Application of PCI-34051 in preparation of medicine for treating or preventing aortic dissection

Abstract

The invention discloses an application of PCI-34051 in preparation of a medicine for treating or preventing aortic dissection, and finds that a mouse aortic dissection model induced by BAPN through intraperitoneal injection of PCI-34051 can significantly reduce the occurrence rate of aortic dissection / dilatation (the decreasing amplitude is greater than or equal to 30%) and can relieve pathological damage of a vascular wall. The invention discloses the protection effect of the PCI-34051 on the aortic dissection induced by the BAPN for the first time, and shows that the PCI-34051 can be used as a potential medicine for preventing or treating the aortic dissection.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to the application of PCI-34051 in the preparation of a medicament for treating or preventing aortic dissection. Background Art

[0002] Aortic dissection refers to the tearing of the aortic intima, with blood flowing through the tear into the aortic wall, causing the media to separate from the adventitia and thus forming a false lumen attached to the vessel wall. The main pathological features of aortic dissection are the degradation of the vascular matrix and the rupture of the elastic fiber layer. Its etiological factors are divided into genetic factors such as mutations in matrix metalloproteinase Fibrillin 1, smooth muscle actin MYH11, and TGF signal TGFβR1 / 2, as well as environmental factors such as atherosclerosis, hypertension, smoking, and metabolism. Multiple pathogenic factors such as increased matrix degradation, especially the up-regulation of matrix metalloproteinases 2 / 9; chronic inflammation; oxidative stress; apoptosis of smooth muscle cells and the dedifferentiation of smooth muscle cells are all involved in the occurrence of aortic dissection. Clinically used drugs for the treatment of aortic dissection, such as β-blockers, angiotensin-converting enzyme inhibitors, and calcium channel antagonists, have uncertain curative effects. A large number of clinical studies have shown that these first-line drugs cannot improve the incidence of vascular complications and the long-term survival rate of aortic dissection patients. Currently, a considerable number of aortic dissection patients in China cannot receive timely and effective diagnosis and treatment, which may lead to the occurrence of various complications, such as acute pericardial tamponade, acute myocardial infarction, stroke, ischemia of abdominal organs, etc., and in more severe cases, it may endanger life.

[0003] Therefore, there is an urgent need to develop a new and effective medicament for treating or preventing aortic dissection. Summary of the Invention

[0004] The object of the present invention is to provide the application of PCI-34051 in the preparation of a medicament for treating or preventing aortic dissection.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] The present invention provides the application of PCI-34051 in the preparation of a medicament for treating or preventing aortic dissection, and the structural formula of the PCI-34051 is shown as follows:

[0007]

[0008] Specifically, it is manifested in the application of PCI-34051 in the preparation of a medicament for inhibiting β-aminopropionitrile-induced aortic dissection in mice.

[0009] The PCI-34051 in the embodiment of the present invention is an inhibitor of the HDAC8 protein and can be purchased from Selleck, product number: S2012.

[0010] Further, the drug for treating or preventing aortic dissection further comprises a pharmaceutically acceptable excipient.

[0011] Further, the excipient comprises at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetening agent or a coloring agent.

[0012] Further, the dosage form of the drug comprises at least one of a granule, a tablet, a pill, a capsule, an injection or a dispersant.

[0013] Further, the dosage of PCI-34051 in the drug is 30 mg / kg / day.

[0014] Further, PCI-34051 in the drug is used as the main active ingredient of the drug.

[0015] Further, PCI-34051 in the drug is used as the sole active ingredient of the drug.

[0016] In a second aspect of the present invention, there is provided a pharmaceutical composition, which comprises PCI-34051.

[0017] Further, the pharmaceutical composition further comprises a pharmaceutical carrier.

[0018] Further, the pharmaceutical carrier comprises dimethyl sulfoxide, physiological saline, phosphate buffer solution, or an injection solution containing a stabilizer.

[0019] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0020] The present invention provides an application of PCI-34051 in the preparation of a drug for treating or preventing aortic dissection. The present invention discovers that intraperitoneal injection of PCI-34051 to a BAPN-induced mouse aortic dissection model can significantly reduce the incidence rate of aortic dissection / dilatation (the reduction rate is ≥ 30%). The present invention for the first time reveals the protective effect of PCI-34051 on BAPN-induced aortic dissection, and proposes a new indication for PCI-34051: primary prevention of aortic dissection and its complications. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0022] Figure 1 Results of the incidence of aortic dissection / dilatation.

[0023] Figure 2 Results verified by pathology, where Figure A shows the results of aortic morphological changes, Figure B shows hematoxylin-eosin (HE) staining, and Figure C shows Verhoeff's Van Gieson (EVG) elastic fiber staining. Detailed implementation manners

[0024] The present invention will be specifically described below in combination with the detailed implementation manners and examples, and the advantages and various effects of the present invention will be presented more clearly therefrom. Those skilled in the art should understand that these detailed implementation manners and examples are used to illustrate the present invention, rather than to limit the present invention.

[0025] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as having the meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In case of conflict, this specification shall prevail.

[0026] Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the present invention can be obtained through market purchase or can be obtained by existing methods.

[0027] The application of a PCI-34051 in the preparation of a drug for treating or preventing aortic dissection will be described in detail below in combination with examples and experimental data.

[0028] Example 1: PCI-34051 inhibits the β-aminopropionitrile-induced mouse aortic dissection model

[0029] 1. Experimental animals and model construction

[0030] (1) Experimental animals:

[0031] Healthy 3-week-old C57BL / 6 mice (SPF grade), weighing 8-10 g, were randomly grouped and then the experiment was started.

[0032] (2) Model construction:

[0033] β-aminopropionitrile (BAPN) drinking water intervention: BAPN (0.6%, purchased from Sigma) was added to the drinking water, and the mice were continuously fed for 4 weeks to induce aortic dissection.

[0034] BAPN formulation: "BAPN (Sigma-Aldrich, Cat#2079-89-2) was added to the drinking water at a concentration of 0.6%, accounting for 0.6% of the total weight of the drinking water."

[0035] Animal grouping: 50 mice were randomly divided into a control group (n = 29) and a PCI-34051 group (30 mg / kg, n = 21).

[0036] Drug preparation: "PCI-34051 was dissolved in DMSO (stock solution concentration 60 mg / mL). Before use, an injection solution was prepared with 5% DMSO solution + 5% Tween-80 + 40% PEG400 + 50% H2O and stored in the dark.

[0037] Control group setting:

[0038] Control group (BAPN + DMSO): BAPN was given in drinking water + intraperitoneal injection of DMSO solution (solvent control, prepared according to the above formula).

[0039] Treatment group (BAPN + PCI-34051): BAPN was given in drinking water + intraperitoneal injection of PCI-34051 solution (dissolved in DMSO, prepared according to the above formula).

[0040] 2. Drug treatment protocol

[0041] PCI-34051 dosage and administration:

[0042] Dosage: 30 mg / kg.

[0043] Administration frequency: once a day for 4 consecutive weeks.

[0044] Administration volume: calculated at 0.1 mL / 10 g body weight and given by intraperitoneal injection.

[0045] Control group treatment:

[0046] An equal volume of DMSO solution was injected intraperitoneally, and the other conditions were the same as those in the treatment group.

[0047] 3. Observation indicators and detection methods

[0048] (1) Incidence of aortic dissection / dilatation

[0049] Detection time point: The survival status of the mice was observed daily until the end of the experiment (week 4), and the aortas of all mice were obtained by dissection.

[0050] Calculate the incidence of aortic dissection / dilatation: Number of mice with aortic dissection or dilatation / Total number of mice × 100%.

[0051] Table 1

[0052] Group Occurrence number (a) Non-occurrence number (b) Total BAPN + DMSO (control group) 16 13 29 BAPN + PCI-34051 (treatment group) 5 16 21 Total 21 29 50

[0053] Table 2

[0054] Grouping Incidence rate of aortic dissection / dilatation BAPN + DMSO (control group) 55.17％ BAPN + PCI-34051 (treatment group) 23.81％

[0055] From Figure 1 the data in Table 1 - Table 2, it can be seen that: compared with the control group, the incidence of aortic dissection / dilatation in the treatment group decreased by 31.36%. The experimental data indicate that PCI - 34051 can significantly reduce the incidence of BAPN - induced aortic dissection / dilatation in mice (χ2 = 4.93, p = 0.026).

[0056] 4. Pathological verification

[0057] Tissue sample processing: Sacrifice the surviving mice, take the thoracic aorta tissue, fix it with 4% paraformaldehyde, and embed it in paraffin.

[0058] Staining analysis: HE staining: Observe the morphological changes of the aorta. EVG staining: Evaluate the degree of elastic fiber degradation.

[0059] Control group: β - alanine nitrile (BAPN) + dimethyl sulfoxide (DMSO)

[0060] Treatment group: BAPN + PCI - 34051

[0061] (1) Morphological changes of the aorta:

[0062] The results of the morphological changes of the aorta are as Figure 2 shown in A and 2B. In the control group, obvious aortic dissection was observed (media tear, hematoma formation). In the treatment group, the incidence of dissection decreased and the integrity of the vascular wall improved.

[0063] (2) EVG staining analysis (elastic fiber specific staining)

[0064] The results of EVG staining analysis are as Figure 2 shown in C. In the control group, elastic fibers were fragmented, while in the treatment group, the continuity of elastic fibers was restored and the degree of degradation decreased.

[0065] In summary, it can be known that PCI - 34051 can significantly reduce the incidence of BAPN - induced aortic dissection / dilatation in mice, and PCI - 34051 can alleviate the pathological damage of the vascular wall. It indicates that PCI - 34051 can be used as a potential drug for the prevention or treatment of aortic dissection and has great application prospects.

[0066] Finally, it should also be noted that the term "including", "comprising" or any other variant thereof is intended to cover non - exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device.

[0067] Although the preferred embodiments of the present invention have been described, additional changes and modifications can be made by those skilled in the art once they learn of the basic inventive concept. Therefore, the appended claims are intended to be construed to include the preferred embodiments as well as all changes and modifications that fall within the scope of the present invention.

[0068] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. Use of PCI-34051 in the preparation of a medicament for treating or preventing aortic dissection, characterized in that: The structural formula of the PCI-34051 is shown below:

2. The use according to claim 1, characterized in that: The medicament for treating or preventing aortic dissection also includes pharmaceutically acceptable excipients.

3. The use according to claim 1, characterized in that: The dosage form of the drug for treating or preventing aortic dissection includes at least one of granules, tablets, pills, capsules, injections and dispersions.

4. The use according to claim 1, characterized in that: The dosage of PCI-34051 in the drug for treating or preventing aortic dissection is 30 mg / kg / day.

5. The use according to any one of claims 1 to 4, characterized in that: In the drug, PCI-34051 is used as the main active ingredient of the drug.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition includes PCI-34051.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition also includes a pharmaceutical carrier.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical carrier comprises one of dimethyl sulfoxide, physiological saline, phosphate buffer, and an injection containing a stabilizer.

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