Application of PF-543 and its derivatives in the preparation of formulations for treating aortic dissection

Abstract

This invention belongs to the field of biomedical technology, specifically relating to the application of PF-543 and its derivatives in the preparation of agents for treating aortic dissection. This invention discovers that PF-543 can effectively reduce macrophage-mediated inflammatory damage by specifically inhibiting the function of SPHK1 in aortic dissection macrophages, significantly reducing the incidence of aortic dissection (AD) and its associated rupture mortality in animal experiments. The results of this invention confirm that PF-543, by targeting and inhibiting acute-phase inflammatory damage, has the potential to delay the progression of AD and reduce the risk of aortic rupture.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of PF-543 and its derivatives in the preparation of a formulation for treating aortic dissection. Background Technology

[0002] Aortic dissection (AD) is a rapidly progressing and extremely deadly vascular surgical condition, and the most common type of acute aortic syndrome. Its pathological basis is a tear in the aortic intima, allowing blood to flow into the arterial wall media, forming a dissecting hematoma and causing detachment of the vessel wall. As the dissection extends, it can lead to catastrophic complications such as aortic rupture, cardiac tamponade, and poor organ perfusion, severely threatening the patient's life.

[0003] Currently, while surgery is the primary treatment for aortic dissection, especially Stanford type A dissection, the overall prognosis remains unfavorable. The root cause lies in the fact that the exact molecular pathogenesis of aortic dissection is not fully understood, resulting in a lack of safe and effective targeted therapies for its key pathological processes. Existing drugs used to treat aortic dissection mainly fall into the following categories: 1) analgesics / sedatives such as morphine and pethidine; 2) antihypertensive drugs such as sodium nitroprusside and urapidil; 3) beta-blockers such as metoprolol and esmolol. While these drugs can alleviate aortic dissection to some extent, their efficacy is unsatisfactory. Therefore, providing a new strategy for treating aortic dissection is of great clinical significance and urgently needed. Summary of the Invention

[0004] The purpose of this invention is to provide an application of PF-543 and its derivatives in the preparation of formulations for treating aortic dissection, thereby solving the problems existing in the prior art.

[0005] The technical solution adopted in this invention is: This invention provides the application of PF-543 and its derivatives in the preparation of formulations for treating aortic dissection.

[0006] Preferably, the derivative is a citrate of PF-543.

[0007] Preferably, the aortic dissection treatment formulation uses PF-543 or a PF-543 derivative as the sole active ingredient.

[0008] Preferably, the dosage form of the aortic dissection treatment is an injectable formulation.

[0009] Preferably, the formulation of the aortic dissection treatment agent is as follows: Dissolve PF-543 or a PF-543 derivative in physiological saline and mix well to obtain a solution with a concentration of 0.2 mg / mL, which is the aortic dissection preparation.

[0010] Preferably, the aortic dissection formulation further includes pharmaceutically acceptable excipients.

[0011] Preferably, the pharmaceutically acceptable excipient is one or more of the following: diluent, dispersant, suspending agent, isotonic agent, preservative, and stabilizer.

[0012] Preferably, the diluent includes at least one of sterile water for injection, physiological saline, and glucose injection.

[0013] Preferably, the dispersant comprises at least one of polysorbate 80, mannitol, and polyvinylpyrrolidone K30.

[0014] Preferably, the suspending agent includes at least one of gelatin, sodium carboxymethyl cellulose, and mannitol.

[0015] Preferably, the isotonic agent includes at least one of sodium chloride, glucose, and mannitol.

[0016] Preferably, the preservative includes at least one of benzyl alcohol and sodium metabisulfite.

[0017] Preferably, the stabilizer includes at least one of sucrose, mannitol, and glycerol.

[0018] Preferably, the treatment of aortic dissection refers to at least one of the following: 1) Reduce the degree of elastin breakage; 2) Reduce the level of inflammatory factors; 3) Reduce the level of matrix metalloproteinases.

[0019] Preferably, the inflammatory factor is IL-1β and / or IL-6; The matrix metalloproteinases are MMP2 and MMP9.

[0020] Compared with the prior art, the beneficial effects of the present invention are: This invention provides the application of PF-543 and its derivatives in the preparation of agents for treating aortic dissection. This invention discovers that PF-543 can effectively reduce macrophage-mediated inflammatory damage by specifically inhibiting the function of SPHK1 in aortic dissection macrophages, significantly reducing the incidence of aortic dissection (AD) and its associated rupture mortality in animal experiments. The results of this invention confirm that PF-543, by targeting and inhibiting acute-phase inflammatory damage, has the potential to delay the progression of AD and reduce the risk of aortic rupture.

[0021] This invention provides a new strategy for drug treatment of Alzheimer's disease (AD): for low-risk AD patients, surgery may be avoided through drug control; for medium- and high-risk patients, it can buy valuable time for safe transfer to the surgical center or adequate preoperative preparation. Attached Figure Description

[0022] Figure 1 PF-543 was used to reduce aortic dilatation in AD mice. A: Schematic diagram of the drug treatment process, 20 mice per group, treatment lasted for 28 days. B: Changes in mouse body weight during drug treatment. C: Aortic ultrasound image. Scale bar, 1 mm.

[0023] Figure 2 PF-543 was used to reduce the incidence of aortic atrial rupture (AD) and the aortic rupture rate in mice. A: Kaplan-Meier survival curves showing survival rates. B: Macroscopic representative photographs of the aorta; the image in the upper right corner of the BAPN+saline group is a magnified view showing aortic dilation, rupture, and intramural edema. Scale bar = 5 mm. C: Proportion of mice with different degrees of injury in each group. D: Incidence of AD. E: Aortic rupture rate.

[0024] Figure 3 To illustrate the role of PF-543 in inhibiting BAPN-induced aortic dissection. A: Representative image of aortic sections stained with H&E, scale bar, 50 μm. B: Representative image of aortic sections stained with EVG, scale bar, 50 μm. C: Quantitative data on aortic elastin breakage. Independent samples t-tests were used to compare differences between groups across multiple assays. Error bars represent standard deviation (SD). * P <0.05, *** p <0.001.

[0025] Figure 4 CD68 in normal aorta and dissected tissue of mice + SPHK1 + Detection of regional matrix metalloproteinases. A: CD68 in mouse aortic tissue. + SPHK1 + Regional MMP2 expression levels. B: CD68 in mouse aortic tissue. + SPHK1 + Regional MMP9 expression levels. Scale bar, 20 μm.

[0026] Figure 5 To detect the level of matrix metalloproteinases in mouse aortic tissue by immunohistochemistry.

[0027] Figure 6 This study aims to analyze the immunoreactivity scores and correlations of matrix metalloproteinases based on immunohistochemical staining.

[0028] A: Immunohistochemical staining-based MMP2 immune response score.

[0029] B: Immunohistochemical staining-based MMP9 immune response score.

[0030] C: Correlation analysis between SPHK1 immune response score and MMP2 immune response score.

[0031] D: Correlation analysis between SPHK1 immune response score and MMP9 immune response score.

[0032] Figure 7 To validate the effect of SPHK1 inhibitors on matrix metalloproteinases and inflammatory factors in mouse AD tissue at the mRNA level. A-D represent the expression levels of MMP2, MMP9, IL-1β, and IL-6 in different groups of mice, respectively. E-H represent the correlation analysis between SPHK1 and MMP2, MMP9, IL-1β, and IL-6 in mouse AD tissue, respectively.

[0033] Figure 8 The effects of SPHK1 inhibitors on matrix metalloproteinase levels in mouse aplastic syndrome (AD) tissues and peripheral blood inflammatory cytokines were detected by Western blotting (WB) and ELISA. A and B represent the relative protein expression levels of MMP9 and MMP2 in different groups of mice, respectively. C and D represent the expression levels of IL-1β and IL-6 in different groups of mice, respectively. Independent samples t-tests were used to compare differences between groups in multiple assays. Error bars represent standard deviation (SD), *P<0.05, **P<0.01, ***P<0.001.

[0034] Figure 9 The effect of SPHK1 inhibitors on the expression levels of different S1PR subtypes in mouse AD tissues. A~E represent S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5, respectively.

[0035] Figure 10 Correlation analysis of SPHK1 with S1PR2 and S1PR3 respectively. A: Correlation analysis of SPHK1 with S1PR3; B: Correlation analysis of SPHK1 with S1PR2.

[0036] Figure 11 The effect of SPHK1 inhibitor on the expression levels of RhoA and ROCK1 in mouse AD tissues. A: Western blot results; B: Statistical results of relative RhoA protein expression level; C: Statistical results of relative ROCK1 protein expression level. Error bars represent SD. Compared with the control group, * P <0.05.

[0037] Figure 12This is a schematic diagram illustrating the research results of the present invention.

[0038] Figure 13 For safety verification. A-C represent: systolic blood pressure, diastolic blood pressure, and heart rate of the two groups of mice; unpaired Student's t-test was used, and ns indicates no significant difference. D: Changes in mouse body weight. E: H&E staining of each group, scale bar 50 μm. Detailed Implementation

[0039] The present invention will be further illustrated below with specific embodiments, but these embodiments do not limit the scope of the invention. Modifications or substitutions to the details and form of the technical solutions of the present invention may be made without departing from the spirit and scope of the invention, but all such modifications or substitutions fall within the protection scope of the present invention.

[0040] The inventive concept of this invention is as follows: Inflammatory cell infiltration leading to arterial wall inflammation, extracellular matrix degradation, elastic fiber damage, and increased arterial wall fragility is considered a major factor in the pathogenesis of aortic atrophy (AD). Macrophages constitute a large proportion of the infiltrating inflammatory cells and are the most important inflammatory cells. Macrophages exhibit functional heterogeneity. In the acute phase of AD, macrophages significantly infiltrate at intimal tears and hematomas, clearing necrotic material from sites of vascular injury and secreting various cytokines and matrix metalloproteinases, causing aortic wall inflammation and extracellular matrix degradation, thus participating in the development of AD. In the subacute and chronic phases, macrophages primarily exhibit inhibitory inflammatory responses and tissue repair characteristics. The specific mechanisms regulating macrophage inflammatory responses during AD development require further investigation. Sphingosine kinase is an important kinase in sphingolipid metabolism. In macrophages, it can phosphorylate sphingosine to produce the biologically active lipid mediator sphingosine-1-phosphate. Through autocrine and paracrine mechanisms, sphingosine binds to the S1P receptor on the cell surface, activating receptor-related downstream signaling pathways and influencing macrophage inflammatory responses. Therefore, this invention studies the key genes and their mechanisms of action in the sphingolipid metabolism pathway that regulate the inflammatory response of macrophages and cause vascular damage leading to the development of AD, providing a theoretical reference for subsequent drug target research.

[0041] To enable those skilled in the art to better understand and implement the technical solutions of this invention, the invention will be further described below with reference to specific embodiments. In the description of this invention, unless otherwise specified, all reagents used are commercially available, and all methods used are conventional techniques in the art.

[0042] The list of abbreviations for this invention is shown in Table 1.

[0043] Table 1. List of abbreviations for this invention Example 1 The applications of PF-543 and its derivatives in the preparation of formulations for treating aortic dissection are as follows: 1. Experimental materials and methods.

[0044] 1.1 Experimental materials.

[0045] PF-543: The PF-543 used in this invention is PF-543 Citrate, CAS 1415562-83-2, purchased from MedChemExpress, catalog number HY-15425A. For ease of description, PF-543 Citrate in this invention will be referred to as PF-543.

[0046] BAPN: The BAPN used in this invention was purchased from MedChemExpress, catalog number HY-Y1750.

[0047] 1.2 Experimental methods.

[0048] Preparation of PF-543 injection: Dilute PF-543 Citrate with physiological saline to 0.2 mg / mL.

[0049] Male C57BL / 6 mice were randomly divided into three groups: control group, BAPN + saline group, and BAPN + PF-543 group. The grouping is shown in Table 2.

[0050] Table 2 Grouping of C57BL / 6 mice BAPN+PF-543 group: Mice were given dissolved BAPN in their drinking water at a dose of 1 g / kg for 28 days starting at 3 weeks of age to induce an AD model. At the same time, PF-543 was injected intraperitoneally at a dose of 10 mg / kg for a total of 5 injections, on days 1, 5, 10, 15 and 20 of the modeling process.

[0051] BAPN + saline group: Mice were given dissolved BAPN in their drinking water at a dose of 1 g / kg for 28 days starting at 3 weeks of age to induce an AD model. At the same time, they were injected intraperitoneally with saline, and the amount of saline injected was the same as that of PF-543 injected in the BAPN + PF-543 group.

[0052] Control group: Mice were fed normally and started receiving intraperitoneal injections of saline from 3 weeks of age. The amount of saline injected was the same as that injected into the BAPN+PF-543 group.

[0053] Throughout the entire process, the weight of the mice was recorded. If any mice died during the treatment, an autopsy was performed immediately to confirm whether the model was successful, whether they died from aortic rupture, and the survival time was recorded.

[0054] 2. Results and Analysis.

[0055] 2.1. The proportion of pro-inflammatory macrophages in human AD tissues is increased and their expression is high. SPHK1 Gene.

[0056] (1) scRNA-seq analysis showed that the proportion of macrophages in human AD tissue was significantly increased.

[0057] scRNA-seq analysis revealed significant inflammatory cell infiltration in the aorta of human aortic lesions compared to normal aortic tissue, with an increased proportion of macrophages and a decreased proportion of T cells and B cells. Compared to other cell types, differentially expressed genes in inflammatory cells were primarily enriched in pathways related to cell adhesion, leukocyte activation, and leukocyte proliferation. Classification of inflammatory cells showed a significantly increased proportion of macrophages, while T cells, B cells, and dendritic cells were reduced.

[0058] (2) Pro-inflammatory subclusters of macrophages increase significantly and are enriched in inflammatory response pathways during AD development.

[0059] Macrophages were dimensionality-reduced into six subclusters, and the main functions of each subcluster were analyzed based on gene set variations. Subcluster a exhibited a marked pro-inflammatory phenotype. Pseudo-time series analysis showed that subcluster a significantly increased in different AD cases during progression. Compared with other subclusters and normal tissues, the intersection of differentially expressed genes in macrophage subcluster a was mainly enriched in inflammation-related pathways such as TNF, IL-17, and NF-κB.

[0060] (3) Integrate scRNA-seq and GEO data to screen and obtain key genes highly expressed in pro-inflammatory macrophage subclusters. SPHK1 .

[0061] The Venn diagram integrates differentially expressed genes from GSE153434 and GSE52093, as well as core node genes differentially expressed in macrophage subclusters a, suggesting... SPHK1 It may be a key gene regulating the pro-inflammatory response of macrophage subclusters a.

[0062] 2.2. Inflammatory damage and extracellular matrix destruction in human AD tissues are significantly positively correlated with SPHK1 expression levels: macrophage infiltration and increased matrix metalloproteinase expression in SPHK1-positive areas of human AD tissues.

[0063] Immunohistochemical analysis revealed that, compared with normal aortic tissue, human AD aortic tissue showed significant macrophage infiltration, consistent with the results of scRNA-seq analysis.

[0064] In CD68 + SPHK1 + In the expression region, MMP2 and MMP9 expression was elevated, and extracellular matrix disruption and elastic fiber breakage were significant. Correlation analysis showed that SPHK1 levels were positively correlated with MMP2 and MMP9 levels.

[0065] 2.3 Inhibition of SPHK1 reduced aortic inflammatory damage and decreased the incidence and development of AD in mice.

[0066] (1) Inhibition of SPHK1 slowed down aortic dilation.

[0067] Key genes of macrophage subcluster a SPHK1 Promoting inflammatory responses, this invention demonstrates that intervention... SPHK1 To slow the progression of Alzheimer's disease (AD), the following measures are taken: This invention uses PF-543 to block the action of SPHK1 in a BAPN-induced AD mouse model, the process of which is described in [link to documentation]. Figure 1 A. During the 4-week drug treatment period, no significant differences in mouse body weight were observed among the control group, the BAPN + saline group, and the BAPN + PF-543 group. Figure 1 B. Vascular ultrasound images on day 21 post-modeling showed that PF-543 reduced BAPN-induced aortic dilation compared to the BAPN + saline group (see [reference needed]). Figure 1 C.

[0068] (2) Inhibition of SPHK1 reduced the incidence and mortality of AD.

[0069] Survival analysis showed that the survival time of the BAPN + PF-543 group was significantly longer compared with that of the BAPN + saline group. Figure 2 The A; PF-543 reduces the cumulative range of AD, see Figure 2 B.

[0070] In the control group, no aortic aspiration (AD) or mortality was observed. In the BAPN + saline group, 15 out of 20 mice successfully developed AD, with an AD incidence rate of 75%, of which 10 mice died due to aortic rupture. In the BAPN + PF-543 group, 8 out of 20 mice successfully developed AD, with an AD incidence rate of 40%, of which 3 mice died due to aortic rupture. This indicates that PF-543 can significantly reduce the incidence of AD and mortality from aortic rupture in mice. Figure 2 C~E.

[0071] (3) Inhibiting SPHK1 reduces aortic wall and elastin rupture.

[0072] To observe pathological changes in the mouse aorta, H&E staining and EVG staining were used. Results showed that the aorta of mice in the BAPN + saline group exhibited a large false lumen, thickened tunica media, and significant inflammatory infiltration at the lesion site. In the BAPN + PF-543 group, intramural hematoma was reduced, and the tunica media thickness was less than that in the BAPN + saline group. (See attached figures). Figure 3 In mice in groups A and B, the BAPN+saline group showed elastin disorder, with significantly higher levels of elastin breakage compared to the BAPN+PF-543 group. (See A and B). Figure 3 C.

[0073] The above results indicate that PF-543 can effectively inhibit aortic wall damage and reduce the formation and development of aortic aortic lesions (AD).

[0074] (4) CD68 in mouse aortic tissue + SPHK1 + High expression of matrix metalloproteinases in the region.

[0075] This invention utilizes immunofluorescence to verify CD68 in the aortic tissues of three groups of mice. + SPHK1 + Expression of regional inflammatory mediators. Results showed that SPHK1 macrophages in mouse aortic tissue expressed regional inflammatory mediators. + In the region, expression of the inflammatory mediators MMP2 and MMP9 was observed. Figure 4 .

[0076] (5) Inhibition of SPHK1 reduces the levels of inflammatory factors and MMPs in AD mice.

[0077] The above results suggest SPHK1 As a key gene in aortic dissection macrophage subclusters a, it has a pro-inflammatory function. To investigate the effect of SPHK1 inhibitors on inflammatory cell infiltration in aortic dissection, the levels of inflammatory mediators MMP2 and MMP9 in CD68-positive regions of aortic tissue were detected using IHC. The results showed that in the AD model induced by BAPN + saline, the protein levels of MMP2 and MMP9 were significantly increased; compared to the BAPN + saline group, the BAPN + PF-543 group showed a significant decrease in the number of MMP2 and MMP9-positive cells accumulated in the mesentery and intima of AD tissue, and a significant decrease in the protein levels of MMP2 and MMP9. Figure 5 and Figure 6 In the BAPN + saline group, the level of SPHK1 was significantly positively correlated with the levels of MMP2 and MMP9, see [reference needed]. Figure 6 C and D.

[0078] 2.4. Transcriptional verification: PF-543 downregulates inflammatory factors in AD.

[0079] Similarly, the transcriptional level was tested to determine whether SPHK1 inhibitors could downregulate inflammatory factors in AD. Results showed that after administration of the SPHK1 inhibitor PF-543, the expression levels of MMP2, MMP9, IL-1β, and IL-6 in the aorta of BAPN-induced mice were significantly reduced.

[0080] Next, the correlation between SPHK1 and inflammatory factor levels was analyzed in a BAPN-induced mouse AD model. In mice in the BAPN + saline group, SPHK1 expression levels were significantly positively correlated with the expression levels of IL-1β, IL-6, MMP2, and MMP9. These results are shown in [see attached table]. Figure 7 . Figure 7 For results A through D, an independent samples t-test was used to compare the differences between groups across multiple tests. The error bar represents the standard deviation (SD). * P <0.05, ** P <0.01, *** P <0.001. Figure 7 E~H, P The values ​​were analyzed using Pearson correlation analysis, when P A difference of <0.05 is statistically significant.

[0081] WB analysis can be found Figure 8 PF-543 significantly inhibited the protein levels of MMP2 and MMP9 in AD tissues of mice, as indicated by PF-543 (A and B). ELISA analysis revealed that compared with the BAPN + saline group, the levels of inflammatory factors IL-6 and IL-1β in peripheral blood plasma of mice in the BAPN + PF-543 group were significantly decreased. Figure 8 C and D.

[0082] These results suggest that SPHK1 plays an important role in the inflammatory response of Alzheimer's disease (AD), and inhibiting SPHK1 may slow the progression of AD by reducing inflammation. SPHK1 has the potential to become a therapeutic target for AD.

[0083] 2.5. RhoA / ROCK1 signaling slows down the development and progression of AD.

[0084] Subsequently, this invention examined the expression of five S1PR subtypes in mice in the control group, BAPN+saline group, and BAPN+PF-543 group.

[0085] Following treatment with the SPHK1 inhibitor PF-543, the expression levels of S1PR2 and S1PR3 in AD significantly decreased; while the expression levels of S1PR1, S1PR4, and S1PR5 showed no significant change. Figure 9Analysis of the relationship between SPHK1 expression level and S1PR2 and S1PR3 in a BAPN-induced mouse AD model revealed that SPHK1 was significantly positively correlated with both S1PR2 and S1PR3. (See attached text.) Figure 10 This indicates that SPHK1 participates in the occurrence and development of AD through S1PR2 and S1PR3. Further investigation will be conducted to verify how SPHK1 functionally regulates the downstream / RhoA / ROCK1 signaling of S1PR2 and S1PR3 in the AD model.

[0086] In in vitro experiments, intervention on macrophage SPHK1 function regulated the expression of RhoA and ROCK1 signaling downstream of S1PR. In a mouse AD model, SPHK1 function was inhibited using PF-543, and the expression of RhoA and ROCK1 in the aortic tissue of mice in the control group, BAPN + saline group, and BAPN + PF-543 group was examined. The results indicated that the expression levels of RhoA and ROCK1 in the mouse aorta were significantly decreased after using the SPHK1 inhibitor PF-543. Figure 11 This indicates that in the AD model, SPHK1 participates in the occurrence and development of AD through S1P / S1PR2 / S1PR3 / RhoA / ROCK1.

[0087] In summary, macrophage subclusters a and their key genes in AD SPHK1 Increased expression of inflammatory factors IL-1β, IL-6, and arterial wall-damaging MMP2 and MMP9 through S1P / S1PR2 / S1PR3 / RhoA / ROCK1 signaling upregulates macrophage inflammatory damage function, promotes the occurrence and development of AD; SPHK1 inhibitor PF-543 can reduce the inflammatory response, thereby improving the incidence and progression of AD.

[0088] In AD, the increase of macrophage a subclusters and their key gene SPHK1 catalyzes the conversion of sphingosine to S1P. S1P, through autocrine and paracrine processes, activates the S1P-S1PR2 / S1PR3-RhoA-ROCK1 pathway, promoting the secretion of inflammatory factors and MMPs. The secreted MMPs lead to the degradation of aortic ECM components, thereby promoting the development and progression of AD. See the full schematic diagram below. Figure 12 .

[0089] 2.6 Security verification.

[0090] Before establishing the AD model, WT mice were treated with PF-543 at a dose of 10 mg / kg for 28 consecutive days to assess its potential toxicity. During this period, all mice in the WT+saline group and the WT+PF-543 group maintained normal physiological status, including stable blood pressure and heart rate, regular food intake, active behavior, glossy fur, and normal fecal characteristics. Notably, no significant adverse effects on hemodynamics or signs of tissue damage were observed. To further assess safety, tissues from the heart, liver, spleen, kidney, and lungs were collected after 28 days for hematoxylin-eosin staining and subsequent analysis. The results showed no significant difference in body weight among the groups, and no histopathological abnormalities were observed in any of the examined organs. Figure 13 Overall, these findings suggest that PF-543 treatment does not harm the health of mice at the administered doses.

[0091] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0092] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. Application of PF-543 and its derivatives in the preparation of formulations for treating aortic dissection.

2. The application as described in claim 1, characterized in that, The derivative is the citrate of PF-543.

3. The application as described in claim 1, characterized in that, The aortic dissection treatment formulation uses PF-543 or a PF-543 derivative as the sole active ingredient.

4. The application as described in claim 3, characterized in that, The acceptable dosage form for treating aortic dissection is injection.

5. The application as described in claim 4, characterized in that, The formulation of the treatment for aortic dissection is as follows: Dissolve PF-543 or a PF-543 derivative in physiological saline and mix well to obtain a solution with a concentration of 0.2 mg / mL, which is the aortic dissection preparation.

6. The application as described in claim 5, characterized in that, The aortic dissection formulation also includes pharmaceutically acceptable excipients.

7. The application as described in claim 6, characterized in that, The pharmaceutically acceptable excipients are one or more of the following: diluents, dispersants, suspending agents, isotonic agents, preservatives, and stabilizers.

8. The application as described in claim 1, characterized in that, Treatment of aortic dissection includes at least one of the following: 1) Reduce the degree of elastin breakage; 2) Reduce the level of inflammatory factors; 3) Reduce the level of matrix metalloproteinases.

9. The application as described in claim 8, characterized in that, The inflammatory factors are IL-1β and / or IL-6; The matrix metalloproteinases are MMP2 and MMP9.

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