CN113712960B

CN113712960B - Application of R-ketorolac in prevention and treatment of aortic dissection and aortic aneurysm

Info

Publication number: CN113712960B
Application number: CN202111115983.XA
Authority: CN
Inventors: 季勇; 张昊; 张艳; 张旭红; 严科; 韩艺; 谢利平
Original assignee: Nanjing Medical University
Current assignee: Nanjing Medical University
Priority date: 2021-09-23
Filing date: 2021-09-23
Publication date: 2023-04-07
Anticipated expiration: 2041-09-23
Also published as: CN113712960A

Abstract

The R-ketorolac is applied to prevention and treatment of aortic dissection and aortic aneurysm, and can inhibit pathological expansion of aorta by oral administration of the R-ketorolac, so as to reduce incidence and mortality of aortic dissection and aortic aneurysm; and R-ketorolac can inhibit inflammatory reaction of vascular wall, reduce rupture of aortic aneurysm body, inhibit hematoma in lumen, maintain integrity of vascular wall elastic fiber, and treat aortic dissection and aortic aneurysm. The invention develops a new application field of R-ketorolac, and provides meaningful reference for preventing and treating aortic dissection and aortic aneurysm diseases and improving vasculopathy conditions.

Description

Application of R-ketorolac in prevention and treatment of aortic dissection and aortic aneurysm

Technical Field

The invention belongs to the technical field of aortic dissection and aortic aneurysm treatment, and particularly relates to application of R-ketorolac in prevention and treatment of aortic dissection and aortic aneurysm.

Background

Aortic aneurysm, which is a permanent and irreversible local dilatation of the aorta, and aortic dissection (AAD), which is a life-threatening disease caused by aortic intimal tear or intra-aortic wall hemorrhage leading to dissection of the aortic wall layer, are among the cardiovascular diseases that seriously jeopardize human health. At the population level, rupture of the aortic aneurysm is the major cause of death. Aortic dissection is most common in the 65-75 year old population with 35 cases per 100,000 per year. Early stage aortic aneurysms are usually asymptomatic, with typical symptoms appearing as sudden onset severe chest or back pain when the tumor body ruptures and no evidence of myocardial ischemia, and severe leading to patient death, and therefore early prevention and treatment of AAD is important.

At present, the treatment method aiming at the aortic dissection and the aortic aneurysm is still mainly performed by operation, but the operation wound is large, the cost is high, and the incidence rate and the death rate of complications are high. And there is controversy as to whether surgery is required for patients with aortic diameters less than 5.0 cm. Clinical commonly used drugs comprise an epinephrine beta receptor blocker, an angiotensin converting enzyme inhibitor, statins and the like, but the drugs can only slow down the disease process by controlling indexes such as blood pressure, heart rate, blood fat and the like, have many adverse reactions and side effects, and have no specific drugs for preventing and treating AAD. Therefore, there is a need for safer and more effective agents capable of preventing AAD.

Ketorolac (ketorolac) is a nonsteroidal anti-inflammatory drug with antipyretic, analgesic and anti-inflammatory effects, and is generally clinically used as an analgesic agent in perioperative and postoperative short-term administration. And ketorolac has both S-and R-enantiomers and is typically administered as a racemic mixture of 1:1. Research shows that S-ketorolac has strong analgesic effect, but has certain gastrointestinal and cardiovascular side effects and renal toxicity, while R-ketorolac has no obvious toxic or side effect. Research shows that ketorolac used in perioperative period can reduce recurrence rate of breast cancer and death rate of ovarian cancer, improve cancer prognosis, and R-ketorolac in a mouse model can delay development of breast tumor and ovarian cancer. However, whether R-ketorolac can improve aortic dissection and aortic aneurysm and the mechanism thereof have not been studied and reported at present.

Disclosure of Invention

The technical problem to be solved is as follows: the invention provides application of R-ketorolac in prevention and treatment of aortic dissection and aortic aneurysm, which effectively improves aortic dissection and aortic aneurysm diseases. The method comprises orally administering R-ketorolac to aortic dissection and aortic aneurysm model mice to prevent occurrence of aortic dissection and aortic aneurysm and reduce mortality of aortic dissection and aortic aneurysm.

The technical scheme is as follows: application of R-ketorolac in preparing medicine for treating aortic dissection and aortic aneurysm is provided.

Application of R-ketorolac in preparing medicine for preventing aortic dissection and aortic aneurysm is provided.

A medicine for preventing or treating aortic dissection and aortic aneurysm contains R-ketorolac as effective component.

Has the beneficial effects that: the R-ketorolac can inhibit pathological expansion of aorta by oral administration, and reduce incidence and mortality of aortic dissection and aortic aneurysm; and the R-ketorolac can inhibit the generation of inflammatory reaction of the vascular wall, reduce the rupture of an aortic aneurysm body, inhibit the generation of hematoma in the inner wall of the lumen of the vessel, maintain the integrity of elastic fibers of the vascular wall and treat aortic dissection and aortic aneurysm. The invention develops a new application field of R-ketorolac, and provides meaningful reference for preventing and treating aortic dissection and aortic aneurysm diseases and improving vasculopathy conditions.

Drawings

FIG. 1 is a graph of a mouse model for Abdominal Aortic Aneurysm (AAA) constructed by an AngII osmotic micro pump, and the incidence of AAA was counted by postoperative gavage with placebo control and R-ketorolac (2 mg/kg/day).

Fig. 2 shows the aortic inner diameter and tumor formation in mice, wherein a: detecting the aorta internal diameter and the tumor formation of the AngII modeled mouse by vascular ultrasound; b: statistical plot of aortic internal diameter in mice, < 0.05.

Fig. 3 is a gross image of a dissected aorta to observe aortic aneurysm formation (Scale bar =0.5 mm).

FIG. 4 is a schematic representation of aortic aneurysm morphology and vascular elastic plate detection by paraffin-embedded section of aorta, H & E, EVG tissue staining (Scale bar =100 μm).

Detailed Description

The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications and substitutions to methods, steps or conditions of the present invention may be made without departing from the spirit and scope of the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. The reagents and materials used in the following examples are all commercially available products. The R-Ketorolac used in the examples is a commercially available product, purchased from https:// www.medchemexpress.cn/.

Example 1: inhibition of aortic aneurysm tumor formation and rupture by R-ketorolac

To explore the effect of R-kerorlac on the tumor formation and rupture of mice as model of aortic aneurysm, we selected 8 week male ApoE-/-SPF mice (purchased from experimental animal technologies ltd. Of viton, beijing) randomly divided into four groups: placebo control group (Saline + placebo), administration control group (Saline +2mg/kg/day R-ketorolac), aortic aneurysm model placebo control group (AngII + placebo), and aortic aneurysm model administration group (AngII +2mg/kg/day R-ketorolac). That is, at the age of 8 weeks, mice were administered with physiological saline through a dorsal subcutaneous implantation of an osmotic micropump (Alzet, USA,2004 model), a control group, ang II (1000 ng/kg/min) through an aortic aneurysm model placebo control group and an aortic aneurysm model administration group, and a placebo or R-ketolac (2 mg/kg/day) through oral administration. Mice were observed every 5 days for mortality and were examined by ultrasound for aortic aneurysm formation at 4 weeks. And isolating mouse aorta, and counting the incidence rate and the death rate of aortic aneurysm.

By counting the survival condition of the mice and the situation of the aortic aneurysm, the R-ketorolac (2 mg/kg/day) taken orally by the mice with the aortic aneurysm can obviously reduce the incidence rate of the aortic aneurysm in figure 1.

The aortic aneurysm formation of the mice is detected by ultrasonic, and figure 2 shows that the aortic inner diameter of the mice orally administered with R-ketorolac (2 mg/kg/day) is obviously smaller than that of the mice with aortic aneurysm, and the aortic aneurysm formation is inhibited.

The gross picture of dissected aorta (FIG. 3) shows that oral administration of R-ketorolac can significantly inhibit the intravascular wall hematoma and tumor rupture.

H & E tissue staining results show that the administration group shown in FIG. 4 can obviously inhibit pathological expansion of aorta and tumor formation (A); EVG tissue staining results show that the administration group can obviously improve the integrity of the aortic elastic plate (B).

Claims

1.R-ketorolac is used in preparing medicine for treating aortic aneurysm.

2.R-ketorolac is used in preparing medicine for preventing aortic aneurysm.