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Application of Vanoxerine in medicine for persistent atrial fibrillation

1. Vanoxerine, a continuous technology, applied in the direction of medical preparations containing active ingredients, drug combinations, pharmaceutical formulas, etc., can solve problems such as unclear clinical effects

Inactive Publication Date: 2020-06-26
杭州健石药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drugs that have been used to treat Parkinson's and depression, but the clinical effect is unclear

Method used

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  • Application of Vanoxerine in medicine for persistent atrial fibrillation
  • Application of Vanoxerine in medicine for persistent atrial fibrillation
  • Application of Vanoxerine in medicine for persistent atrial fibrillation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Perfusion treatment with VX of mongrel dogs with atrial fibrillation induced by acetylcholine.

[0030] Specific steps: Anesthetize the mongrel dog with pentobarbital sodium, intubate the trachea, open the chest cavity, fix four electrodes in the high left / right atrium and low left / right atrium respectively, determine the pacing threshold, and double the pacing threshold Stimulation was carried out, and the basic state and pacing atrial diagram were recorded by a multi-conductive physiological instrument. Eight basic stimulations were performed continuously with a programmed stimulator, and the stimulation cycle was 200 ms (8 S1pulse); the high-frequency stimulation of 50 Hz, the stimulation time was 1 sec ( 50 Hz × 1 sec), and 0.1 μM acetylcholine (Ach) was added to the coronary artery, the left atrium was stimulated by the S1S2 atrium program to induce atrial fibrillation (AF) in mutt dogs, reperfused with different concentrations of VX, and the normal no S...

Embodiment 2

[0032] Example 2: Whole-cell patch clamp technique was used to record the hKv1.5 (IKur) potassium channel treated with different concentrations of VX.

[0033] Specific steps: culture HEK-293 cells overexpressing human Kv1.5 potassium channel with 83% DMEM, 15% fetal bovine serum, 1% non-essential amino acids and 1% 100x penicillin-streptomycin, and use standard whole-cell patch clamp The technical recording method depolarizes the cell to 0mv / 500ms to activate the Kv1.5 (IKur) ion channel, then clamps the cell back to -80mv / s, the stimulation frequency is 10s once, and the maximum current recorded at 0mv is the desired value Recorded Kv1.5 channel current amplitude;

[0034] Experimental results such as Figure 4 As shown, the figure contains the IC50 fitting curve and current curve of VX inhibiting Kv1.5. From the results, it is found that VX can inhibit Kv1.5 channel at a low dose, and the inhibitory effect is time-dependent. The increase of , the stronger its effect. Sin...

Embodiment 3

[0035] Example 3: Using the whole-cell patch clamp technique to record the ion channels of hERG, IK1 (Kir2.1), hNav1.5, IKs (KvLQT1 / minK), and Cav1.2 treated with different concentrations of VX.

[0036]Specific steps: culture HEK-293 cells overexpressing human hERG potassium channel with 84% DMEM, 15% fetal bovine serum and 1% 100x penicillin-streptomycin, 89% DMEM / F12, 10% fetal bovine serum, 1% 100x HEK-293 cells overexpressing human hNav1.5 potassium ion channel were cultured with penicillin-streptomycin and G418, and the cell membrane current was recorded by standard whole-cell patch clamp technique. The hERG recording method is to depolarize the cell to 40mv / 5ms to activate the hERG ion channel, and then clamp the cell back to -50mv / s to record the inactivation process of the channel. The stimulation frequency is 15s once, and the recorded at -50mv The maximum current is the hERG channel current amplitude to be recorded. The hNav1.5 recording program is to depolarize the...

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Abstract

The invention discloses an application of Vanoxerine (VX) in a medicine for persistent atrial fibrillation. The inventors find through experiments that the medicine VX can prolong the activation time(ACT) and effective refractory period (ERP) duration of atrial fibrillation induced by acetylcholine (Ach) and improve an atrial fibrillation threshold (AFT) in a concentration-dependent manner; in addition, the medicine has a strong time-dependent inhibitory effect on an atrial fibrillation target Kv1.5 (Ikur) potassium channel; the VX has no significant effects on IK1 and IKs (IC50 is all greater than 300 [mu]M), but the VX has inhibitory effects on hERG (IC50=54.07 nM), Nav1.5 (IC50=1.95 [mu]M) and Cav1.2 (IC50=11.1 [mu]M), so that a medicine blocking effect due to certain ion channel can be cancelled; and in the action potential of rabbit Purkinje fibers, the inventors find that the VX only slightly prolongs APD90 at an appropriate dose, and has no or slight frequency dependence. The above results show that the VX can effectively inhibit the persistent atrial fibrillation at an appropriate concentration and does not cause ventricular arrhythmia caused by prolonged ventricular APD90and excessive prolonged QTc.

Description

technical field [0001] The invention belongs to the field of new drug research and development, specifically proposes a novel drug Vanoxerine (VX) capable of inhibiting persistent atrial fibrillation, and explains its mechanism of action. Background technique [0002] Atrial fibrillation (AF) and atrial flutter (AFL) are a worldwide epidemic of cardiac arrhythmias that is on the rise as the world's population ages, especially among those over the age of 40. According to relevant forecasts, by 2050, the number of people suffering from atrial fibrillation in the United States will reach 5.6 million, and that in China will reach 20 million. This has brought huge market development space and attracted the attention of many pharmaceutical companies. [0003] There are three types of atrial fibrillation, one is paroxysmal atrial fibrillation, which is characterized by a sudden increase in heartbeat, which lasts within a week, usually within 24 hours, and can be terminated spontan...

Claims

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Application Information

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IPC IPC(8): A61K31/495A61P9/06
CPCA61K31/495A61P9/06
Inventor 张之颢付声姣
Owner 杭州健石药业有限公司
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