Application of β3-adrenaline receptor agonist in the preparation of drugs for preventing and / or treating abdominal aortic aneurysm

Abstract

The present application belongs to the field of medical technology, and in particular, relates to the use of β3-adrenergic receptor agonists in the preparation of drugs for preventing or / and treating abdominal aortic aneurysms. The present application discloses the use of β3-adrenergic receptor agonists in the preparation of drugs for preventing or / and treating abdominal aortic aneurysms. The present application aims at the problem that there is no effective drug in the prior art that can delay the progression of abdominal aortic aneurysms, and discloses a new application of β3-adrenergic receptor agonists.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and in particular relates to the use of a β3-adrenaline receptor agonist in the preparation of a drug for preventing and / or treating abdominal aortic aneurysm. Background Art

[0002] Aneurysm refers to localized dilation of an artery, which is more than 50% larger than the expected normal artery diameter. If the diameter of the abdominal aorta is greater than 3cm, it can be diagnosed as abdominal aortic aneurysm (AAA). Rupture of abdominal aortic aneurysm is one of the most dangerous diseases in vascular surgery. When it develops to a certain stage, it may suddenly rupture. If it is not repaired in time, the patient's survival rate within 24 hours is only 50%. Once the abdominal aortic aneurysm ruptures, the mortality rate is as high as 90%. Early diagnosis, slowing the progression of abdominal aortic aneurysm and timely and correct surgical treatment are the key to saving the lives of such patients. However, there is currently no effective drug that can slow the progression of abdominal aortic aneurysm. Summary of the invention

[0003] In view of this, the present application discloses the use of β3-adrenergic receptor agonists in the preparation of drugs for preventing and / or treating abdominal aortic aneurysms, and finds that β3-adrenergic receptor agonists can significantly reduce the incidence of abdominal aortic aneurysms and delay the progression of the disease.

[0004] The present application discloses the use of a β3-adrenaline receptor agonist in the preparation of a drug for preventing and / or treating abdominal aortic aneurysm.

[0005] Preferably, the β3-adrenergic receptor agonist is selected from one or more of β3-adrenergic receptor agonist CL316243, mirabegron, vibegron, β3-adrenergic receptor agonist N-5984, β3-adrenergic receptor agonist BMS-194449, β3-adrenergic receptor agonist BMS-196085, β3-adrenergic receptor agonist, β3-adrenergic receptor agonist SR58611A, β3-adrenergic receptor agonist CP11427l and β3-adrenergic receptor agonist CP80625.

[0006] More preferably, the β3-adrenergic receptor agonist is selected from the β3-adrenergic receptor agonist CL316243.

[0007] Preferably, the β3-adrenaline receptor agonist is used to prepare an injection preparation or an oral preparation for preventing and / or treating abdominal aortic aneurysm.

[0008] Preferably, the β3-adrenaline receptor agonist CL316243 is used to prepare an injectable preparation for preventing and / or treating abdominal aortic aneurysm.

[0009] Preferably, the β3-adrenaline receptor agonist is used to reduce the incidence of abdominal aortic aneurysm.

[0010] Preferably, the β3-adrenaline receptor agonist is used to inhibit the growth of abdominal aortic aneurysm.

[0011] Preferably, the β3-adrenaline receptor agonist is used to reduce the incidence of elastic fiber rupture in the abdominal aorta.

[0012] Preferably, the β3-adrenaline receptor agonist is used to increase the elastic fiber collagen content of the abdominal aorta.

[0013] In view of the problem that there is no effective drug in the prior art that can delay the progression of abdominal aortic aneurysm, this application discloses a new application of existing drugs of β3-adrenergic receptor agonists. This application finds that β3-adrenergic receptor agonists can inhibit the occurrence and progression of abdominal aortic aneurysm. This embodiment shows that the β3-adrenergic receptor agonist CL316243 significantly reduces the incidence of abdominal aortic aneurysm and significantly inhibits the growth of abdominal aortic aneurysm by reducing the degree of elastic fiber breakage in the abdominal aorta and increasing the elastic fiber collagen content in the abdominal aorta. The results show that β3-adrenergic receptor agonists can effectively prevent and / or treat abdominal aortic aneurysm diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0015] Figure 1 The statistics of the number of deaths and the number of survivals of mice in the PBS group and the CL316243 group of the present application are shown;

[0016] Figure 2 The incidence statistics of abdominal aortic aneurysm in the PBS group and the CL316243 group of the present application example are shown;

[0017] Figure 3 The abdominal aorta pictures of the PBS group and the CL316243 group in the present application example are shown;

[0018] Figure 4 The results of staining of abdominal aorta vascular tissue in the PBS group and the CL316243 group in the present example are shown;

[0019] Figure 5 The collagen content statistics of the abdominal aorta of mice in the PBS group and the CL316243 group of the present application example are shown;

[0020] Figure 6The maximum abdominal aorta diameter and the elastic fiber rupture degree of the abdominal aorta of the PBS group and the CL316243 group in the example of the present application are shown in the figure on the left, wherein the maximum abdominal aorta diameter result is shown, and the right figure is the elastic fiber rupture degree result of the abdominal aorta. DETAILED DESCRIPTION

[0021] The present application provides the use of a β3-adrenaline receptor agonist in the preparation of a drug for preventing and / or treating abdominal aortic aneurysm, which is used to fill the gap that there is currently no effective drug that can delay the progression of abdominal aortic aneurysm.

[0022] The technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0023] Among them, the clinical β3-adrenergic receptor agonists include mirabegron and vibegron. The β3-adrenergic receptor agonists under development include Kyorin's N-5984, BMS-194449 and BMS-196085 (Phase I clinical trials) from Bristol-Myers Squibb, SR58611A from Sanofi-San Pierce, CP11427l and CP80625 from Pfizer, all of which have the effect of preventing and / or treating abdominal aortic aneurysms.

[0024] All the β3-adrenaline receptor agonists CL316243 in the following examples were purchased from Sigma, and CL316243 was administered by injection.

[0025] The mouse model of abdominal aortic aneurysm in the following examples is induced by angiotensin II. - / - Male mice (ApoE knockout mice) were used to construct abdominal aortic aneurysm.

[0026] Example

[0027] The present application provides an animal experiment to verify the preventive and therapeutic effects of the β3-adrenergic receptor agonist CL316243 on abdominal aortic aneurysm, specifically including:

[0028] 1. Take APOE from 3-month-old - / -Male mice were randomly divided into two groups, one group was intraperitoneally injected with PBS (labeled as PBS group), and the other group was intraperitoneally injected with β3-adrenergic receptor agonist CL316243 (purchased from Sigma, 1 mg / kg / day) (labeled as CL316243 group), and the injections were continued for 9 days. Then, a capsule osmotic pump (purchased from Alzet) loaded with Angiotensin II solution was implanted subcutaneously on the back of the mice. The dosage of Angiotensin II was 1.44 mg / kg / day to induce APOE - / - Abdominal aortic aneurysm model was established in male mice. The survival of mice was observed after surgery. After 28 days, samples were collected from the two groups of mice. The maximum outer diameter of the abdominal aorta of the two groups of mice was measured, and the incidence of abdominal aortic aneurysm was calculated (abdominal aortic aneurysm was defined as aortic diameter > 1.22 mm). The abdominal aorta vessels of the two groups of mice were taken for OCT embedding, and the vascular tissue lesions of the two groups were detected.

[0029] 2. Histological staining of abdominal aorta vessels of two groups of mice, including:

[0030] The blood vessels containing the largest diameter of the mouse abdominal aorta were taken and quickly frozen at -80°C in OCT. Continuous cross-sectional sections (8 μm each) were cut from the proximal to the distal end of the aorta and stained with hematoxylin and eosin. They were then stained with the ElasticavanGieson staining kit (source: leagene) and the Sirius red staining kit (source: pythonbio), respectively. The staining results were quantified using ImageJ software.

[0031] 3. Count the number of surviving mice in the PBS group and the CL316243 group. The results are as follows: Figure 1 Compared with the PBS-treated group, the number of surviving mice in the CL316243 group increased ( Figure 1 ).

[0032] 4. The incidence of abdominal aortic aneurysm in the PBS group and the CL316243 group was analyzed and statistically analyzed. Figure 2 Compared with the PBS-treated group, the incidence of abdominal aortic aneurysms in mice in the CL316.243 group was significantly reduced ( Figure 2 ).

[0033] 5. Analyze and count the maximum abdominal aorta diameters of the PBS group and the CL316243 group. The results are as follows: Figure 3 Compared with the PBS-treated group, the maximum abdominal aorta diameter of mice in the CL316.243 group was significantly reduced ( Figure 3 ).

[0034] 6. The staining results of abdominal aorta vascular tissue in the PBS group and CL316243 group are as follows Figure 4The elastic fiber rupture degree and collagen content of the abdominal aorta of mice in the PBS group and the CL316243 group were analyzed and statistically analyzed. The results are as follows Figure 5 shown. Figure 4 and Figure 5 The results showed that compared with the PBS-treated group, the elastic fiber rupture degree of the abdominal aorta of mice in the CL316.243 group was significantly reduced, and the collagen content was significantly increased.

[0035] In summary, the present application discovered that β3-adrenaline receptor agonists can significantly reduce the incidence of abdominal aortic aneurysm and delay the progression of the disease.

[0036] The above is only a preferred implementation of the present application. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present application. These improvements and modifications should also be regarded as the scope of protection of the present application.

Claims

1. Use of a β3-adrenaline receptor agonist in the preparation of a drug for preventing and / or treating abdominal aortic aneurysm; the β3-adrenaline receptor agonist is selected from the β3-adrenaline receptor agonist CL316243.

2. The use according to claim 1, characterized in that: The beta 3-adrenaline receptor agonist is used for preparing an injection preparation or an oral preparation for preventing and / or treating abdominal aortic aneurysm.

3. The use according to claim 1, characterized in that: The β3-adrenaline receptor agonist is used to reduce the incidence of abdominal aortic aneurysm.

4. The use according to claim 1, characterized in that: The β3-adrenaline receptor agonist is used to inhibit the growth of abdominal aortic aneurysm.

5. The use according to claim 1, characterized in that: The beta 3-adrenaline receptor agonist is used for reducing the incidence of elastic fiber rupture in the abdominal aorta.

6. The use according to claim 1, characterized in that: The β3-adrenaline receptor agonist is used to increase the elastic fiber collagen content of the abdominal aorta.

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