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WO2025150987A1 - Composition pharmaceutique pour la prévention ou le traitement d'une cardiopathie ischémique comprenant de l'acide aspartique - Google Patents

Composition pharmaceutique pour la prévention ou le traitement d'une cardiopathie ischémique comprenant de l'acide aspartique

Info

Publication number
WO2025150987A1
WO2025150987A1 PCT/KR2025/000648 KR2025000648W WO2025150987A1 WO 2025150987 A1 WO2025150987 A1 WO 2025150987A1 KR 2025000648 W KR2025000648 W KR 2025000648W WO 2025150987 A1 WO2025150987 A1 WO 2025150987A1
Authority
WO
WIPO (PCT)
Prior art keywords
acceptable salt
pharmaceutical composition
ischemic heart
aspartic acid
heart disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/000648
Other languages
English (en)
Korean (ko)
Inventor
김규석
범진호
유제성
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industry Academic Cooperation Foundation of Yonsei University
Industry Academic Cooperation Foundation of College of Medicine Pochon CHA University
Original Assignee
Industry Academic Cooperation Foundation of Yonsei University
Industry Academic Cooperation Foundation of College of Medicine Pochon CHA University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Industry Academic Cooperation Foundation of Yonsei University, Industry Academic Cooperation Foundation of College of Medicine Pochon CHA University filed Critical Industry Academic Cooperation Foundation of Yonsei University
Publication of WO2025150987A1 publication Critical patent/WO2025150987A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/02—Acid
    • A23V2250/06—Amino acid
    • A23V2250/061—Aspartic acid
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/02—Acid
    • A23V2250/06—Amino acid
    • A23V2250/0636—Ornithine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • It relates to a pharmaceutical composition for preventing or treating ischemic heart disease containing aspartic acid.
  • Ischemia is a condition in which blood supply to an organ, tissue, or part of the body is reduced due to constriction or occlusion of blood vessels.
  • Ischemic heart disease is a condition in which the amount of oxygen supplied to the heart is significantly insufficient compared to the amount required due to blockage of blood flow to the heart. After ischemia, even if reperfusion of blood occurs, heart cells are damaged, ultimately leading to irreversible damage to the heart muscle, that is, necrosis of cells and tissues.
  • reperfusion therapy such as percutaneous coronary intervention, coronary artery bypass grafting, and other surgical/procedure/therapy or drug therapy using thrombolytics can be used.
  • reperfusion damage such as recurrence of myocardial infarction, decline in cardiac function, and arrhythmia occur at a high rate even after such reperfusion therapy.
  • Ischemic heart disease caused by myocardial cell damage and decline in cardiac function during ischemia/reperfusion has a high morbidity and mortality rate and is difficult to cure, so intensive basic and clinical research has been conducted for the past 50 years.
  • Blood vessels are the passages that circulate blood between the heart and each organ and tissue of the body. If some of these blood vessels become narrowed or bleed, the tissues cannot receive oxygen or nutrients properly, causing serious damage to the cells.
  • vascular endothelial growth factor is used as a treatment for ischemic diseases.
  • Nitric oxide (NO) is well known as a regulator of endothelial function and plays an important role in endothelial vasodilation. NO also upregulates VEGF (Vascular Endothelial Growth Factor), a major stimulator of angiogenesis.
  • VEGF Vascular Endothelial Growth Factor
  • the inventors of the present invention intend to provide a pharmaceutical composition for preventing or treating ischemic heart disease, containing aspartic acid, in order to develop a treatment agent for ischemic heart disease that can slow the progression of cardiomyocyte damage caused by ischemia and alleviate reperfusion damage.
  • One aspect is to provide a pharmaceutical composition for preventing or treating ischemic heart disease, comprising aspartic acid or a pharmaceutically acceptable salt thereof.
  • Another aspect is to provide a health functional food for preventing or improving ischemic heart disease, comprising aspartic acid or a food-wise acceptable salt thereof.
  • Another aspect provides the use of aspartic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of ischemic heart disease.
  • One aspect provides a pharmaceutical composition for preventing or treating ischemic heart disease, comprising aspartic acid or a pharmaceutically acceptable salt thereof.
  • the above aspartic acid or a pharmaceutically acceptable salt thereof reduces the volume of the infarcted area in the myocardium, increases perfusion, increases the density of CD31-positive capillary lumen, and promotes angiogenesis by overexpressing VEGF, thereby exhibiting an excellent effect in preventing or treating ischemic heart disease.
  • composition may further comprise ornithine or a pharmaceutically acceptable salt thereof.
  • the ornithine may be L-ornithine, D-ornithine or a mixture thereof, specifically, it may be L-ornithine, and more specifically, it may be a compound represented by the following chemical formula 2:
  • the ornithine or a pharmaceutically acceptable salt thereof may be derived from nature or may be synthesized using a known organic synthesis method.
  • the ornithine or a pharmaceutically acceptable salt thereof may be a non-protein compound, a peptide, an extract of plant-derived tissue or cells, or a product obtained by culturing microorganisms (e.g., bacteria or fungi, and particularly yeast).
  • the ornithine or a pharmaceutically acceptable salt thereof is converted into citrulline or a pharmaceutically acceptable salt thereof within the mitochondria.
  • the aspartic acid or a pharmaceutically acceptable salt thereof contained in the composition produces more arginine, ultimately exhibiting a better angiogenic effect and an excellent preventive or therapeutic effect on ischemic heart disease.
  • salt means a salt prepared using a specific compound and a relatively non-toxic acid or base, depending on the nature of the substance.
  • salt in the present specification may be a “pharmaceutically acceptable salt.”
  • pharmaceutically acceptable means that a compound exhibits the property of being non-toxic to cells or humans when exposed to it in one form or another.
  • pharmaceutically acceptable salt means a salt prepared using a compound according to one aspect and a relatively nontoxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a base, either in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines, or magnesium or similar salts.
  • an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of an acid, either in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate ion, phosphoric acid, monohydrogen phosphate ion, dihydrogen phosphate ion, sulfuric acid, hydrogen sulfate ion, hydroiodic acid or phosphorous acid, and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and further include salts of amino acids (e.g., arginine, etc.) and salts of organic acids such as glucuronic acid.
  • inorganic acids such as hydrochloric acid, hydrobro
  • the pharmaceutically acceptable salts described above can be synthesized by conventional chemical methods from parent compounds containing acidic or basic moieties. Typically, these salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a base or acid in water or an organic solvent or a mixture of the two. Typically, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the composition may reduce the volume of an infarcted area within the myocardium.
  • the composition may reduce apoptosis of cardiac cells.
  • the reduction in apoptosis of cardiac cells may be at least one selected from the group consisting of a reduction in apoptotic cardiac cells and an inhibition of apoptosis of cardiac cells, and more specifically, both a reduction in apoptotic cardiac cells and an inhibition of apoptosis of cardiac cells.
  • treatment may mean any action by which the symptoms of ischemic heart disease in a subject are improved or beneficially changed by administration of a pharmaceutical composition according to one aspect.
  • the pharmaceutical composition may further comprise an agent for treating ischemic heart disease in addition to aspartic acid or a pharmaceutically acceptable salt thereof and/or ornithine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising aspartic acid or a pharmaceutically acceptable salt thereof may be administered at a dose of 0.1 mg/kg to 1000 mg/kg.
  • the pharmaceutical composition comprising the aspartic acid or a pharmaceutically acceptable salt thereof is present in an amount of 0.1 mg/kg to 1000 mg/kg, 0.1 mg/kg to 800 mg/kg, 0.1 mg/kg to 500 mg/kg, 0.1 mg/kg to 300 mg/kg, 0.1 mg/kg to 100 mg/kg, 0.1 mg/kg to 10 mg/kg, 10 mg/kg to 1000 mg/kg, 10 mg/kg to 800 mg/kg, 10 mg/kg to 500 mg/kg, 10 mg/kg to 300 mg/kg, 10 mg/kg to 100 mg/kg, 100 mg/kg to 1000 mg/kg, 100 mg/kg to 800 mg/kg, 100 mg/kg to 500 mg/kg, It may be administered at 100 mg/kg to 300 mg/kg, 300 mg/kg to 1000 mg/kg, 300 mg/kg to 800 mg/kg, 300 mg/kg to 500 mg/kg, It
  • the pharmaceutical composition comprising the aspartic acid or a pharmaceutically acceptable salt thereof; and ornithine or a pharmaceutically acceptable salt thereof may be administered at 0.1 mg/kg to 1000 mg/kg.
  • a pharmaceutical composition significantly reduces the volume of an infarcted area in the myocardium, increases perfusion, increases the density of CD31-positive capillary lumen, and promotes angiogenesis by overexpressing VEGF by containing aspartic acid or a pharmaceutically acceptable salt thereof, and when the pharmaceutical composition further contains ornithine or a pharmaceutically acceptable salt thereof, it exhibits a superior effect of reducing the volume of an infarcted area in the myocardium and angiogenesis compared to administration of aspartic acid alone, and therefore, the pharmaceutical composition can be effectively utilized as an agent for preventing, improving, or treating ischemic heart disease.
  • Another aspect provides a health functional food for preventing or improving ischemic heart disease, comprising aspartic acid or a food-wise acceptable salt thereof.
  • the above aspartic acid or a food-based acceptable salt thereof reduces the volume of the infarcted area in the myocardium, increases perfusion, increases the density of CD31-positive capillary lumen, and promotes angiogenesis by overexpressing VEGF, thereby exhibiting an excellent effect in preventing or improving ischemic heart disease.
  • the aspartic acid or a food acceptable salt thereof promotes the conversion of citrulline or a food acceptable salt thereof into arginine or a food acceptable salt thereof within an administered subject.
  • the converted arginine produces nitric oxide (NO) together with endothelial nitric oxide synthase (eNOS), and the nitric oxide upregulates the expression of VEGF, thereby exhibiting an excellent angiogenic effect and an excellent preventive or ameliorating effect on ischemic heart disease.
  • the health functional food may further contain ornithine or a food scientifically acceptable salt thereof.
  • the above health functional food further contains ornithine or a food-related acceptable salt thereof, it further reduces the volume of the infarcted area in the myocardium, further promotes angiogenesis, and thereby exhibits a better effect in preventing or improving ischemic heart disease.
  • the ornithine or a food-based acceptable salt thereof is converted into citrulline or a food-based acceptable salt thereof within the mitochondria.
  • the aspartic acid or a food-based acceptable salt thereof contained in the health functional food produces more arginine, ultimately exhibiting a better angiogenic effect and an excellent preventive or improving effect on ischemic heart disease.
  • the term "improvement” may mean any action that at least reduces a parameter related to the condition being treated, for example, the degree of symptoms.
  • the health functional food may be used before or after the onset of the disease, simultaneously with or separately from a drug for treatment, for the purpose of preventing or improving ischemic heart disease.
  • the active ingredient can be added to the food as it is or used together with other food or food ingredients, and can be used appropriately according to a conventional method.
  • the mixing amount of the active ingredient can be appropriately determined according to its purpose of use (prevention or improvement).
  • the health functional food can be added in an amount of about 15 wt% or less, more specifically about 10 wt% or less, based on the raw material.
  • the amount can be below the above range.
  • the above health functional food may be formulated as one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, and may further include one or more of a carrier, a diluent, an excipient, and an additive.
  • Foods to which a compound according to one aspect may be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, and health functional foods.
  • carrier excipient, diluent and additive
  • the carrier, excipient, diluent and additive may include at least one selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.
  • the above health functional food in addition to containing the effective ingredient, may contain other ingredients as essential ingredients without special limitation.
  • it may contain various flavoring agents or natural carbohydrates as additional ingredients, like a typical beverage.
  • natural carbohydrates may include common sugars such as monosaccharides, such as glucose, fructose, etc.; disaccharides, such as maltose, sucrose, etc.; and polysaccharides, such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, erythritol, etc.
  • natural flavoring agents thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the proportion of the above-mentioned natural carbohydrates may be appropriately determined by a person skilled in the art.
  • health functional foods may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
  • flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (
  • the health functional food may further include a health functional food for preventing or improving ischemic heart disease in addition to aspartic acid or a food scientifically acceptable salt thereof and/or ornithine or a food scientifically acceptable salt thereof.
  • the above health functional food further includes a health functional food for preventing or improving ischemic heart disease, it is important to mix the amount that can achieve the maximum effect with the minimum amount without causing side effects, and this can be easily determined by a person skilled in the art.
  • the health functional food may be consumed alone or in combination with a health functional food for preventing or improving ischemic heart disease.
  • the above health functional food can be taken in parallel with a known composition having an effect of preventing or improving ischemic heart disease or a newly developed health functional food for preventing or improving ischemic heart disease, and can be taken simultaneously, separately, or sequentially, and can be taken singly or in multiple doses. It is important to take the amount that can obtain the maximum effect with the minimum amount without side effects by considering all of the above factors, and this can be easily determined by a person skilled in the art.
  • the aspartic acid or a pharmaceutically acceptable salt thereof when the aspartic acid or a pharmaceutically acceptable salt thereof is administered simultaneously with ornithine or a pharmaceutically acceptable salt thereof, the aspartic acid or a pharmaceutically acceptable salt thereof; and ornithine or a pharmaceutically acceptable salt thereof may be administered at 0.1 mg/kg to 1000 mg/kg.
  • aspartic acid or a pharmaceutically acceptable salt thereof; and ornithine or a pharmaceutically acceptable salt thereof for the manufacture of a drug for preventing or treating ischemic heart disease may be administered at 0.1 mg/kg to 1000 mg/kg.
  • Apoptotic cells were identified by TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) assay using the DeadEndTM Fluorometric TUNEL system (Promega, WI) according to the manufacturer's instructions.
  • TUNEL terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling
  • TUNEL terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) assay using the DeadEndTM Fluorometric TUNEL system (Promega, WI) according to the manufacturer's instructions.
  • TUNEL terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) assay using the DeadEndTM Fluorometric TUNEL system (Promega, WI) according to the manufacturer's instructions.
  • mice Male Sprague Dawley rats (Seongnam, Republic of Korea) weighing 280–320 g (8 weeks old) were used. The rats were housed in a controlled environment (room temperature 20–24°C, humidity 40–60%) with unlimited access to standard food and water during the experiment. Then, unilateral femoral artery ligation was performed on the rats.
  • Perfusion imaging was performed before surgery. Immediately after surgery, perfusion images were taken (postoperative day 0). The rats were then randomly distributed into three groups, with eight rats per group:
  • control group Saline solution administration
  • Group 1 was injected intraperitoneally with saline (1.7 ml/kg), Group 2 was injected with distilled water, sorbitol, and saline (20:2:30, 1.7 ml/kg), and Group 3 was injected with LOLA (333 mg/kg) (Hepa-Merz infusion, Hanwha Pharma, Chuncheon, Republic of Korea) five times at 3, 5, 7, and 10 ALC 12 POD. Since Herpa-Merz infusion consists of LOLA, sorbitol, and distilled water, the same amount of sorbitol and distilled water together with saline was administered to Group 2 instead of LOLA. To create a normal control group, the same amount of saline was assigned to Group 2. Perfusion imaging was scanned at 7 and 14 POD. Immunohistochemical analysis and Western blotting of rats with induced ischemic disease were performed after the final perfusion imaging.
  • mice were imaged for approximately 3 minutes using a laser Doppler imaging device (Moor LDI, Axminster, UK). Images were analyzed with Moor LDI Imaging Review. Perfusion ratios were calculated by comparing preoperative and postoperative results.
  • mice were euthanized and fixed by perfusion with 4% paraformaldehyde 14 days after surgery. They were then embedded in paraffin, sectioned at 5 ⁇ m using a microtome, and mounted on glass slides. The sections were blocked with Proteinase K (S3020, Agilent DAKO, Santa Clara, CA, USA) and incubated with antibodies to VEGF (1:100, MA1-16629, Thermo Scientific, Waltham, MA, USA) and CD31 (1:100, MA1-80069, Thermo Scientific, Walthan, MA, USA) for 10 min.
  • VEGF 1:100, MA1-16629, Thermo Scientific, Waltham, MA, USA
  • CD31 1:100, MA1-80069, Thermo Scientific, Walthan, MA, USA
  • Frozen muscle samples were homogenized in RIPA Lysis and Extraction Buffer (Thermo Fisher Scientific, Walthan, MA, USA) with 1% HaltTM Protease Inhibitor Cocktail (Thermo Fisher Scientific, Walthan, MA, USA) and centrifuged at 13,000 g for 15 min at 4°C. Protein concentrations were determined using the BCA assay kit (cat. no. 23250; Pierce; Thermo Fisher Scientific, Walthan, MA, USA) according to the manufacturer's instructions. Equal amounts of proteins were loaded onto 12% Tris-glycine SDS-polyacrylamide gels and separated by SDS-PAGE (Bio-Rad, Hercules, CA, USA).
  • the rats used were prepared according to Reference Example 1, and the control and experimental groups were prepared according to Reference Example 2. Thereafter, TUNEL-positive cells, i.e., apoptotic cells, according to drug treatment were identified according to Reference Example 4.
  • the pharmaceutical composition containing aspartic acid exhibited a high perfusion recovery rate for rats induced with ischemic disease, thereby having a significantly excellent effect in the prevention or treatment of ischemic disease.
  • VEGF expression was significantly higher in LOLA-treated rats (group 3) than in the other groups (group 1 vs group 2 vs group 3: 0.76 ⁇ 0.12 vs 0.63 ⁇ 0.14 vs 1.00 ⁇ 0.19; p ⁇ 0.001).
  • staining for VEGF was enhanced in group 3 compared to the other groups in immunohistochemistry (Figs. 8 to 10).

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Abstract

Un aspect concerne une composition pharmaceutique pour la prévention ou le traitement d'une cardiopathie ischémique, la composition comprenant de l'acide aspartique ou un sel pharmaceutiquement acceptable de celui-ci. La composition pharmaceutique réduit significativement le volume de zones infarcie à l'intérieur du myocarde, présentant ainsi un excellent effet de prévention ou de traitement d'une cardiopathie ischémique. De plus, en comprenant en outre de l'ornithine ou un sel pharmaceutiquement acceptable de celui-ci, la composition induit une réduction plus importante du volume de zones infarcie à l'intérieur du myocarde par rapport à l'administration d'acide aspartique ou d'un sel pharmaceutiquement acceptable de celui-ci seul, ce qui permet d'obtenir un effet supérieur de prévention ou de traitement d'une cardiopathie ischémique.
PCT/KR2025/000648 2024-01-10 2025-01-10 Composition pharmaceutique pour la prévention ou le traitement d'une cardiopathie ischémique comprenant de l'acide aspartique Pending WO2025150987A1 (fr)

Applications Claiming Priority (2)

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KR20240004424 2024-01-10
KR10-2024-0004424 2024-01-10

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WO2025150987A1 true WO2025150987A1 (fr) 2025-07-17

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WO2014139469A1 (fr) * 2013-03-15 2014-09-18 Wuhan Qr Science And Technology Development Co. Compositions comprenant de l'ornithine ou de l'aspartate et utilisations associées
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KR102536092B1 (ko) 2020-09-29 2023-05-24 조선대학교산학협력단 Lrp5 발현 또는 활성 억제제를 포함하는 허혈성 심장질환의 예방 또는 치료용 약학적 조성물

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