Use of astaxanthin in preparation of drugs for preventing and treating aortic dissection

Abstract

This invention provides the application of astaxanthin in the preparation of drugs for the prevention and treatment of aortic dissection. This invention found that astaxanthin can significantly reduce the mortality rate of mice with aortic dissection, improve the survival rate of mice, and reduce the degree of aortic arch dilation and vascular diameter; it also inhibits the occurrence of aortic dissection and the cavity and rupture of the aortic medial structure, thus providing a new potential drug for the prevention and treatment of aortic dissection.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and in particular relates to the application of astaxanthin in the preparation of drugs for the prevention and treatment of aortic dissection. Background Technology

[0002] Aortic dissection is a life-threatening condition, usually caused by a tear in the aortic intima or intramural hemorrhage, leading to the separation of the intima, media, and adventitia of the aortic wall, forming a dissection. As blood continues to flow into the aortic wall, the intimal flap can extend proximally and distally from the initial tear or hemorrhage site, potentially affecting collateral arteries. The first two weeks after the onset of aortic dissection are considered the acute phase, during which patients are highly susceptible to life-threatening complications and death. Treatment methods for aortic dissection mainly include drug therapy, interventional therapy, and surgical treatment. Although these treatments have made significant progress, the high difficulty of aortic dissection surgery, postoperative multi-organ dysfunction, coagulation disorders, and other complications cannot be completely avoided. Furthermore, postoperative vascular degeneration can lead to further degenerative changes, posing a risk of secondary surgery and rupture. Therefore, preventive and therapeutic drugs for patients with acute aortic dissection remain a hot topic in current clinical research.

[0003] Astaxanthin is a natural carotenoid widely found in algae, yeast, shrimp, crab, and other organisms. All-trans-L-astaxanthin (Sigma-Aldrich-41659) is the most bioactive form of the astaxanthin stereoisomer, possessing the advantages of both the levorotatory and all-trans configurations. In terms of source, all-trans-L-astaxanthin is primarily extracted from Haematococcus pluvialis, and its structure is highly consistent with naturally occurring astaxanthin in humans and animals, thus exhibiting excellent biocompatibility and absorption efficiency. Regarding bioactivity, all-trans-L-astaxanthin not only exhibits the strong antioxidant and anti-inflammatory properties characteristic of the levorotatory configuration, but the trans configuration further enhances its molecular stability and bioavailability, demonstrating significant potential in scavenging free radicals and regulating cell signaling pathways. Currently, all-trans-L-astaxanthin has been widely studied and applied in the fields of antioxidation, anti-aging, and immune regulation, becoming one of the hot topics in natural active ingredient research. Currently, there are no research reports on the use of astaxanthin in the prevention and treatment of aortic dissection. Therefore, exploring the potential applications of astaxanthin in the prevention and treatment of aortic dissection has significant scientific and social value. Summary of the Invention

[0004] In view of this, the present invention aims to propose the application of astaxanthin in the preparation of drugs for the prevention and treatment of aortic dissection, so as to provide a new potential therapeutic drug for the treatment of aortic dissection.

[0005] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0006] In a first aspect, the present invention provides the use of penicillin in the preparation of drugs for the prevention and treatment of aortic dissection.

[0007] Preferably, the chemical structure of the astaxanthin is a six-membered ring structure consisting of four isoprene units connected by conjugated double bonds, with two isoprene units at each end.

[0008] Preferably, the astaxanthin is all-trans-L-astaxanthin;

[0009] More preferably, the astaxanthin is as shown in Formula I:

[0010] .

[0011] Furthermore, the astaxanthin is the sole active ingredient.

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

[0013] (1) Application in the preparation of drugs that reduce the incidence and / or mortality of aortic dissection, preferably application in the preparation of drugs that reduce the mortality and / or improve the survival rate of aortic dissection;

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

[0015] (3) Application in the preparation of drugs that slow down aortic dilation, preferably application in the preparation of drugs that reduce the degree of aortic arch dilation and / or vascular diameter;

[0016] (4) Application in the preparation of drugs that inhibit cavitation and / or rupture of the aortic media structure;

[0017] (5) Application in the preparation of drugs that reduce the breakage of elastic fibers in the neutral membrane of the aorta;

[0018] (6) Application in the preparation of drugs that reduce collagen deposition in the neutral membrane of the aorta;

[0019] (7) Application in the preparation of drugs that reduce the accumulation of glycosaminoglycans in the neutral membrane of the aorta;

[0020] (8) Application in the preparation of drugs that inhibit the expression level of phenotypic transformation genes in aortic smooth muscle cells.

[0021] Furthermore, the daily dose of the astaxanthin shall not exceed 100 mg / kg.

[0022] Furthermore, the daily dosage of astaxanthin can vary depending on the patient's needs, the severity of the condition being treated, and the compound used. Generally, treatment begins with a smaller dose than the optimal dose of the compound, and then the dose is gradually increased to achieve the best effect. For convenience, the total daily dose can be further subdivided into multiple doses throughout the day if necessary.

[0023] Furthermore, the aortic dissection includes acute aortic dissection or repair aortic dissection.

[0024] In a second aspect, the present invention provides a pharmaceutical preparation for the prevention and treatment of aortic dissection, wherein the active ingredient of the pharmaceutical preparation includes astaxanthin.

[0025] Preferably, the astaxanthin is all-trans-L-astaxanthin;

[0026] More preferably, the structure of the astaxanthin is shown in Formula I:

[0027] ;

[0028] Furthermore, the astaxanthin is the sole active ingredient.

[0029] Furthermore, the pharmaceutical preparation also includes pharmaceutically acceptable excipients.

[0030] Furthermore, the excipients include at least one of the following: diluent, binder, wetting agent, lubricant, disintegrant, solvent, emulsifier, cosolvent, preservative, pH adjuster, osmotic pressure adjuster, surfactant, coating material, antioxidant, or buffer.

[0031] Furthermore, the pharmaceutical formulation includes clinically acceptable oral, injectable, or inhaled formulations.

[0032] Furthermore, the dosage form of the pharmaceutical preparation is one of the following: suspension, granules, capsules, powder, tablets, pills, injections, suppositories, aerosols, or drops.

[0033] Furthermore, the drug preparation is administered via one of the following routes: intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration, or nebulized administration.

[0034] For the preparation of pharmaceutical formulations suitable for this invention, a pharmaceutically acceptable carrier may be a solid or a liquid.

[0035] Solid dosage forms include powders, tablets, tablets, capsules, flat capsules, and dispersible granules. Solid carriers can be one or more substances that also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is a finely divided solid that is mixed with a finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier possessing the necessary binding properties in an appropriate proportion and compressed into the desired shape and size. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc.

[0036] Liquid formulations include solutions, suspensions, and emulsions, such as aqueous solutions or water-propylene glycol solutions. For example, parenteral liquid formulations can be formulated as water-polyethylene glycol solutions.

[0037] Therefore, the medicaments used in this invention can be formulated into preparations for parenteral administration (e.g., injection, such as rapid concentration or continuous infusion), and can be present in unit doses in ampoules, pre-filled syringes, small-volume infusion bags, or multi-dose containers together with added preservatives. The composition can be in the form of suspensions, solutions, or emulsions with oily or aqueous carriers, and may contain formulation components such as suspending agents, stabilizers, and / or dispersants. Additionally, the active ingredient can be in powder form, obtained by aseptic separation of sterile solids or by lyophilization of solutions, for reconstitution with a suitable carrier, such as sterile, pyrogen-free water, immediately before use.

[0038] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the desired colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions suitable for oral administration can be prepared by dispersing finely divided active ingredients in water containing a viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

[0039] This also includes solid dosage forms designed to be converted into liquid formulations for oral administration shortly before market launch. These liquid formulations include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0040] Inhalational administration can also be achieved via aerosols, in which the active ingredient is packaged with a suitable propellant in a pressurized container. Suitable propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. Aerosols may also contain surfactants, such as lecithin, as appropriate. The dosage of the drug can be controlled via a dispensing valve.

[0041] Alternatively, the active ingredient can be in the form of a dry powder, such as astaxanthin mixed with a suitable powder matrix such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). The powder carrier can easily form a gel in the nasal cavity. The powder composition can be present in unit dose form, for example, in capsules or cartridges (such as gelatin sheets or cartridges), or in blister packs in which the powder can be administered via an inhaler.

[0042] Alternatively, compositions suitable for sustained release of active ingredients can be applied when needed.

[0043] Compared with existing technologies, the astaxanthin described in this invention has the following advantages in the preparation of drugs for the prevention and treatment of aortic dissection:

[0044] (1) The present invention found that astaxanthin can significantly reduce the mortality rate of mice with aortic dissection, improve the survival rate of mice, and reduce the degree of aortic arch dilation and vascular diameter; inhibit the occurrence of aortic dissection and the cavity and rupture of the aortic media structure, thus providing a new potential therapeutic drug for the treatment of aortic dissection.

[0045] (2) Through the study of the pharmacological effects of astaxanthin, this invention has discovered and verified the use of astaxanthin in the prevention and treatment of acute aortic dissection. Astaxanthin has a significant effect in improving acute aortic dissection, providing a solid pharmacodynamic basis for new clinical research and application of this drug. After systematic development, it has a broad market prospect and also provides an example for the medicinal route of classic health products and the "new use of old drugs".

[0046] (3) This invention not only established a mature animal disease model of acute aortic dissection, providing a solid foundation for subsequent drug development, but also, based on the established animal disease model, discovered and verified that astaxanthin plays a therapeutic and preventive role in improving the prognosis of acute aortic dissection. Attached Figure Description

[0047] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0048] Figure 1 A schematic diagram illustrating the principle of drug intervention in each group of mice;

[0049] Figure 2 This is a schematic diagram of the survival curves for each group of mice;

[0050] Figure 3 A schematic diagram showing the incidence of aortic dissection in each group of mice;

[0051] Figure 4A representative macroscopic diagram of the aorta of each group of mice;

[0052] Figure 5 The diagram shows the statistical results of aortic ultrasound diameter in each group of mice. From left to right, they are the control group (CK), BAPN group, low-dose astaxanthin prevention group (Ast-Pre-LD), and high-dose astaxanthin prevention group (Ast-Pre-HD).

[0053] Figure 6 A schematic diagram showing the Masson, EVG, and AB staining results of the aorta of mice in each group;

[0054] Figure 7 This diagram illustrates the gene expression of systolic and synthetic smooth muscle cells in the aorta of mice in each group. Detailed Implementation

[0055] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0056] Raw material sources: BAPN (β-aminopropionitrile) was purchased from Sigma-Aldrich, A3134, and all-trans-L-astaxanthin was purchased from Sigma-Aldrich, 41659.

[0057] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0058] This invention establishes a recognized animal model of acute aortic dissection, specifically by feeding C57BL / 6J mice with β-aminopropionitrile for 4 weeks. This induces the destruction of cross-linking of elastic fibers in the aortic wall, leading to aortic dissection formation. The model simulates clinical acute aortic dissection injury. The successful establishment of the model was verified through multiple indicators, including gross pathological morphology of the aorta and pathological staining of lesion sections. This model can be used to verify the efficacy of astaxanthin. The specific methods are as follows:

[0059] 1. Experimental Methods

[0060] All animal experiments were conducted in accordance with the guidelines for the use and care of laboratory animals and were approved by the Ethics Committee of China Agricultural University.

[0061] Three-week-old male C57Bl / 6J mice (purchased from Spiford Beijing Biotechnology Co., Ltd.) were randomly divided into four groups (n=12 per group):

[0062] (1) Control group (CK): The mice were fed normal diet for 22 consecutive days. After the first mouse in the BAPN group died due to aortic rupture, each mouse was given 100uL of physiological saline by gavage every day.

[0063] (2) BAPN group: The aortic dissection model was established by feeding the mice with a diet containing 0.4% BAPN for 22 consecutive days, and each mouse was given 100 uL of physiological saline by gavage every day.

[0064] (3) Astaxanthin prevention low-dose group (Ast-Pre-LD): The aortic dissection model was established by feeding mice with a diet containing 0.4% BAPN for 22 consecutive days. At the same time, each mouse was given 25 mg / kg astaxanthin dissolved in 100 uL of physiological saline by gavage.

[0065] (4) Astaxanthin prevention high-dose group (Ast-Pre-HD): The aortic dissection model was established by feeding mice with a diet containing 0.4% BAPN for 22 consecutive days. At the same time, 100 mg / kg astaxanthin was dissolved in 100 uL of physiological saline and administered to each mouse by gavage daily.

[0066] All groups were treated for 22 days. During this period, mouse weight and mortality were recorded. After treatment, the vascular diameter of the mice was measured, and the formation of aortic dissection was observed after dissection. The incidence rate was also recorded. Mice were sacrificed on day 22. The timeline of model establishment and drug intervention is as follows: Figure 1 As shown.

[0067] 2. Experimental Results

[0068] Data processing was performed using SPSS 13.0 software. Statistical results are expressed as mean ± standard error (±SEM). Differences between two groups were analyzed using t-tests. When comparing multiple groups, ANOVA was used, and Bonferroni tests were employed for further analysis and validation. A p-value < 0.05 was considered statistically significant. * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001.

[0069] according to Figure 2 The results showed that, compared with the BAPN group, the survival rate of mice in the astaxanthin prevention group was significantly improved, proving that astaxanthin can reduce the mortality rate of aortic dissection in mice and has a dose-response effect. Figure 3 The results showed that on day 22, the mortality rate (aortic dissection rupture) of mice in the BAPN group was as high as 75%, and the morbidity rate (the percentage of mice with morbidity other than death) was 25%. In contrast, the mortality rate of the low-dose astaxanthin prevention group was 33%, the morbidity rate was 17%, and the health rate was 50%. The mortality rate of the high-dose astaxanthin prevention group was 0%, the morbidity rate was 17%, and the health rate was 83%. This indicates that astaxanthin has a significant effect on the prevention and treatment of aortic dissection.

[0070] according to Figure 4The representative macroscopic results of the aorta in mice of each group on day 22 showed that the BAPN group mice developed severe aortic dissection. The different astaxanthin prevention groups also developed aortic dissection, but the symptoms were significantly reduced compared to the BAPN group. Moreover, the high-dose astaxanthin prevention group had a better overall effect.

[0071] according to Figure 5 On day 22, ultrasound results of the aortic rings in mice from each group showed that, compared with the control group (A), the BAPN group (B) developed severe aortic dissection. Different astaxanthin groups (C, D) also developed aortic dissection, but the symptoms were significantly less severe compared to the BAPN group. The aortic width (maximum diameter) of the control group mice was 1.308 mm, while that of the BAPN group mice was 1.771 mm. Compared with the control group, the aortic width of the BAPN group mice was significantly increased. The aortic width of the low-dose astaxanthin prevention group mice was 1.425 mm, and that of the high-dose astaxanthin prevention group mice was 1.328 mm, showing relatively small changes compared to the control group. This demonstrates that astaxanthin can reduce aortic diameter. Furthermore, statistical analysis showed that the change in aortic width in the high-dose astaxanthin prevention group was smaller than that in the low-dose group, indicating a dose-dependent preventive effect of astaxanthin.

[0072] The occurrence of aortic dissection is closely related to the disruption of the structural integrity of the aortic wall's media. Elastic fibers in the media, the core component that gives blood vessels elasticity, become rigid and lose their buffering capacity when degraded or broken, forming the initial pathological basis for dissection. Collagen, as a tensile element, weakens the ultimate strength of the blood vessel if its synthesis is defective or its compensation is unbalanced, failing to prevent tearing and its propagation. Simultaneously, abnormal accumulation of glycosaminoglycans disrupts the lamellar structure of the media, forming hydrated, vulnerable areas, further reducing the tissue's mechanical strength. The successive imbalances in the functions of these three components collectively make the media prone to tearing under blood flow impact, ultimately leading to aortic dissection. Figure 6 The results showed that, compared with the BAPN group, the astaxanthin group had reduced elastic fiber rupture, collagen deposition, and glycosaminoglycan accumulation in the aortic neutral lamina. The high-dose group showed a more significant reduction than the low-dose group. Therefore, further histopathological analysis proved that astaxanthin treatment can inhibit the occurrence of aortic dissection.

[0073] according to Figure 7The results showed that, compared with the control group (CK), the expression of BAPN combinatorial genes Col5A1, Col1A1, Fn1, and Cxcl2 was increased, while the expression of contractile genes Myh11, Myl9, Acta2, and Cnn1 was decreased. Compared with the BAPN group, astaxanthin intervention altered the expression levels of phenotypic transformation genes in mouse aortic smooth muscle cells. Specifically, the expression of combinatorial genes Col5A1, Col1A1, Fn1, and Cxcl2 was decreased, while the expression of contractile genes Myh11, Myl9, Acta2, and Cnn1 was increased. Furthermore, the expression levels of these genes in the high-dose prevention group were closer to those in the low-dose prevention group than in the control group, thus influencing the occurrence and progression of aortic dissection.

[0074] The above results demonstrate that astaxanthin intervention significantly reduced the incidence and mortality of aortic dissection in mice, alleviated the dilation of the aortic diameter, and significantly inhibited the formation of aortic dissection in mice, providing a new potential therapeutic drug for the prevention and treatment of aortic dissection.

[0075] The embodiments described above are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

Claims

1. The application of astaxanthin as the sole active ingredient in the preparation of drugs for the prevention and / or treatment of aortic dissection.

2. Use according to claim 1, characterized in that: The astaxanthin is all-trans-L-astaxanthin, and its structural formula is shown in Formula I: 。 3. The application according to claim 1, characterized in that: The aortic dissection includes acute aortic dissection or repair aortic dissection.

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