Application of methylene blue in preparation of medicine for preventing and treating aortic dissection and aortic aneurysm

Abstract

The invention discloses an application of methylene blue in preparation of drugs for preventing and treating aortic dissection and aortic aneurysm, which proves that after methylene blue is orally taken in an aortic aneurysm mouse model, expansion of aortic diameter can be inhibited and occurrence rate of aortic dissection and aortic aneurysm can be reduced after methylene blue is given. Abnormal aorta dilatation of mice and disorder and fracture of elastic fibers caused by BAPN water drinking are improved. Therefore, the death rate of the BAPN-induced aortic dissection and aortic aneurysm mice can be reduced and the disease progress of the aortic dissection and aortic aneurysm can be delayed by giving the methylene blue, so that the expansion condition of the aorta of the mice is improved and the survival rate is increased.

Description

Technical Field

[0001] This invention belongs to the field of gene therapy and biomedicine technology, specifically involving the application of methylene blue in the prevention and treatment of aortic dissection and aortic aneurysm. Background Technology

[0002] Aortic aneurysm and dissection (AAD) is a serious cardiovascular disease that severely threatens human health. An aortic aneurysm is a permanent and irreversible local dilation of the aorta, while aortic dissection mainly manifests as a tear in the aortic intima or intramural hemorrhage, leading to pulsatile blood flow between the tunica media and forming a dissecting flap that separates the true and false lumens. Recent population-based studies have reported an incidence of aortic dissection ranging from 2.5 / 100,000 to 7.2 / 100,000 per year. Acute aortic dissection has a high mortality rate in untreated patients with significant symptoms; therefore, early prevention and treatment of AAD are crucial.

[0003] Currently, open surgery remains the primary treatment for aortic dissection and aortic aneurysm, with thoracic endovascular aortic repair (TEVAR) becoming the preferred treatment for acute complex type B aortic dissection accompanied by signs of poor perfusion. However, this procedure is highly invasive, expensive, and has a high incidence of complications and mortality. Furthermore, not all patients with aortic dissection (AAD) meet the criteria for open surgery or TEVAR. Therefore, developing therapeutic drugs for aortic dissection and aortic aneurysm could enrich the treatment options for these conditions from another perspective.

[0004] Traditional drug therapy primarily slows disease progression by controlling heart rate and blood pressure to reduce stress on the aortic wall. Commonly used drugs include beta-adrenergic receptor blockers, angiotensin II receptor inhibitors, angiotensin-converting enzyme inhibitors, and statins. However, these drugs have many adverse reactions and side effects, and currently, no specific drugs have been found for the prevention and treatment of AAD. Therefore, there is a need for safer and more effective drugs to prevent and treat AAD. Summary of the Invention

[0005] The purpose of this invention is to study and prepare drugs for treating aortic dissection and aortic aneurysm, specifically providing the application of methylene blue in the treatment of aortic dissection and aortic aneurysm, including the role of methylene blue in the preparation of drugs for treating aortic dissection and aortic aneurysm.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] This invention provides the use of methylene blue in the preparation of drugs for the prevention and / or treatment of aortic dissection and aortic aneurysm.

[0008] The methylene blue described in this invention ( Methylene Blue (MB), CAS No. 61-73-4. The structural formula is as follows:

[0009] .

[0010] The methylene blue described in this invention can be administered in clinically common forms.

[0011] The drug described in this invention can be a clinically commonly used dosage form, such as tablets, capsules, oral liquids, aqueous injections, powder injections, etc. The formulation may use pharmaceutically acceptable excipients, including but not limited to coating materials, solvents, solubilizers, fillers, disintegrants, binders, stabilizers, antioxidants, pH adjusters, osmotic pressure adjusters, flavoring agents, and taste masking agents. Those skilled in the art can select these excipients based on pharmaceutical knowledge.

[0012] The beneficial effects of this invention are:

[0013] Previous research by the applicant showed that the level of S-nitrosylation (SNO) modification of GNB1 was significantly increased in the aortic tissue of mice with aortic dissection and aortic aneurysm. Its abnormal accumulation may lead to dysfunction of vascular wall cells, resulting in a significantly increased risk of vascular wall loss, dilation, and rupture. We found that knocking down BLRRB in HASMCs followed by TNF-α stimulation significantly decreased the SNO modification level of GNB1. Furthermore, we found that the interaction between GNB1 and BLRRB increased in HASMCs after TNF-α stimulation, but this interaction was inhibited after administration of methylene blue. Given the important role of SNO modification of GNB1 in aortic aneurysms, we believe that methylene blue affects the progression of aortic dissection and aortic aneurysm by influencing the interaction between GNB1 and BLRRB, thereby inhibiting SNO modification of GNB1. Using mouse models of aortic dissection and aortic aneurysm, oral administration of methylene blue demonstrated that it inhibited aortic diameter dilation, reduced the incidence of aortic dissection and aortic aneurysm, and improved BAPN-induced aortic dilation and elastic fiber disorder and rupture in mice. This indicates that methylene blue administration can reduce the mortality rate of mice with BAPN-induced aortic dissection and aortic aneurysm, delay the disease progression, and thus improve aortic dilation and survival rate in mice. Attached Figure Description

[0014] Figure 1To establish mouse models of aortic dissection and aortic aneurysm by administering β-aminopropionitrile (BAPN, 1 g / kg / day) via drinking water, methylene blue (0.5 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day) and a control solvent were administered orally. Gross images of the aorta were taken after dissection to observe the formation of aortic dissection and aortic aneurysm (Scale bar = 0.5 mm).

[0015] Figure 2 To observe and statistically analyze the incidence and survival rate of aortic dissection and aortic aneurysm during the modeling period. A: Detection of the incidence of aortic dissection and aortic aneurysm in mice; B: Detection of the survival rate of mice with aortic dissection and aortic aneurysm models.

[0016] Figure 3 To assess the aortic diameter and aneurysm formation in mice, the aortic diameter of BAPN-modeled mice was detected by vascular ultrasound, and the results were statistically analyzed.

[0017] Figure 4 A schematic diagram of aortic aneurysm morphology and vascular elastic lamina detected by H&E and EVG tissue staining using paraffin-embedded sections of the aorta (Scale bar=100μm). Detailed Implementation

[0018] The following examples are provided to better understand the present invention, but are not intended to limit the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples were purchased from conventional biochemical reagent stores.

[0019] Example 1: Aortic dissection and aortic aneurysm model were established in C57BL / 6J mice via oral administration of methylene blue.

[0020] Three-week-old male SPF-grade C57BL / 6J mice (purchased from the Experimental Animal Center of Nanjing Medical University) were randomly divided into five groups: a placebo control group (Saline + placebo), a placebo control group for aortic dissection and aortic aneurysm models (BAPN + placebo), and three groups receiving aortic dissection and aortic aneurysm models at different methylene blue concentrations (0.5 mg / kg / day, 1 mg / kg / day, and 2 mg / kg / day). The aortic dissection and aortic aneurysm models were established at 3 weeks of age by infiltrating β-aminopropionitrile (BAPN) at 1 g / kg / day into the drinking water, while simultaneously administering different concentrations of methylene blue (0.5 mg / kg / day, 1 mg / kg / day, and 2 mg / kg / day) orally for 28 days. During the four-week modeling period, the blood vessel diameter of the mice was monitored using Doppler ultrasound to observe the formation of aortic dissection and aortic aneurysm. Four weeks later, aortic vascular tissue was extracted to determine the incidence and mortality rates of aortic dissection and aortic aneurysm, and to measure relevant pathological indicators.

[0021] The results are as follows Figures 1-4 As shown in the gross images of the dissected aorta, oral administration of methylene blue significantly inhibited the formation of aortic dissection and aortic aneurysm, and suppressed intraluminal hematoma and aneurysm rupture. Figure 1 By statistically analyzing the survival rate of mice and the formation of aortic dissection and aneurysm, the results showed that oral administration of methylene blue to mice with aortic dissection and aneurysm significantly reduced the incidence of aortic dissection and aneurysm, as well as the mortality rate. Figure 2 Ultrasound examination of aortic dissection and aneurysm formation in mice showed that the aortic diameter of mice orally administered methylene blue was significantly smaller than that of mice with aortic dissection and aortic aneurysm. Figure 3 HE staining results showed that the methylene blue intervention group significantly inhibited the pathological dilation of the aorta and the formation of aortic dissection; EVG staining results showed that the methylene blue intervention group significantly improved the integrity of the aortic elastic lamina. Figure 4 ).

[0022] The above results indicate that methylene blue can prevent and reduce the mortality rate of mice with BAPN-induced aortic dissection and aortic aneurysm, improve the survival rate of mice, and thus delay the disease progression of aortic dissection and aortic aneurysm.

Claims

1. Use of methylene blue in the preparation of drugs for the prevention and / or treatment of aortic dissection and aortic aneurysm.

2. The application according to claim 1, characterized in that, The drug is available in oral or injectable form.

3. The application according to claim 2, characterized in that, The drug is in the form of tablets, capsules, oral liquid, water injection, or powder injection.

4. The application according to any one of claims 1 to 3, characterized in that, The drug contains methylene blue and pharmaceutically acceptable excipients.

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