Alda-1 solutions, methods of making and using the same

Abstract

The application provides an Alda-1 solution, a preparation method and application thereof, the solution takes Alda-1 as an active ingredient, and takes ethanol, polyethylene glycol 400 and physiological saline as solvents, solves the problem that solubility of Alda-1 is poor and the Alda-1 cannot be applied in clinic. The Alda-1 solution can be used as an injection for intravenous injection, can well improve heart function, has good stability, high safety, no hemolysis phenomenon, and the solution has no obvious irritability to blood vessels when being diluted by physiological saline 1:1 for intravenous injection.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to Alda-1 solution, its preparation method, and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] The aldehyde dehydrogenase 2 (ALDH2) gene is located on chromosome 12q24, consisting of 13 exons and 12 introns, composed of 43,437 base pairs, encoding 517 amino acids. ALDH2 is located in mitochondria and is a tetrameric enzyme containing three domains, metabolizing various endogenous and exogenous aldehydes; it is mainly distributed in tissues such as the liver, heart, and brain. The wild-type ALDH2 gene is designated ALDH2*1, and the single-base mutation gene ALDH2*2. The ALDH2*2 mutation site is where glutamic acid at position 487 is replaced with lysine, resulting in a 60%-80% reduction in enzyme activity in the mutant heterozygous form. ALDH2 possesses dehydrogenase activity, metabolizing various aldehydes; it also possesses reductase activity, metabolizing nitroglycerin. Globally, 6% of the population carries this mutation site, with 30%-40% of the population in East Asia carrying this mutation site.

[0004] Alda-1, or N-(1,3-benzodioxacyclopenten-5-ylmethyl)-2,6-dichlorobenzamide (CAS number 349438-38-6), is a small-molecule activator of ALDH2 identified through high-throughput screening. It enhances ALDH2 activity through allosteric activation, increasing the activity of wild-type ALDH2 by 2-fold and the activity of mutant ALDH2 by 11-fold. (NAD) + Under certain conditions, Alda-1 can increase the activity of mutant ALDH2 by 100-fold. Pre-ischemic administration of Alda-1 to rats can reduce the infarct area by about 60%, improve ventricular function after acute myocardial infarction and alleviate mitochondrial dysfunction, promote acetaldehyde metabolism, reduce acetaldehyde accumulation in the body, and reduce the inactivation effect of 4-HNE on ALDH2 (Science 2008 Sep12; 321(5895)).

[0005] Acute myocardial infarction and cardiac arrest are two common and extremely dangerous cardiovascular diseases that often cause severe myocardial damage, cardiac dysfunction, and even death. Currently, there are no effective means to protect the myocardium. Alda-1 reduces acute ischemia-reperfusion injury and chronic heart failure, and reduces the area of ​​myocardial infarction by about 60%, possessing clinical translational value and drug development potential. However, clinical translation currently faces difficulties. Alda-1 is insoluble in water and has poor solubility in most organic solvents, making it unsuitable for use as an injection. The inventors have found that current solvents for dissolving Alda-1 are DMSO (dimethyl sulfoxide), PEG400 (polyethylene glycol 400), and DMF (N,N-dimethylformamide). However, DMSO and DMF are both toxic and, according to the 2015 edition of the Chinese Pharmacopoeia, cannot be used in injections or in humans. Alda-1 has poor solubility in PEG400, making its clinical application impossible. Furthermore, the physicochemical properties of Alda-1 are rarely reported in the literature, so further exploration of these properties is needed. Summary of the Invention

[0006] Therefore, the purpose of this invention is to solve the problems of low solubility of Alda-1 and the inability of existing dissolution methods to be used clinically, and to provide an Alda-1 solution, its preparation method and application. This solution can be used as an Alda-1 injection, has good solubility, high stability, and is non-irritating. It can be used for intravenous injection to prevent and / or treat acute myocardial infarction, cardiac arrest, acute ischemia-reperfusion injury and / or chronic heart failure.

[0007] Specifically, the technical solution of the present invention is as follows:

[0008] In a first aspect, the present invention provides an Alda-1 solution, wherein Alda-1 is the active ingredient and ethanol, polyethylene glycol 400 and physiological saline are used as solvents.

[0009] The Alda-1 solution described in this invention is colorless and transparent, does not precipitate within 24 hours of storage at room temperature, has a certain degree of volatility, and will not crystallize within 4 days.

[0010] In an embodiment of the present invention, the pH of the Alda-1 solution is 5-6.8.

[0011] In some embodiments of the present invention, the PEG400 described herein has a degree of polymerization n of 8.2-9.1, a molecular weight of 380-420, and a viscosity of (6.8-8.0)×10⁻⁶. -2 Pa·second (116.6K).

[0012] In an embodiment of the present invention, the volume ratio of the solvent in the Alda-1 solution is ethanol: polyethylene glycol 400: physiological saline = (3-5):(3-5):(2-4), preferably 5:(3-5):(2-4), and more preferably 5:3:(2-4).

[0013] In a preferred embodiment, the volume ratio of the solvent in the Alda-1 solution is ethanol: polyethylene glycol 400: physiological saline = 5:3:2. When the solvent is prepared in this volume ratio, the solution has higher stability and can remain clear and free of precipitation for a longer period of time, with the stability time extended by at least 3 hours.

[0014] Furthermore, in some embodiments, the inventors have found that excessively high or low amounts of ethanol, polyethylene glycol 400, and saline solution can affect the solubility of Alda-1 and the stability of the resulting solution.

[0015] In some embodiments, the present invention has also verified other combinations of solvents and their preparation ratios, but their stability is not as good as that of the solution of the present invention.

[0016] In an embodiment of the present invention, the concentration of Alda-1 is 4-10 mg / mL.

[0017] In a preferred embodiment, the concentration of Alda-1 is 10 mg / mL. At this concentration, in conjunction with the solvent ratio of the present invention, especially when the volume ratio of ethanol:polyethylene glycol 400:physiological saline is 5:3:2, the solution has relatively higher stability. The solution can remain clear and free of precipitation for a longer period of time, and the stability time can be extended by at least 3 hours. The time of crystallization is also delayed, and no crystallization occurs for at least 5 days, but partial crystallization will occur after 5 days.

[0018] In a second aspect of the invention, the invention provides a method for preparing the Alda-1 solution described in the first aspect, comprising adding ethanol to Alda-1 and sonicating it, then adding polyethylene glycol 400 and physiological saline, and mixing well to obtain the solution.

[0019] In an embodiment of the present invention, the solvent is added in the following order: ethanol, polyethylene glycol 400, and physiological saline.

[0020] In embodiments of the present invention, polyethylene glycol 400 and physiological saline can be added simultaneously or physiological saline can be added first and then polyethylene glycol. However, the stability of the solution obtained by such an order is not as good as that obtained by using ethanol, polyethylene glycol 400 and physiological saline in sequence.

[0021] In an embodiment of the present invention, the volume ratio of the solvent in the Alda-1 solution is ethanol: polyethylene glycol 400: physiological saline = (3-5):(3-5):(2-4), preferably 5:3:2; the concentration of Alda-1 is 4-10 mg / mL, preferably 10 mg / mL.

[0022] In the embodiments of the present invention, the type of solvent, the preparation method, the order of addition, and the amount of active ingredient are key factors affecting the clarity and stability of the solution. The solution prepared accordingly has good solubility and high stability.

[0023] In an embodiment of the present invention, the ultrasound can be performed by ultrasonic oscillation, for example, ultrasonic oscillation for 3-5 minutes; in an embodiment of the present invention, polyethylene glycol 400 and physiological saline are added and mixed, and the mixing method can be a conventional mixing method in the art, as long as uniform mixing can be achieved, for example.

[0024] In a third aspect, the present invention provides a pharmaceutical composition comprising the Alda-1 solution described in the first aspect above.

[0025] Furthermore, in a fourth aspect of the invention, the invention provides a pharmaceutical preparation comprising the Alda-1 solution described in the first aspect above.

[0026] In embodiments of the present invention, the pharmaceutical preparation is a solution, preferably an injection, which can be used for intravenous or intramuscular injection.

[0027] In an embodiment of the present invention, the injection solution is composed of the Alda-1 solution described in the first aspect above. When used, it is diluted 1:1 (with physiological saline). It does not irritate blood vessels or muscles, does not cause hemolysis, and is safe to use.

[0028] In order to achieve further effects, those skilled in the art can selectively add commonly used additives for injections, such as antibacterial agents, to the injection solution of the present invention through conventional experiments, without affecting the efficacy of the drug or causing toxicity or excessive stimulation.

[0029] Furthermore, based on the injection solution described in this invention, those skilled in the art may conceive of attempting to prepare it as a lyophilized agent to further improve its stability.

[0030] In a fifth aspect, the present invention also provides the use of the Alda-1 solution described in the first aspect above, or a pharmaceutical composition or pharmaceutical preparation containing the solution, in the preparation of a medicament for the prevention and / or treatment of acute myocardial infarction, cardiac arrest, acute ischemia-reperfusion injury, and / or chronic heart failure.

[0031] Furthermore, the present invention also provides the use of the Alda-1 solution described in the first aspect above, or a pharmaceutical composition or pharmaceutical preparation containing the solution, in the preparation of a medicament or reagent for upregulating the expression of Bcl2 in the heart, and / or reducing the expression of Bax in the heart, and / or reducing the expression of 4-HNE in the heart.

[0032] In a preferred embodiment of the present invention, the drug used for the prevention and / or treatment of acute myocardial infarction, cardiac arrest, acute ischemia-reperfusion injury, and / or chronic heart failure is Alda-1 injection. In embodiments of the present invention, the improvement effect of the Alda-1 injection on cardiac function was verified by ultrasound detection of cardiac function, TTC staining, and Western blot analysis. Furthermore, Alda-1 injection can upregulate the expression of Bcl2 in the heart and reduce the expression of 4-HNE in the heart.

[0033] The Alda-1 injection solution of the present invention has the following advantages:

[0034] 1. All solvents used in Alda-1 injection are suitable for intravenous injection.

[0035] 2. According to the experimental example of the present invention, mice injected with Alda-1 injection after myocardial infarction showed an improvement of cardiac function by about 15% when measured by ultrasound.

[0036] 3. According to experimental data, injecting Alda-1 into mice after myocardial infarction reduced the infarct area by approximately 15%.

[0037] 4. According to the experimental examples of the present invention, the safety of the injection solution is guaranteed. The results of the hemolytic test of the injection solution show that the injection solution does not cause obvious hemolysis. In the vascular irritation test, the injection solution has no obvious irritation to blood vessels at a 1:1 dilution (diluted with physiological saline). Attached Figure Description

[0038] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments and descriptions of this application are used to explain this application and do not constitute an undue limitation of this application. Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, wherein:

[0039] Figure 1 This is a light microscopic observation of the HE staining results in Experiment Example 1.

[0040] Figure 2 The image shows the results of HE staining observed by the naked eye in Experiment Example 1.

[0041] Figure 3The image shows the visual observation results of the hemolysis experiment in Experiment Example 2. The centrifuge tubes in the purified water group show red, while no red appears in the other groups.

[0042] Figure 4 This is a microscopic observation (200 μm) of the hemolysis experiment in Experiment Example 2.

[0043] Figure 5 The graph shows the analysis of cardiac function results detected by ultrasound in Experiment Example 3 (*P<0.05).

[0044] Figure 6 The image shows the cardiac function detected by ultrasound in Experiment Example 3.

[0045] Figure 7 The image shows the TTC staining results in Experiment Example 3.

[0046] Figure 8 This is a statistical analysis chart of the TTC staining results (infarct area) in Experiment Example 3.

[0047] Figure 9 The figures and analysis diagrams show the Western blot results (Bcl2, Bax, β-actin) from Experiment Example 3.

[0048] Figure 10 The results of the Western blot experiment (4-HNE, β-actin) in Experiment Example 3 are shown in the figure and analysis diagram. Detailed Implementation

[0049] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they shall be used in accordance with conventional methods or product instructions. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0051] Example 1: Preparation of Alda-1 Injection

[0052] Solvents: Ethanol, polyethylene glycol 400, physiological saline

[0053] Accurately weigh 20 mg of Alda-1 and add it to a clean 5 ml EP tube. Add ethanol to the EP tube and sonicate for 3 minutes. Add PEG400 and physiological saline, mix well, and sterilize. The solvent usage is shown in Table 1.

[0054] Table 1 Solvent usage

[0055] solvent ethanol Polyethylene glycol 400 physiological saline Preparation Example 1 1mL 600μL 400μL Preparation Example 2 1mL 600μL 800μL Preparation Example 3 1mL 1mL 400μL Preparation Example 4 1mL 1mL 800μL Preparation Example 5 1mL 1mL 600μL

[0056] The injection solutions prepared in Preparation Examples 1-5 were all colorless and transparent liquids with pH values ​​ranging from 5 to 6.8. The injection solutions prepared in Preparation Examples 1-5 were stored at room temperature, and their properties were observed. The results are shown in Table 2.

[0057] Table 2

[0058] change Preparation Example 1 No precipitation was observed within 30 hours of storage at room temperature, and no crystallization occurred within 5 days. Preparation Example 2 No precipitation was observed within 27 hours of storage at room temperature, and no crystallization occurred within 4.5 days. Preparation Example 3 No precipitation was observed within 24 hours of storage at room temperature, and no crystallization occurred within 4 days. Preparation Example 4 No precipitation was observed within 24 hours of storage at room temperature, and no crystallization occurred within 4 days. Preparation Example 5 No precipitation was observed within 24 hours of storage at room temperature, and no crystallization occurred within 4 days.

[0059] Safety verification and effectiveness verification experiments

[0060] Experimental Example 1: Vascular Irritation Test of Alda-1 Injection

[0061] Experimental Methods: Three healthy rabbits were used. The left ear marginal vein was injected intravenously with Alda-1 injection stock solution (from Preparation Example 1) (stock solution group), Alda-1 injection stock solution (from Preparation Example 1) diluted 1:1 with physiological saline (1:1 dilution group), or 0.9% sodium chloride injection (NS group), respectively. The injection volume was 1 mL / kg. Each rabbit served as a self-control. The right ear marginal vein was given an equal volume of 0.9% sodium chloride injection intravenously once daily for 3 consecutive days. Forty-eight hours after the last administration, the injection site was visually inspected for redness, swelling, congestion, or other irritation. The animals were then euthanized. Three 1 cm segments of the blood vessel, along with surrounding tissue, were harvested from the ear marginal vein injection point in a centripetal direction. These were fixed in 4% neutral formaldehyde solution, routinely dehydrated, embedded in paraffin, cut into 6 μm thin sections, stained with hematoxylin and eosin (HE), and examined under a light microscope for histopathological examination. The negative control blood vessel on the other side was processed in the same manner.

[0062] The rating criteria are shown in Table 3:

[0063] Table 3 Scoring criteria for vascular irritation tests

[0064]

[0065]

[0066] Note: Criteria for judging vascular stimulation results: ≤0.5 no irritation, ≤2.5 slight irritation, ≤4.5 moderate irritation, ≤6.0 severe irritation.

[0067] Results Analysis: The experimental results are as follows: Figure 1 and Figure 2 As shown.

[0068] (1) In the NS group and the 1:1 dilution group, "needle scars" were observed at the injection site, with occasional mild vascular dilation around the "needle scars." However, no obvious congestion, edema, or thrombosis was observed in the proximal vein at the injection site. Histopathological examination under light microscopy showed that the vascular structure at the injection site was intact, with no obvious degeneration or necrosis of the vascular endothelial cells, and no thrombosis in the lumen. The results indicate that intravenous injection of Alda-1 solution at a 1:1 dilution has no significant irritant effect on blood vessels.

[0069] (2) In addition to needle scars, thrombosis was also observed in the veins of the injection site of the original injection solution group. The veins proximal to the heart at the needle puncture site showed obvious congestion. Under light microscopy, the vascular structure at the injection site was broken, the vascular endothelial cells showed degeneration and necrosis, and thrombosis was formed in the lumen.

[0070] Experiment Example 2: Hemolytic Experiment of Alda-1 Injection

[0071] Experimental Method: Take one healthy rabbit and collect approximately 20 mL of blood from its heart. Place the blood in an Erlenmeyer flask containing glass beads and shake for 5 minutes to remove fibrin and obtain defibrinated blood. Transfer the defibrinated blood to a centrifuge tube, add physiological saline, gently mix, and centrifuge at 1500 rpm for 15 minutes. Discard the supernatant, add physiological saline again, mix, and centrifuge. Repeat 2-3 times until the supernatant no longer appears red. Dilute the obtained red blood cells with physiological saline to prepare a 2% suspension for later use. Take a clean centrifuge tube and add different volumes of Alda-1 injection stock solution (Preparation Example 1), i.e., the injection group. Two tubes are used for each concentration. A negative control (physiological saline) and a positive control (purified water) are also included. After adding all the solution, mix well and immediately incubate at 37°C.

[0072] The observation indicators are divided into four types: total hemolysis, partial hemolysis, no hemolysis, and agglutination, as described below:

[0073] Total hemolysis: The solution is clear and red, with no cells remaining at the bottom of the tube;

[0074] Partial hemolysis: The solution is clear and red or brown, with a small number of red blood cells remaining at the bottom of the tube;

[0075] No hemolysis: all red blood cells have settled, and the supernatant is colorless and clear;

[0076] Agglutination: Although there is no hemolysis, red blood cells agglutinate and cannot be dispersed after shaking.

[0077] Among them, the results of visual observation are as follows Figure 3As shown, after incubation at 37°C for 3 hours, no obvious hemolysis or agglutination was observed in the 0.1ml, 0.2ml, 0.3ml, 0.4ml, and 0.5ml injection groups, and the supernatant was clear. Complete hemolysis occurred in the purified water group (positive control group) after 15 minutes.

[0078] Among them, the results of microscopic observation (200μm) are as follows: Figure 4 As shown, after incubation at 37°C for 3 hours, no obvious red blood cell rupture was observed in the saline group, the 0.1ml injection group, the 0.2ml injection group, the 0.3ml injection group, the 0.4ml injection group, and the 0.5ml injection group; however, in the purified water group (positive control group), a large number of red blood cells were observed to rupture after 15 minutes, and only red blood cell residues were observed after 3 hours.

[0079] The results showed that no hemolysis occurred with Alda-1 injection.

[0080] Experiment Example 3: Animal Therapy Verification Experiment

[0081] Animal species: C57 wild-type mouse

[0082] Test methods: ultrasound to detect cardiac function, TTC staining to detect myocardial infarction area, serum Ntpro-BNP, and Western blot test.

[0083] Experimental protocol: 40 minutes of ischemia, followed by 4 hours of reperfusion, and continuous tail vein injection for 3 days. Samples were collected 7 days later. Unless otherwise specified, all injections mentioned in this embodiment refer to tail vein injection.

[0084] The experiment was divided into 6 groups, with each group receiving the same injection dose of 20 mg / kg of mouse body weight. The details of each group are as follows:

[0085] Group 1: SHAM (Sham Surgery Group);

[0086] Group 2: I / R (myocardial ischemia-reperfusion group)

[0087] Group 3: I / R + DMSO (myocardial ischemia-reperfusion group + DMSO injection)

[0088] Group 4: I / R + DMSO + Alda-1 (myocardial ischemia-reperfusion group + Alda-1 dissolved in DMSO for intraperitoneal injection)

[0089] Group 5: I / R + ALC + PEG + NS (myocardial ischemia-reperfusion group + injection of Alda-1-free solution)

[0090] Group 6: I / R + ALC + PEG + NS + Alda-1 (myocardial ischemia-reperfusion group + Alda-1 injection group)

[0091] In this context, SHAM represents the sham surgery group, I / R represents ischemia-reperfusion, DMSO represents injection of dimethyl sulfoxide, DMSO+Alda-1 represents Alda-1 dissolved in DMSO for injection (5 mg Alda-1 dissolved in 1 ml DMSO), ALC+PEG+NS represents the pure solvent group without Alda-1, namely ethanol, polyethylene glycol 400, and physiological saline (solvent volume as in Preparation Example 1), and ALC+PEG+NS+Alda-1 represents the Alda-1 injection solution group (its composition is the same as in Preparation Example 1). The specific details are as follows:

[0092] Results of ultrasound examination of cardiac function as follows Figure 5 , Figure 6 As shown, FS represents the fractional shortening, primarily reflecting the heart's contractile function. EF represents the ejection fraction, reflecting the heart's ejection energy. Increases in both parameters indicate improvement. Both tail vein injection of Alda-1 (Group 6) and intraperitoneal injection (DMSO+Alda-1, Group 4) improved cardiac function, and the results of tail vein injection of Alda-1 (Group 6) and intraperitoneal injection of DMSO+Alda-1 (Group 4) were comparable. Figure 5 Experimental data showed that mice injected with Alda-1 injection (Group 6) after myocardial infarction showed at least 15% improvement in cardiac function compared to Group 2 (no drug injection), as measured by ultrasound.

[0093] TTC staining results and analysis are as follows: Figure 7 and Figure 8 As shown, Figure 8 yes Figure 7 The statistical chart, TTC staining, shows the infarcted area of ​​the heart, the pale area (in... Figure 7 The light-colored area (shown in the center) is the infarct area, and the bright red area (in...) Figure 7 The dark areas shown in the image represent non-infarct areas. According to experimental statistics, mice injected with Alda-1 injection (Group 6) after myocardial infarction showed at least a 15% reduction in myocardial infarction area compared to Group 2 (the group without drug injection).

[0094] The results of the Western blot experiment are as follows: Figure 9 and Figure 10As shown, both tail vein injection of Alda-1 (Group 6) and intraperitoneal injection of (DMSO+Alda-1, Group 4) can upregulate the expression of Bcl2 in the heart. Both tail vein injection of Alda-1 (Group 6) and intraperitoneal injection of (DMSO+Alda-1, Group 4) can reduce the expression of Bax in the heart. Both tail vein injection of Alda-1 (Group 6) and intraperitoneal injection of (DMSO+Alda-1, Group 4) can reduce the expression of 4-HNE in the heart. Moreover, the Alda-1 injection of the present invention (Group 6) is more effective than intraperitoneal injection of DMSO+Alda-1 (Group 4) in upregulating the expression of Bcl2, reducing the expression of Bax, and reducing the expression of 4-HNE in the heart.

[0095] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An Alda-1 injection solution, which, when used, can be used for intravenous injection by diluting 1:1 with normal saline, wherein, The Alda-1 injection takes Alda-1 as an active ingredient, and takes ethanol, polyethylene glycol 400 and physiological saline as solvents; the volume ratio of ethanol, polyethylene glycol 400 and physiological saline is 5:3-5:2-4; the pH of the Alda-1 solution is 5-6.8; The preparation method comprises: adding ethanol into Alda-1 for ultrasonic treatment, then adding polyethylene glycol and physiological saline, and mixing to obtain the Alda-1 injection; the polyethylene glycol 400 and the physiological saline can be added simultaneously or the physiological saline is added first and then the polyethylene glycol is added; The concentration of the Alda-1 is 4-10 mg / mL.

2. The Alda-1 injection of claim 1, wherein The volume ratio of the solvents in the Alda-1 solution is ethanol: polyethylene glycol 400: physiological saline = 5:3:

2.

3. The Alda-1 injection according to claim 1 or 2, characterized by, The concentration of the Alda-1 is 10 mg / mL.

4. Use of the Alda-1 injection in any one of claims 1 to 3 in the preparation of a medicament for preventing and / or treating acute myocardial infarction, cardiac arrest, acute ischemia-reperfusion injury and / or chronic heart failure.

5. Use according to claim 4, characterized in that, The Alda-1 injection up-regulates the expression of Bcl2 in the heart, and / or reduces the expression of Bax in the heart, and / or reduces the expression of 4-HNE in the heart.

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