Application of chlorogenic acid in preparation of medicine for preventing and treating aortic dissection

Abstract

The invention provides an application of chlorogenic acid in preparation of a medicine for preventing and treating aortic dissection, and the pharmacological action of chlorogenic acid is studied by establishing a recognized animal disease model to find and verify that chlorogenic acid has the effects of reducing the morbidity and mortality of the aortic dissection; the aortic dilatation is retarded; the application of chlorogenic acid in prevention and treatment of aortic dissection is proved, and a solid pharmacodynamic basis is provided for new clinical research and application of the medicine.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to the application of chlorogenic acid in the preparation of drugs for preventing and treating aortic dissection. Background Art

[0002] Chlorogenic acid (CGA) is a phenolic acid produced by the action of caffeic acid and quinic acid. It is the main phenolic compound in honeysuckle and is produced in the plant body through the shikimic acid pathway. CGA is an orally active antioxidant ingredient. Its hemihydrate appears as needle-shaped crystals and is easily soluble in hot water, ethanol, and propanol. CGA has significant anti-inflammatory, antioxidant, anti-cancer, and antibacterial properties. Existing studies have shown that CGA can relax blood vessels, lower blood pressure, and lower blood lipids.

[0003] CGA has good anti-inflammatory and antioxidant effects. Studies have shown that CGA can inhibit LPS-induced mammary inflammatory cell infiltration; can prevent rheumatoid arthritis and its complications; and alleviate renal damage in rats by inhibiting inflammation and oxidative stress. CGA pretreatment can upregulate antioxidant enzymes and inhibit the expression of related inflammatory factors; at the same time, due to the close connection between inflammation and oxidative stress, CGA activates Nrf2 in PC12 cells by clearing ROS to restore mitochondrial function and induce the expression of antioxidant enzymes.

[0004] CGA also plays an important role in lowering blood sugar and blood lipids. It resists obesity by inhibiting the increase of fat and free fatty acids, while reducing total cholesterol, low-density lipoprotein content, increasing high-density lipoprotein content, and improving dyslipidemia. Studies have shown that CGA can improve endothelial cell function through anti-inflammatory / antioxidant effects and inhibition of angiotensin-converting enzyme. CGA has been widely studied in the treatment of cardiovascular diseases: CGA can inhibit hypochlorous acid-induced endothelial cell oxidative stress, improve in vitro angiogenesis by increasing the levels of NO and heme oxygenase-1, and reduce oxidative stress damage to endothelial cells; in addition, CGA alleviates ox-LDL-induced endothelial oxidative stress and mitochondrial dysfunction by activating SIRT1 and regulating the AMPK / PGC-1 signaling pathway.

[0005] Aortic dissection (AD) is a serious cardiovascular emergency. When a rupture occurs in the intima of the arterial wall, blood enters the arterial wall through the rupture to form a hematoma, and further peels off the intima and media of the aorta, aortic dissection will occur. The generally recognized cause of the disease is the structural abnormality and hemodynamic abnormality of the aortic media itself, and the high-risk groups include patients with hypertension, older age, aortic atherosclerosis and hereditary vascular diseases.

[0006] Aortic dissection develops rapidly and is a serious disease. Once it occurs, it is incurable; it has become a world-class problem in the cardiovascular field. Compared with healthy people, patients with aortic dissection have severe dysfunction of aortic smooth muscle cells, including barrier function damage and mitochondrial function damage, and inflammation often occurs in patients with aortic dissection. Currently, CGA is extremely important both in vascular and cardiac protection, but there is a gap in the role of CGA in aortic dissection, which needs further exploration. Summary of the invention

[0007] In view of this, the present invention aims to propose the use of chlorogenic acid in the preparation of drugs for preventing and treating aortic dissection, so as to solve the problems existing in the above-mentioned prior art.

[0008] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0009] In a first aspect, the present invention provides the use of chlorogenic acid in the preparation of a drug for preventing and treating aortic dissection, wherein the structure of the chlorogenic acid is shown in the following formula I:

[0010]

[0011] Furthermore, the chlorogenic acid is the only active ingredient.

[0012] Furthermore, the application includes at least one of the following:

[0013] (1) Application in the preparation of drugs for reducing the morbidity and mortality of aortic dissection;

[0014] (2) Application in the preparation of drugs for repairing damaged aortic walls;

[0015] (3) Application in the preparation of drugs for slowing down aortic dilatation;

[0016] (4) Application in the preparation of drugs for protecting the elastic structure of smooth muscle layer;

[0017] (5) Application in the preparation of drugs for restoring the elastic phenotype of smooth muscle cells.

[0018] Furthermore, the smooth muscle layer is a vascular smooth muscle layer; preferably an arterial vascular smooth muscle layer; and more preferably an aortic vascular smooth muscle layer.

[0019] Further, the daily dosage of chlorogenic acid does not exceed 15 mg / kg; preferably 1-12 mg / kg; further preferably 2-10 mg / kg, for example, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg. These doses can vary according to the needs of the patient, the severity of the condition being treated, and the compound used. Generally speaking, treatment is started with a smaller dose that is less than the optimal dose of the compound, and thereafter, the dose is increased in small amounts to achieve the best effect. For convenience, the total daily dose can be further divided into divided doses within a day if necessary.

[0020] Furthermore, the aortic dissection includes acute aortic dissection or repair aortic dissection.

[0021] In a second aspect, the present invention provides a pharmaceutical preparation for preventing and treating aortic dissection, wherein the active ingredient of the pharmaceutical preparation includes chlorogenic acid, and the structure of the chlorogenic acid is shown in the following formula I:

[0022]

[0023] Furthermore, the chlorogenic acid is the only active ingredient.

[0024] Furthermore, the pharmaceutical preparation also includes pharmaceutically acceptable excipients.

[0025] Furthermore, the auxiliary materials include: at least one of a diluent, a binder, a wetting agent, a lubricant, a disintegrant, a solvent, an emulsifier, a solubility promoter, a preservative, a pH regulator, an osmotic pressure regulator, a surfactant, a coating material, an antioxidant or a buffer.

[0026] Furthermore, the pharmaceutical preparation includes a clinically acceptable oral preparation, injection preparation or inhalation preparation.

[0027] Furthermore, the pharmaceutical preparation includes at least one of powder, granules, pills, capsules, tablets, injections, powder injections, lyophilized agents, and atomizers.

[0028] Furthermore, the administration route of the pharmaceutical preparation includes at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration or aerosol administration.

[0029] To prepare suitable pharmaceutical formulations of the present invention, pharmaceutically acceptable carriers may be solid or liquid.

[0030] Solid form preparations include powders, granules, pills, capsules, tablets. Solid carriers can be one or more substances that also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, adhesives, preservatives, tablet disintegrating agents, or encapsulation materials. In powders, the carrier is a subdivided solid that is mixed with the subdivided active ingredient. In tablets, the active ingredient is mixed with a carrier with the necessary adhesive properties in an appropriate ratio and compressed into a desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, etc.

[0031] Liquid preparations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as water-polyethylene glycol solutions.

[0032] Therefore, the medicament used in the present invention can be formulated into a preparation for parenteral administration (e.g., injection, such as bolus injection or continuous infusion), and can be present in the form of a unit dose in an ampoule, a prefilled syringe, a small volume infusion bag or a multi-dose container together with an added preservative. The composition can take the form of a suspension, solution or emulsion of an oily or aqueous carrier, and can contain formulation ingredients such as suspending agents, stabilizers and / or dispersants. In addition, the active ingredient can be in the form of a powder, which can be obtained by aseptic separation of a sterilized solid or freeze-drying from a solution, for reconstitution with a suitable carrier such as sterile, pyrogen-free water before use.

[0033] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding desired colorants, flavoring agents, stabilizers and thickeners. Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water containing a viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

[0034] Also included are solid preparations designed to be converted into liquid preparations for oral administration shortly before use. Such liquid preparations include solutions, suspensions and emulsions. In addition to the active ingredient, such preparations may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0035] Respiratory administration can also be achieved by aerosols, wherein the active ingredient is contained in a pressurized package together with a suitable propellant, and a suitable propellant includes fluorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. Aerosols can also suitably contain surfactants, such as lecithin. The dosage of the drug can be controlled by a metering valve.

[0036] In addition, the active ingredient may be in the form of a dry powder, for example a powder mixture of chlorogenic acid and a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier can conveniently form a gel in the nasal cavity. The powder composition may be in the form of a unit dose, for example, in capsules or cartridges (such as gelatin capsules or cartridges), or in blister packs where the powder can be administered via an inhaler.

[0037] As an alternative, when desired, compositions adapted for sustained release of the active ingredient may be employed.

[0038] Compared with the prior art, the use of chlorogenic acid in the present invention in the preparation of drugs for preventing and treating aortic dissection has the following advantages:

[0039] (1) The present invention has discovered and verified the use of chlorogenic acid in preventing and treating aortic dissection through the study of the pharmacological effects of chlorogenic acid. Chlorogenic acid has a significant effect in improving aortic dissection, providing a solid pharmacodynamic basis for new clinical research and application of the drug. The drug has broad market prospects after development, and also provides an example for the medicinal use of classic health products and "new uses of old drugs";

[0040] (2) The present invention has established a mature animal disease model of aortic dissection, providing a solid foundation for subsequent drug development. Based on the established animal disease model, the present invention has discovered and verified the therapeutic and preventive effects of chlorogenic acid in improving the prognosis of aortic dissection.

[0041] (3) The present invention establishes a recognized animal disease model, and fully studies the role of chlorogenic acid in reducing the mortality rate of aortic dissection from multiple indicators such as the pathological morphology of the aorta, pathological sections of the lesion site, Masson staining, and comparison of mouse survival rates, thereby providing a solid scientific basis for the clinical application of the drug;

[0042] (4) The experimental results of the present invention show that chlorogenic acid has the effect of reducing the morbidity and mortality of aortic dissection; chlorogenic acid has the effect of slowing down aortic dilatation. These results prove that chlorogenic acid has a protective effect on aortic dissection. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the accompanying drawings:

[0044] Figure 1 This is a schematic diagram of the animal experiment process according to an embodiment of the present invention, where the horizontal axis represents the number of intervention days;

[0045] Figure 2This is a schematic diagram of the mouse survival curve described in an embodiment of the present invention;

[0046] Figure 3 This is a schematic diagram of mouse cardiac ultrasound according to an embodiment of the present invention;

[0047] Figure 4 This is a schematic diagram of the maximum diameter of the mouse aorta according to an embodiment of the present invention;

[0048] Figure 5 This is a schematic diagram of the incidence of aortic dissection in mice according to an embodiment of the present invention;

[0049] Figure 6 This is a schematic diagram of the mouse pathological staining results described in an embodiment of the present invention. DETAILED DESCRIPTION

[0050] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0051] The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with embodiments.

[0052] The present invention uses C57BL / 6J mice as experimental subjects and uses chlorogenic acid to intervene in aortic dissection-induced mice for animal experiments.

[0053] (1) Experimental Materials

[0054] Animal experiment grouping: 3-week-old mice were selected, and 12 mice were included in the Control group (hereinafter referred to as the Control group); 12 mice were included in the BAPN+chlorogenic acid intervention group (hereinafter referred to as the Intervention group); 12 mice were included in the BAPN-induced dissection group (hereinafter referred to as the dissection group);

[0055] BAPN feed: weigh BAPN powder according to 0.4% by weight;

[0056] Preparation of chlorogenic acid: Weigh the chlorogenic acid powder and calculate the daily gavage volume (H2O) based on the gavage volume of 100 μL per mouse per day. Dissolve the weighed chlorogenic acid powder in 50 μL DMSO, ultrasonically homogenize, add appropriate amount of distilled water to dilute, and store at -20°C.

[0057] (2) Experimental methods

[0058] like Figure 1As shown in Table 1: The control group was fed with normal feed for 21 consecutive days, the intervention group and the dissection group were fed with feed containing 0.4% BAPN by mixing BAPN powder into the feed, and the intervention group was also administered with chlorogenic acid powder dissolved in DMSO and diluted with water according to the weight of the mice at 25 mg / kg / day, with a gavage volume of 100 μL per mouse per day for 21 days. During the administration period, the death of mice was recorded, and after the end of the administration, the inner diameter of the aorta of the mice was measured, and the formation of aortic dissection in the mice was observed after dissection, and the incidence rate was calculated.

[0059] Table 1 Animal experiment of chlorogenic acid intervening in aortic dissection-induced mice

[0060] Select mouse Mouse age BAPN induction dose Chlorogenic acid intervention dose Intervention time C57 3week 0.4％ 25 mg / kg / day 21d

[0061] The present invention establishes a recognized animal disease model of aortic dissection, that is, 3-week-old C57BL / 6J mice are fed with a feed containing 0.4% β-aminopropionitrile (BAPN) for 21 days to establish a model, which causes the cross-linking and destruction of the elastic fibers in the aortic wall, leading to the formation of aortic dissection aneurysms, simulating clinical aortic dissection injury, and the model is successfully established based on multiple indicators such as the pathological morphology of the aorta, pathological sections of the lesion site, and Masson staining, which can be used to verify the efficacy of chlorogenic acid.

[0062] (3) Evaluation of pathological indicators in animal experiments

[0063] like Figure 2 As shown in the figure, by counting the death time of dissection in different groups of mice, an overall survival curve was drawn up and statistically analyzed until 21 days. The results showed that the survival rate of mice in the intervention group was significantly higher than that in the dissection group, proving that chlorogenic acid intervention significantly reduced the mortality rate of mice with aortic dissection model.

[0064] The animal experiment was induced to 21 days, and the surviving mice were subjected to aortic ultrasound experiments. The intervention effect of chlorogenic acid was evaluated by measuring the maximum diameter of the aortic dilation and performing statistical analysis. The results are as follows Figure 3 and Figure 4 As shown, *** indicates p<0.001. According to the results, the maximum diameter of the aorta dilation in the intervention group mice (1.45mm) was significantly smaller than that in the dissection group (1.74mm) and the control group (1.55mm), and chlorogenic acid intervention significantly reduced the aortic diameter dilation in the model mice.

[0065] like Figure 5As shown in the figure, the incidence of dissection in different groups of mice was calculated by sampling mice after echocardiography experiment, and the number of aortic dilatation in different groups of mice was counted, and then the incidence of dissection in different groups of mice was calculated, and the graph and statistical analysis were performed. In the figure, red represents the number of mice that died of dissection rupture, blue represents the number of mice that had dissection but not ruptured and died, and black represents the number of mice that did not have dissection. The results showed that the probability of dissection and dissection rupture death in the intervention group was significantly lower than that in the dissection group, and chlorogenic acid intervention reduced the incidence of dissection in the model mice.

[0066] Figure 6 The results of pathological staining of the aorta of mice in each experimental group, including Masson staining, Evans blue staining and elastic fiber staining, which characterize the severity of aortic dissection. In the dissection group, elastic fiber staining found that the elastic plate of the smooth muscle layer was broken and dissolved; Masson staining showed that smooth muscle cells secreted more non-elastic collagen fibers under the stimulation of dissection, which damaged the elasticity of the aorta; in Evans blue staining, there was a large amount of mucin deposition in the smooth muscle layer; the above pathological staining results showed that in the aortic dissection model, the structure and function of the vascular smooth muscle layer were damaged, the elastic phenotype was lost, and the aortic wall underwent degenerative reconstruction. Compared with the dissection group, the deposition of collagen and proteoglycan in the smooth muscle layer was significantly reduced, and the rupture of the elastic fiber plate was also significantly reduced in the intervention group after chlorogenic acid intervention. The above results show that chlorogenic acid intervention can alleviate the progression of aortic dissection by improving the structural and functional damage of the smooth muscle layer and restoring the elastic phenotype of smooth muscle cells.

[0067] According to the results of animal experiments, the incidence and mortality of aortic dissection in mice with aortic dissection model were significantly reduced by oral gavage of chlorogenic acid. Ultrasound results showed that chlorogenic acid intervention alleviated the expansion of the aortic diameter of model mice. The above pathological indicators show that chlorogenic acid intervention effectively alleviated the occurrence and development of aortic dissection in mice.

[0068] The embodiments described above are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work shall all fall within the scope of protection of the present invention.

Claims

1. Use of chlorogenic acid in the preparation of a drug for preventing and treating aortic dissection, characterized in that: The structure of the chlorogenic acid is shown in the following formula I:

2. The use according to claim 1, characterized in that: The chlorogenic acid is the only active ingredient.

3. The use according to claim 1, characterized in that: The application includes at least one of the following: (1) Application in the preparation of drugs for reducing the morbidity and mortality of aortic dissection; (2) Application in the preparation of drugs for repairing damaged aortic walls; (3) Application in the preparation of drugs for slowing down aortic dilatation; (4) Application in the preparation of drugs for protecting the elastic structure of smooth muscle layer; (5) Application in the preparation of drugs for restoring the elastic phenotype of smooth muscle cells.

4. The use according to claim 1, characterized in that: The daily dosage of chlorogenic acid does not exceed 15 mg / kg.

5. The use according to claim 1, characterized in that: The aortic dissection includes acute aortic dissection or repair aortic dissection.

6. A pharmaceutical preparation for preventing and treating aortic dissection, characterized in that: The active ingredient of the pharmaceutical preparation includes chlorogenic acid, and the structure of the chlorogenic acid is shown in the following formula I:

7. The pharmaceutical preparation according to claim 6, characterized in that: The chlorogenic acid is the only active ingredient.

8. The pharmaceutical preparation according to claim 6, characterized in that: The pharmaceutical preparation also includes pharmaceutically acceptable excipients.

9. The pharmaceutical preparation according to claim 8, characterized in that The auxiliary materials include: at least one of a diluent, a binder, a wetting agent, a lubricant, a disintegrant, a solvent, an emulsifier, a cosolvent, a preservative, a pH regulator, an osmotic pressure regulator, a surfactant, a coating material, an antioxidant or a buffer.

10. The pharmaceutical preparation according to claim 6, characterized in that: The pharmaceutical preparations include clinically acceptable oral preparations, injection preparations or inhalation preparations.

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