Application of rilpivirine in preparation of medicine for treating myocardial infarction

Abstract

The invention discloses an application of rilpivirine (RPV) in preparation of a medicine for treating myocardial infarction, and relates to the field of medicines for treating myocardial infarction. The invention belongs to the technical field of biological medicine. According to the present invention, the acute myocardial infarction (AMI) disease mouse model is constructed through the induction of the permanent ligation of the left anterior descending branch; after rilpivirine is orally taken, the conditions of survival, heart function, structure change and the like of the AMI mouse model during X weeks after operation are observed. Results show that rilpivirine (as shown in the formula I) has the effects of remarkably improving the cardiac function of AMI injury, relieving cardiac remodeling and increasing the survival rate of AMI mice. Therefore, a new technical means is provided for treatment of myocardial infarction, and rilpivirine has a wide application prospect in treatment of myocardial infarction diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a new use of Rilpivirine (4-[[(1R)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]methyl]-2-[[(1R)-1-[(4-hydroxyphenyl)methyl]-6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl]oxy]phenol), and in particular to the use of Rilpivirine in the preparation of a drug for treating myocardial infarction. The present invention belongs to the technical field of biomedicine. Background Art

[0002] Acute myocardial infarction (AMI) is a high-risk disease characterized by myocardial ischemia and damage, tissue remodeling, and ultimately cardiac failure caused by thrombosis of the heart and blood vessels. It has clinical characteristics of high morbidity and mortality. In recent years, the treatment of AMI has been continuously updated and has made great progress. Targeted drug therapy has improved the prognosis and survival of patients. However, there is still no effective cure, and it can only delay or prevent the progression of the disease.

[0003] The pathogenesis of myocardial infarction is the interaction of multiple cell types, which ultimately manifests as myocardial cell death and weakened and failed heart function as the final pathological result. The most important cause is the blockage of blood vessels by thrombus, which causes myocardial tissue damage and immune inflammatory response. The vigorous metabolism of myocardial cells requires blood vessels to supply sufficient oxygen and nutrient molecules, and to remove metabolic waste in a timely manner. Vascular obstruction causes a hypoxic microenvironment, which on the one hand leads to myocardial tissue necrosis. Therefore, how to improve the survival of affected myocardial cells is an important direction for the prevention and treatment of myocardial infarction; at the same time, hypoxia can also induce the regeneration of cardiac microvascular endothelial cells and vascular remodeling, and restore blood supply to damaged myocardial tissue. Therefore, promoting angiogenesis is another important direction for the treatment of myocardial infarction.

[0004] Current therapeutic drugs mainly include antiplatelet drugs, anticoagulants, thrombolytic drugs, anti-myocardial ischemic drugs and other auxiliary drugs. The following is a detailed classification and clinical use of these drugs: 1. Antiplatelet drugs (aspirin, clopidogrel, etc.); 2. Anticoagulants (heparin, rivaroxaban, etc.); 3. Thrombolytic drugs (t-PA, r-UK, etc.); 4. Anti-myocardial ischemic drugs, including β-adrenergic receptor antagonists (metoprolol, bisoprolol, etc.) and ACE inhibitors (benazepril, valsartan); 5. Other drugs, such as cholesterol-lowering drugs such as ezetimibe and anti-inflammatory drugs such as tocilizumab. However, the side effects of drugs and the need for individualized treatment are still problems that need to be solved at present. Future research will further optimize drug use strategies, develop new drugs, and explore individualized treatment plans to meet complex clinical needs.

[0005] Rilpivirine (4-[[(1R)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]methyl]-2-[[(1R)-1-[(4-hydroxyphenyl)methyl]-6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl]oxy]phenol) is a non-nucleotide HIV reverse transcriptase inhibitor, which is widely used in the clinical treatment of acquired immune syndrome. Studies have shown that rilpivirine has pharmacological properties such as liver fibrosis, antiplatelet, and relief of ischemia-reperfusion myocardial injury. In recent years, some studies have also found that rilpivirine also has anti-tumor effects. However, there are no reports on its use in myocardial infarction (AMI), post-infarction cardiac remodeling, and terminal heart failure.

[0006] The present invention studies the effect of rilpivirine on myocardial infarction and finds that rilpivirine can effectively improve the left ventricular function and remodeling of the heart of animals with myocardial infarction and increase the survival rate of animals with myocardial infarction. Therefore, rilpivirine can be used as a new type of drug for preventing and treating myocardial infarction for the prevention and treatment of myocardial infarction. Summary of the invention

[0007] The present invention aims to provide use of Rilpivirine (4-[[(1R)-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-1-yl]methyl]-2-[[(1R)-1-[(4-hydroxyphenyl)methyl]-6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl]oxy]phenol) in treating myocardial infarction.

[0008] In order to achieve the above purpose, the present invention adopts the following technical means:

[0009] The present invention constructs a myocardial infarction disease mouse model by permanent ligation of the left anterior descending branch of the heart. After oral administration of rilpivirine, the cardiac function of the myocardial infarction mouse model and the death within 8 weeks after surgery are detected 1 day before surgery and 1, 3, 7, 14, 21, 28, 35, and 42 days after surgery. The results show that rilpivirine can significantly improve the cardiac function and remodeling of myocardial infarction mice and increase the survival rate of myocardial infarction animals, that is, the present invention has found through research that rilpivirine (RPV) has the effect of treating myocardial infarction disease.

[0010] Therefore, based on the above research, the present invention proposes the use of rilpivirine in the preparation of a drug for treating myocardial infarction, and the chemical structural formula of the rilpivirine is shown in Formula I:

[0011]

[0012] Preferably, the rilpivirine achieves the purpose of treating myocardial infarction by alleviating cardiac remodeling in patients with myocardial infarction, alleviating left ventricular heart failure in patients with myocardial infarction, and improving cardiac fibrosis.

[0013] Compared with the prior art, the present invention has the following beneficial effects:

[0014] The present invention proposes a new drug for treating myocardial infarction, rilpivirine, which can be used for the treatment of myocardial infarction. Rilpivirine is a non-nucleoside HIV reverse transcriptase inhibitor approved by the FDA. It is clinically used for the treatment of AIDS at a single oral dose of 25 mg per day. Therefore, the drug is safe at the recommended dose and is suitable for long-term use. The present invention follows the principle of species-based body weight / body surface area conversion. Rilpivirine can achieve the purpose of treating myocardial infarction by improving the cardiac function of patients with myocardial infarction, alleviating myocardial remodeling, and reducing the progression of heart failure in patients with myocardial infarction. Therefore, the present invention provides a new technical means for the treatment of myocardial infarction, and will also give rilpivirine a broad application prospect in the treatment of myocardial infarction. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The survival rates of the permanent ligation of the left anterior descending artery + solvent group (Sol.) and the permanent ligation of the left anterior descending artery + rilpivirine group (RPV) within 56 days after surgery indicate that rilpivirine can improve the survival rate of animals with myocardial infarction;

[0016] Figure 2 Left ventricular ejection fraction (A) and short-axis contraction rate (B) of the permanent ligation of the left anterior descending artery + solvent group (Sol.) and the permanent ligation of the left anterior descending artery + rilpivirine group (RPV) at different days, indicating that rilpivirine has a protective effect on the attenuated cardiac function of animals with myocardial infarction;

[0017] Figure 3 The left ventricular end-systolic and end-diastolic volumes, and systolic and end-diastolic wall thicknesses at different days in the permanent ligation of the left anterior descending artery + solvent group (Sol.) and the permanent ligation of the left anterior descending artery + rilpivirine group (RPV), indicating that rilpivirine can alleviate cardiac remodeling in animals with myocardial infarction;

[0018] Among them, A is a heart tissue section; B is a statistical bar graph of the relative area of ​​myocardial fibrosis, *P<0.05, **P<0.01. DETAILED DESCRIPTION

[0019] The present invention will be further described below in conjunction with specific examples, and the advantages and features of the present invention will become clearer as the description proceeds. However, these examples are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0020] Example 1 Use of Rilpivirine in the Treatment of Myocardial Infarction

[0021] 1. Animals and experimental reagents:

[0022] Mice (strain: C57BL6 / J, purchased from Liaoning Changsheng Biotechnology Co., Ltd.).

[0023] 2. Establishment of hypoxia-induced myocardial infarction model:

[0024] 28 healthy C57BL6 / J male mice (weight 22-25g) were permanently ligated with the left anterior descending artery of the heart and randomly divided into two groups according to the principle of weight balance, namely the permanent ligation of the left anterior descending artery + solvent group (solvent of the same volume as the rilpivirine group, oral method) and the permanent ligation of the left anterior descending artery + rilpivirine group (rilpivirine 5mg / kg / day, oral method). 42 days after surgery, the death and other conditions were observed, and the cardiac function indicators (left ventricular ejection fraction and short-axis contraction rate) of the mice were detected 1 day before surgery and 3 / 7 / 14 / 21 / 28 / 35 / 42 days after surgery. 56 days after surgery, the heart was fixed with 4% paraformaldehyde, paraffin sectioned, and Masson pathological staining was performed to evaluate the degree of cardiac fibrosis.

[0025] 3. Results

[0026] 3.1 Rilpivirine improves the survival rate of animals with myocardial infarction

[0027] After permanent ligation of the left anterior descending branch of the mouse heart, rilpivirine was administered. This time point was marked as day 0 for each group. The Log-rank (Mantel-Cox) test showed the survival rate of myocardial infarction animals at different days after rilpivirine administration (P=0.0254).

[0028] Through research, it was found that the death rate of myocardial infarction model animals gradually increased with the feeding time after surgery. After 56 days, the mortality rate of the permanent ligation of the left anterior descending artery + solvent group reached 57% (8 / 14), while the mortality rate of the permanent ligation of the left anterior descending artery + rilpivirine group (rilpivirine, 5 mg / kg / day, oral method) was only 15% (2 / 14), indicating that rilpivirine can improve the survival rate of myocardial infarction animals. The results are as follows Figure 1 shown.

[0029] 3.2 Rilpivirine can significantly improve cardiac function in mice with myocardial infarction

[0030] The study found that permanent ligation of the left anterior descending artery caused a significant decline in the heart function of mice. Compared with the left anterior descending artery permanent ligation + solvent group, the left ventricular ejection fraction (EF) and short-axis contraction rate (FS) of mice 1 day before surgery (-1 day) showed a significant decline from 1 day after surgery, and continued with the extension of feeding time. Rilpivirine treatment can significantly alleviate the downward trend of EF and FS indicators in mice with myocardial infarction and significantly maintain the heart function of mice with myocardial infarction. The results are as follows Figure 2 shown.

[0031] 3.3 Rilpivirine can significantly improve cardiac fibrosis in mice with myocardial infarction

[0032] The permanent ligation of the left anterior descending artery in myocardial infarction model can lead to cardiac fibrosis in mice. Compared with the permanent ligation of the left anterior descending artery + solvent group, the cardiac fibrosis of the mice with myocardial infarction was significantly improved in the permanent ligation of the left anterior descending artery + rilpivirine group, specifically, the relative area of ​​myocardial fibrosis decreased from 20.27±4.74% in the permanent ligation of the left anterior descending artery + solvent group to 11.07±3.37% in the permanent ligation of the left anterior descending artery + rilpivirine (RPV) group. The results are shown in Figure 3 shown.

Claims

1. Use of rilpivirine in the preparation of a drug for treating myocardial infarction, wherein the chemical structure of rilpivirine (4-[4-[4-[(E)-2-Cyanovinyl]-2,6-dimethylphenylamino]pyrimidin-2-ylamino]benzonitrile) is as shown in Formula I:

2. The use according to claim 1, characterized in that: The rilpivirine achieves the purpose of treating myocardial infarction by alleviating cardiac remodeling, alleviating left ventricular heart failure and improving cardiac fibrosis in patients with myocardial infarction.

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