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Drug cardiotoxicity research technique

2021-08-02
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Cardiotoxicity caused by some drugs during use is one of the life-threatening toxic side effects of patients. For example, adverse cardiac events caused by antiarrhythmic drugs have been reported from time to time. Although the incidence of such events is low, the risk is high, and the main manifestations are To prolong the QT interval of the electrocardiogram, it can cause torsade de pointes ventricular tachycardia in severe cases. Therefore, before a new drug is marketed, when the safety of the drug needs to be evaluated, the potential cardiotoxicity of the drug should be discovered as soon as possible to reduce the investment and risk of new drug research and development. The patch clamp technique, known as the “gold standard” for studying ion channels, is one of the main techniques for early evaluation of drug cardiotoxicity.

The QT interval refers to the entire process of ventricular depolarization and repolarization, that is, the time course from the start of the QRS complex to the end of the T wave. The QTc interval refers to a corrected QT interval that excludes the influence of heart rate. Delayed cardiac repolarization will significantly increase the risk of arrhythmia. The most common one is torsade de pointes ventricular tachycardia (TdP). TdP can easily evolve into ventricular fibrillation and cause sudden death. Therefore, the QT interval is prolonged and is It is considered to be a biomarker that is predicted to induce TdP. In the process of new drug development, when performing cardiotoxicity evaluation for drug safety evaluation, the effect of the study drug on the QT interval should be confirmed to prevent it from causing malignant arrhythmia after it is marketed.

The current generated by the hERG channel is the most important current in ventricular repolarization. The inhibition of the channel by drugs directly leads to Long QT syndrome, which is likely to evolve into torsade de pointes ventricular tachycardia, ventricular fibrillation, and even sudden death. Long QT syndrome (LQTS) is an abnormal repolarization electrical activity of cardiomyocytes. Acquired LQTS is often the result of drug treatment. Studies have found that many commonly used drugs including antiarrhythmic drugs, antipsychotic drugs, antibiotics and cocaine can cause acquired LQTS.

At present, it has been found that almost all LQT or TdP caused by clinical drugs act on hERG. Since the drugs that cause hERG inhibition have no obvious commonalities in their chemical structures, it is difficult to predict, and they can only be solved through experiments. An important application direction of the automatic patch clamp technology is to detect the toxic and side effects of early drug compounds on hERG. Medicilon introduced the HEKA Patch Clamp System, which is an integrated amplifier and digital-to-analog converter. It can be combined with manual operation through software to achieve a more accurate level than full automatic, which will greatly enhance Medicilon. West in vitro drug safety evaluation service.

“Diaphragm” refers to the cell membrane in various recording modes. “Clamp” means control. According to the control of different electrical parameters, it is divided into voltage clamp and current clamp. Patch clamp technology is an electrophysiological technology that clamps the cell membrane potential, monitors and records membrane currents through glass micropipette electrodes. Through patch clamp technology, the changes of membrane current can be observed, and the nature of ion channels can be deeply understood by analyzing current intensity, channel opening and closing process, ion selectivity and other factors. Patch clamp technology can mark changes in cardiac electrophysiological function, and abnormal action potential ion channel currents are closely related to cardiovascular diseases such as arrhythmia, heart failure, and myocardial ischemia. The application of patch clamp technology to drug safety evaluation is helpful to guide clinical medication.

For example, researchers have explored the effect of berberine drugs in combination with the lipid-lowering drug rosuvastatin and the glucose-lowering drug glibenclamide on hERG potassium channels, and evaluated the cardiac safety of the combined application of the above drugs [1]. The researchers used the whole-cell patch clamp technique to observe the effect of the combination of the above-mentioned drugs on the hERG channel of HEK293 cells stably expressing the hERG potassium channel. The results of the study showed that the inhibitory effect of berberine drugs, rosuvastatin, and glibenclamide on hERG currents was significantly stronger than that of single use. The inhibitory effect of berberine and ligustrazine on hERG currents was much lower. There is no significant difference between the berberine single-use group, so when the two drugs that have inhibitory effects on the hERG channel are used in combination, the risk of inducing QT interval prolongation will be significantly increased, and the cardiac safety will be reduced.

In the early drug safety evaluation, the application of patch clamp technology allows the compound to obtain an in vitro safety evaluation, which can quickly eliminate problematic compounds at a lower cost and greatly shorten the drug development cycle. At present, the patch clamp technology has been greatly popularized, and is widely active in the research of ion channels.

[1] Cardiac safety evaluation of berberine combination drugs [J].

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