Use FluxORTM fluorescent dyes to test the effect of compounds on hERG potassium channels. The thallium-sensitive fluorescent dye is loaded into the cell membrane, and the thallium ions outside the cell enter the cell along the concentration gradient through the open hERG potassium ion channel, and then combine with the fluorescent dye to produce fluorescence (Figure 3). FluxORTM thallium assay has been widely used internationally by pharmaceutical companies and scientific research institutions for the detection of compound hERG activity, because it can be tested on 96-well plates or 384-well plates to meet high-throughput requirements, and is suitable for preliminary compound screening and piloting. Compound optimization.

Compound optimization

The above content is about hERG, hERG testing, and preclinical cardiac safety evaluation related content from the website of Medicilon.

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