Pharmaceutical application of difatinib in treatment of aortic aneurysm

Abstract

The invention discloses a pharmaceutical application of difatinib in treatment of aortic aneurysm, and relates to the field of cardiovascular systems. In an aortic aneurysm mouse model, after the difatinib is injected into the stomach, pathological dilatation of the aorta can be improved, and the death rate and the occurrence rate of the aortic aneurysm can be reduced. According to the invention, a new application field of the difatinib is developed, a new prevention and treatment method for the aortic aneurysm is provided, and a new way is provided for development of a novel medicine for the aortic aneurysm.

Description

Technical Field

[0001] The invention belongs to the technical field of aortic aneurysm prevention and treatment, and specifically relates to the application of difatinib in preparing a drug for treating aortic aneurysm. Background Art

[0002]

[0003] Difatinib (C20H 21 F3N8O3S, Defactinib), with a structure as shown in formula (I), is an orally bioavailable small molecule focal adhesion kinase (FAK) inhibitor that can inhibit FAK phosphorylation at the Tyr397 site and has potential anti-tumor activity. Clinical studies have found that Defactinib can inhibit the progression of melanoma, non-small cell lung cancer, low-grade serous ovarian cancer, colorectal cancer, and pancreatic cancer, and can delay the development of breast cancer and pancreatic cancer in mouse models. Its common side effects include nausea, vomiting, fatigue, headache, diarrhea, and loss of appetite.

[0004] Aortic aneurysm is different from tumors, but it is still a high-fatality disease that has no effective drug treatment. It is one of the cardiovascular diseases that seriously endangers human health. When the local blood vessel diameter pathologically expands to more than 1.5 times that of a normal blood vessel, it is defined as an aortic aneurysm. When the aortic aneurysm continues to expand, the vascular wall becomes unstable and the aortic vascular intima is damaged, causing the blood in the lumen to flow into the vascular wall media, forming a false lumen attached to the vascular wall, namely aortic dissection. In severe cases, it will cause aortic vascular rupture and severe internal bleeding. Early aortic aneurysms usually have no obvious symptoms. In the absence of ultrasound screening, most cases are diagnosed by chance. Currently, there is no drug treatment that can effectively limit the growth of aortic aneurysms. Surgical repair is a method that can be used to prevent aortic aneurysm rupture. Aortic aneurysm repair by open surgery or endovascular repair is suitable for large asymptomatic or symptomatic aortic aneurysms of any size. Although some progress has been made in open repair surgery and endovascular stent repair, there is still a lack of safe and effective treatment drugs for this disease, especially for small aneurysms (less than 5.5 cm in diameter for men and less than 5.0 cm in diameter for women) that cannot be operated on. Therefore, finding new and effective methods to treat aortic aneurysms is the key to effectively reduce its high mortality rate clinically. Whether defatinib can inhibit the occurrence of aortic aneurysms and its mechanism has not yet been studied or reported. Summary of the invention

[0005] The purpose of the present invention is to provide a pharmaceutical use of difatinib in treating aortic aneurysm in view of the above-mentioned deficiencies in the prior art.

[0006] The purpose of the present invention can be achieved through the following technical solutions: Use of difatinib in preparing a drug for treating aortic aneurysm.

[0007] As a preferred embodiment of the present invention, difatinib is used in the preparation of a drug for inhibiting pathological dilatation of the aorta and reducing the incidence of aortic aneurysm.

[0008] A medicine for treating aortic aneurysm, wherein the active ingredient includes defatinib.

[0009] As a preferred embodiment of the present invention, the defatinib is defatinib or a pharmaceutically acceptable salt thereof.

[0010] As a preferred embodiment of the present invention, the drug further comprises pharmaceutical excipients for preparing defatinib into a solid preparation or a liquid preparation.

[0011] As a further preferred embodiment of the present invention, the solid preparation is a capsule or a tablet, and the liquid preparation is an injection.

[0012] As a further preferred embodiment of the present invention, the injection is a powder injection or a water injection.

[0013] Beneficial effects: After oral administration of defatinib to mice with aortic aneurysm model, the pathological dilatation of the aorta can be effectively inhibited, and the mortality rate and the incidence of aortic aneurysm can be reduced. Therefore, defatinib can be used to prepare drugs for the treatment of aortic aneurysm. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the efficacy of difatinib after oral administration to aortic aneurysm model mice. - / - Male mice were given a subcutaneous microosmotic pump containing angiotensin II (Ang II, 1000ng / kg / min) for 4 weeks to induce aortic aneurysm, and defatinib and control solvent were given by gavage. A: The mouse aorta was isolated and the maximum diameter of the abdominal aorta was quantified to detect pathological dilatation of the aorta, the scale was 5 mm, n=12, ** P<0.01, *** P<0.001; B: Detection of the incidence of aortic aneurysms in mice, n=6-12, ** P<0.01; C: Detection of mouse survival rate, n=6-12.

[0015] Figure 2The collected mouse aortic vascular tissues were fixed with polyformaldehyde, embedded in paraffin, sectioned, and stained. A: Representative image of H&E tissue staining, the scale of the magnified icon is 50μm, and the scale of the complete icon in the upper right corner is 400μm; B: Representative image of EVG tissue staining, the scale of the magnified icon is 50μm, and the scale of the complete icon in the upper right corner is 400μm; C: Representative image of Masson tissue staining, the scale of the magnified icon is 50μm, and the scale of the complete icon in the upper right corner is 400μm. DETAILED DESCRIPTION

[0016] The following implementation examples may enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The defatinib used in the examples is a commercially available product purchased from selleck.cn. Example 1

[0017] In order to explore the intervention effect of defatinib on aortic aneurysm, we selected 8-week-old SPF male APOE - / - Mice (purchased from the Medical Experimental Animal Center of Nanjing Medical University) were randomly divided into the following 4 groups: ① control group (physiological saline implanted pump, 28 days), ② aortic aneurysm model group (Ang II microosmotic pump implanted subcutaneously, 1000ng / kg / min, 28 days), ③ control mice gavaged with difatinib (20mg / kg / day, 28 days) group. ④ aortic aneurysm mice gavaged with difatinib (20mg / kg / day, 28 days) group. During the study, the vascular diameter of mice was monitored by ultrasound Doppler. The results showed that the aorta of the aortic aneurysm model mice with simple Ang II implanted pump showed obvious pathological dilatation (Figure 1A), the diameter of the abdominal aorta increased significantly (Figure 1A), and the incidence and mortality of aortic aneurysms were significantly increased compared with the control group. After the aortic aneurysm mice were gavaged with difatinib (20 mg / kg / day, 28 days), the dilatation of the aortic diameter and the incidence of aortic aneurysms were inhibited, indicating that difatinib can inhibit the occurrence of aortic aneurysms (Figure 1B, C).

[0018] We collected a section of the suprarenal aorta (tumor area) from the experimental mouse vascular tissue, fixed it with polyformaldehyde, embedded it in paraffin, and sliced ​​it, and then performed H&E, EVG staining, and Masson staining. The results showed that the administration of defatinib (20 mg / kg / day, 28 days) can improve the abnormal dilation of the mouse aorta caused by Ang II implantation pump (Figure 2A), the disorder and rupture of elastic fibers (Figure 2B), and the deposition of collagen (Figure 2C). The above results suggest that defatinib can reduce the mortality of mice with aortic aneurysms, improve the survival rate of mice, and thus delay the progression of aortic aneurysm disease.

Claims

1. Use of difatinib in the preparation of drugs for treating aortic aneurysms.

2. The use according to claim 1, characterized in that The use of difatinib in the preparation of drugs for inhibiting pathological dilatation of the aorta and reducing the incidence of aortic aneurysm.

3. A drug for treating aortic aneurysm, characterized in that The active ingredient includes defatinib.

4. The drug according to claim 3, characterized in that The defatinib is defatinib or a pharmaceutically acceptable salt thereof.

5. The drug according to claim 4, characterized in that The medicine also contains pharmaceutical excipients for preparing defatinib into a solid preparation or a liquid preparation.

6. The drug according to claim 5, characterized in that The solid preparations are capsules and tablets, and the liquid preparations are injections.

7. The drug according to claim 5, characterized in that The injection is a powder injection or a water injection.

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