Pharmaceutical use of difatinib in treatment of aortic aneurysmTechnical Field
The invention belongs to the technical field of aortic aneurysm prevention and treatment, and particularly relates to application of afatinib in preparation of a medicine for treating aortic aneurysm.
Background
The structure of the difatinib (C20H21F3N8O3 S, defactinib) is shown as a formula (I), is an orally-taken bioavailable small molecule Focal Adhesion Kinase (FAK) inhibitor, can inhibit the phosphorylation of FAK at Tyr397 site, and has potential anti-tumor activity. Clinical studies have found that difatinib can inhibit the progression of melanoma, non-small cell lung cancer, low grade serous ovarian cancer, colorectal cancer, pancreatic cancer, and delay the progression of breast and pancreatic cancer in a mouse model. Common side effects include nausea, vomiting, fatigue, headache, diarrhea and anorexia.
Aortic aneurysms are different from tumors, but are still high mortality diseases that have not yet been treated with effective drugs, one of the cardiovascular diseases that seriously jeopardizes human health. When the local vessel diameter pathologically expands to more than 1.5 times that of a normal vessel, it is defined as an aortic aneurysm. When the aortic aneurysm is continuously expanded to cause unstable vessel wall and damage to the intima of the aortic blood vessel, blood in the lumen flows into the intima of the vessel wall to form a false lumen attached to the vessel wall, namely an aortic dissection, and when serious, the aortic aneurysm can cause aortic rupture and serious internal hemorrhage. Early aortic aneurysms are generally asymptomatic, and most cases are diagnosed by chance without ultrasound screening. No drug treatment is currently effective in limiting aortic aneurysm growth and surgical repair is a method that can be used to prevent aortic aneurysm rupture. Aortic aneurysm repair by open surgery or endovascular repair is applicable to large asymptomatic or symptomatic aortic aneurysms of any size. Despite some progress in open repair surgery and endovascular stent repair, safe and effective therapeutic drugs are still lacking for this disease, especially inoperable small aneurysms (male diameters less than 5.5 cm, female diameters less than 5.0 cm). Thus, finding new and effective treatments for aortic aneurysms is critical for clinically effective reduction of high mortality. Whether or not the deferiptinib can inhibit the occurrence of aortic aneurysm and the mechanism thereof have not been studied and reported at present.
Disclosure of Invention
The object of the present invention is to address the above-mentioned deficiencies of the prior art and to provide a pharmaceutical use of difatinib in the treatment of aortic aneurysms.
The aim of the invention can be achieved by the following technical scheme:
use of deferatinib in the manufacture of a medicament for treating an aortic aneurysm.
As a preferred aspect of the invention, the use of prefatinib for the manufacture of a medicament for inhibiting pathological expansion of the aorta and for reducing the incidence of aortic aneurysms.
A medicine for treating aortic aneurysm comprises deferatinib as effective component.
As a preferred aspect of the present invention, the difatinib is difatinib or a pharmaceutically acceptable salt thereof.
Preferably, the medicament further comprises a pharmaceutical excipient for preparing the difatinib into a solid preparation or a liquid preparation.
As a further preferred aspect of the present invention, the solid preparation is a capsule or a tablet, and the liquid preparation is an injection.
As a further preferred mode of the invention, the injection is powder injection or water injection.
The beneficial effects are that:
After the gefitinib is administrated by lavage of an aortic aneurysm model mouse, the pathological expansion of the aorta can be effectively inhibited, and the mortality rate and the occurrence rate of the aortic aneurysm are reduced, so that the gefitinib can be used for preparing medicines for treating the aortic aneurysm.
Drawings
FIG. 1 is a graph showing the efficacy of treatment of an aortic aneurysm model mouse following intragastric administration of difatinib, using 8 week old APOE-/- male mice, following subcutaneous implantation of a micro-osmotic pump containing angiotensin II (Ang II,1000 ng/kg/min) for 4 weeks, to induce aortic aneurysm development, while intragastric administration of difatinib and control solvent. Wherein A is to isolate the aorta of the mouse and quantify the maximum diameter of the abdominal aorta, the pathological expansion of the aorta is detected, the scale is 5 mm, n=12,**P<0.01,*** P <0.001, B is to detect the incidence of aortic aneurysm of the mouse, n=6-12,** P <0.01, C is to detect the survival rate of the mouse, n=6-12.
FIG. 2 shows harvested aortic vascular tissue from mice subjected to paraformaldehyde fixing, paraffin embedding and sectioning and stained, A: H & E tissue staining representative image, scale of enlarged image 50 μm, scale of upper right corner of intact image 400 μm, B: E.V.G tissue staining representative image, scale of enlarged image 50 μm, scale of upper right corner of intact image 400 μm, and C: masson tissue staining representative image, scale of enlarged image 50 μm, scale of upper right corner of intact image 400 μm.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the invention, but are not intended to limit the invention in any way. The fartinib used in the examples is a commercially available product purchased from selleck.
Example 1
To explore the intervention effect of afatinib on aortic aneurysm, we selected SPF class 8 week male APOE-/- mice (purchased from university of medical laboratory animals, nanjing medical university) randomly divided into 4 groups, ① control group (saline-embedded pump, 28 days), ② aortic aneurysm model group (subcutaneously embedded Ang II micro-osmotic pump, 1000ng/kg/min,28 days), ③ control mice were given afatinib (20 mg/kg/day, 28 days) by gavage. ④ The aortic aneurysm mice were given a group of difatinib (20 mg/kg/day, 28 days) by gavage. The results of ultrasonic Doppler monitoring on the blood vessel diameters of mice during the study show that the aortic aneurysm model mice with the simple Ang II buried pump have obvious pathological distension (figure 1A), the abdominal aortic aneurysm diameters are obviously increased (figure 1A), the aortic aneurysm occurrence rate and the death rate are obviously increased compared with those of a control group, and after the aortic aneurysm mice are subjected to the gastric lavage administration of the difatinib (20 mg/kg/day, 28 days), the distension of the aortic aneurysm diameters and the incidence rate of the aortic aneurysm are inhibited, so that the difatinib can inhibit the occurrence of the aortic aneurysm (figures 1B and C).
We cut a section of the blood vessel tissue of the harvested experimental mice from the suprarenal aorta (the tumorigenic area) for paraformaldehyde fixation, paraffin embedding and sectioning, followed by H & E, e.v.g staining and Masson staining, and showed that the administration of difatinib (20 mg/kg/day, 28 days) improved abnormal expansion of the mouse aorta (fig. 2A), disturbance and rupture of spandex (fig. 2B) and collagen deposition (fig. 2C) caused by Ang II infusion pump. The above results suggest that the dimatinib can reduce the death rate of aortic aneurysm mice, improve the survival rate of the mice, and delay the aortic aneurysm disease process.