KR102088689B1 - A pharmaceutical composition for prevention or treatment of acidosis - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating acidosis. The pharmaceutical composition has a remarkable effect on reducing the concentration of acid accumulated in a living body, thereby being expected to be greatly used in medical and health fields. The present invention is the pharmaceutical composition for preventing or treating lactic acidosis, containing pargyline or kynurenic acid as an active component.

Description

A pharmaceutical composition for prevention or treatment of acidosis

The present invention relates to a pharmaceutical composition for the prevention or treatment of acidosis.

Acidosis refers to a state in which the pH is lower than that of a normal person based on the arterial blood pH 7.4 ± 0.05 (high hydrogen ion concentration). It is largely divided into "respiratory acidosis" and "metabolism," and types of metabolic acidosis include diabetic ketoacidosis, lactic acidosis, or poisoning of toxic substances such as salicylic acid, methanol, and ethylene glycol. Among them, lactic acidosis is the accumulation of a large amount of lactic acid in the body and the acidic acid balance is broken and acidosis occurs, which is defined as a state in which lactic acid exceeds 45mg / ㎗ and pH is less than 7.25. Cells metabolize glucose in the presence of oxygen to produce energy. Lactate is produced when glucose metabolism occurs in the absence of oxygen. Therefore, lactic acidosis occurs mainly in a condition where oxygenation in the body is reduced, such as hypoxic shock, blood volume reduction, left ventricular dysfunction, etc., and locally, the effect of drugs / toxins (ethanol / methanol) or increased energy metabolism as in tumors. Even in the state, lactic acid in the tissue increases. If lactic acidosis persists and the acidic equilibrium is broken, symptoms of muscle weakness, hyperventilation, nausea, vomiting, sweating, or coma may occur, and in severe cases, life may be lost. It is important to keep.

However, there is no alternative to providing sufficient oxygen for the treatment of lactic acidosis, and there is no alternative that can control the concentration of lactic acid with a drug, and thus there is a need to develop a therapeutic agent for the prevention or treatment of lactic acidosis.

Therefore, the present invention was devised to solve the problems in the prior art as described above, and relates to a pharmaceutical composition for preventing or treating acidosis. Since the pharmaceutical composition of the present invention has a remarkable effect on reducing the concentration of acid accumulated in an organism, it is expected to be greatly used in the medical and health fields.

(Prior literature) De Paepe P, et al., Disulfiram inhibition of cyanide formation after acetonitrile poisoning; Clin Toxicol (Phila), 2016. 54 (1): 56-60.

The present invention is to solve the problems of the prior art as described above, and relates to a pharmaceutical composition for preventing or treating acidosis.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, for a thorough understanding of the present invention, various specific details, such as specific forms, compositions and processes, are described. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and forms. In other instances, well known processes and manufacturing techniques have not been described in particular detail in order to not unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, the context of “in one embodiment” or “embodiment” expressed at various places throughout this specification does not necessarily represent the same embodiment of the invention. In addition, particular features, forms, compositions, or properties may be combined in any suitable manner in one or more embodiments.

Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In one embodiment of the present invention, "acidosis" refers to a state in which the pH is lower than this based on the arterial blood pH 7.4 ± 0.05 of a normal person (a state where the concentration of hydrogen ions is high). Insufficient oxygen uptake or reduced blood flow in the lungs, depending on the cause of development, causes "oxygenosis" in which the oxygen supply to the tissue is reduced, and the amount of lactic acid in the blood or locally increased, regardless of the reduction in oxygen. It is classified as "metabolism". Causes of respiratory acidosis include bleeding shock, heart attack, congestive heart failure, pulmonary edema, and severe anemia. Metabolic acidosis is caused by one or more of the three mechanisms of acid load or alkali loss, or kidney acid excretion disorders. When the acid is increased, diabetic ketoacidosis, lactic acidosis, or salicylic acid, methanol, ethylene glycol, etc. Poisoning of toxic substances.

In one embodiment of the present invention, "lactic acidosis" is a type of acidosis, in which a large amount of lactic acid is produced and accumulated in the body, resulting in acidic acid breakage due to acidic equilibrium, and lactic acid exceeds 45mg / ㎗ and pH 7.45 It is defined as the following state. Cells metabolize glucose in the presence of oxygen to produce energy. Lactate is produced when glucose metabolism occurs in the absence of oxygen. Therefore, lactic acidosis occurs mainly in a condition where oxygenation in the body is reduced, such as hypoxic shock, blood volume reduction, left ventricular dysfunction, etc., and locally, the effect of drugs / toxins (ethanol / methanol) or increased energy metabolism as in tumors. Even in the state, lactic acid in the tissue increases. If lactic acidosis persists and the acidic equilibrium is broken, symptoms of muscle weakness, hyperventilation, nausea, vomiting, sweating, or coma may occur, and in severe cases, life may be lost. It is important to keep. The causes of lactic acidosis include liver disease, kidney disease, diabetes, leukemia, AIDS, glucose accumulation disease, drugs and poisons, severe infections (systemic pulmonary sepsis and meningitis), tumors, muscular dystrophy and normal ATP There are several genetic metabolism and mitochondrial diseases that affect production, and severe exercise.

In one embodiment of the invention “treatment” refers to a series of activities performed to alleviate or / and ameliorate a desired disease. For the purpose of the present invention, treatment includes an activity of removing the cause of acidosis in the state in which acidosis has occurred, or improving the symptoms of acidosis by reducing the acid concentration generated when the cause cannot be eliminated.

In one embodiment of the present invention, "pharmaceutical composition" means a composition administered for a specific purpose. For the purposes of the present invention, the pharmaceutical composition of the present invention is to prevent or treat acidosis, and may include a compound involved therein and a pharmaceutically acceptable carrier, excipient or diluent. In addition, the pharmaceutical composition according to the present invention comprises 0.1 to 50% by weight of the active ingredient of the present invention relative to the total weight of the composition. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but is not limited thereto.

In one embodiment of the present invention, "administration" means introducing the composition of the present invention to a patient in any suitable way, and the route of administration of the composition of the present invention is through any general route as long as it can reach the target tissue. Can be administered. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, rectal administration, intraperitoneal administration, intraperitoneal administration, intrathecal administration may be performed, but are not limited thereto. Does not. The effective amount in the present invention is the type of disease, the severity of the disease, the type and content of the active ingredients and other ingredients contained in the composition, the type of formulation and the patient's age, weight, general health status, sex and diet, administration time, route of administration And various factors including the secretion rate of the composition, the duration of treatment, and drugs used simultaneously. For adults, the therapeutic pharmaceutical composition can be administered to the body in an amount of 50 ml to 500 ml once, 0.1 ng / kg-10 mg / kg for a compound, and 0.1 ng / kg-10 mg for a monoclonal antibody / kg can be administered. The administration interval may be 1 to 12 times a day, and when administered 12 times a day, it may be administered once every 2 hours. In addition, the pharmaceutical composition of the present invention may be administered alone or in combination with other treatment methods known in the art, such as chemotherapeutic agents, radiation and surgery, for the treatment of desired cancer stem cells. In addition, the pharmaceutical composition of the present invention may be administered in combination with other treatments designed to enhance the immune response, for example, adjuvants or cytokines (or nucleic acids encoding cytokines) as well known in the art. Other standard delivery methods such as bioolistic delivery or ex vivo treatment may also be used. For ex vivo treatment, for example, antigen-presenting cells (APCs), dendritic cells, peripheral blood monocytes, or bone marrow cells can be obtained from a patient or a suitable donor and activated in vitro with this pharmaceutical composition and then administered to the patient. have.

In one embodiment of the present invention "food composition" is used in various ways for the prevention or improvement of the indications intended in the present invention, the food composition comprising the composition of the present invention as an active ingredient is a variety of foods, such as For example, it may be prepared in the form of beverages, gums, teas, vitamin complexes, powders, granules, tablets, capsules, sweets, rice cakes, breads, and the like. Since the food composition of the present invention is configured and improved from the existing food intake which has little toxicity and side effects, it can be used with confidence even for long-term administration for the purpose of prevention. When the composition of the present invention is included in the food composition, the amount may be added at a ratio of 0.1 to 100% of the total weight. Here, when the food composition is prepared in the form of a drink, there is no particular limitation other than the food composition in the ratio indicated, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like, and common sugars such as polysaccharides, dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol. can do. Examples of the flavoring agent include natural flavoring agents (tautin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.), synthetic flavoring agents (saccharin, aspartame, etc.), and the like. Food composition of the various flavors, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH regulators, Stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, etc. These components may be used independently or in combination The ratio of such additives is typically per 100 parts by weight of the composition of the present invention. It is generally selected from the range of 0.1 to 100 parts by weight, but is not limited thereto.

In one embodiment of the invention, citral, CVT-10216 (3-[[[3- [4-[(Methylsulfonyl) amino] phenyl] -4-oxo-4H-1-benzopyran-7-yl ] oxy] methyl] -benzoic acid), cyanamide, retinoic acid, molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-Acetyl- N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, benomyl, cisplatin (cis-diamminedichloridoplatinum; CDDP), chlorpropamide, daidzin, pargyline, Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydr Pharmaceutical composition for the prevention or treatment of acidosis, including any one or more selected from the group consisting of roxynynurenine (3-hydroxy-DL-kynurenine) as an active ingredient To provide.

The pharmaceutical composition is preferably morphinate (N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), phenylglyoxal, benzoyl (benomyl), cis-diamminedichloridoplatinum (CDDP), chlorpropamide, diidzin, pargyline, phospho (enol) pyruvic acid monosodium salt hydrate (phospho (enol) pyruvic acid selected from the group consisting of monosodium salt hydrate, kynurenic acid, diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxy-DL-kynurenine It is to include any one or more of the active ingredients.

The pharmaceutical composition is more preferably benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daidzin, pargyline, phospho (enol) pyruvic acid monosodium Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxykynurenine (3-hydroxy- DL-kynurenine) is to include any one or more selected from the group consisting of.

In addition, the pharmaceutical composition is more preferably diethylaminobenzaldehyde (Diethylaminobenzaldehyde; DEAB), disulfiram (disulfiram), and 3-hydroxykynurenine (3-hydroxy-DL-kynurenine) any one selected from the group consisting of This is to include the above as an active ingredient.

In the above, the acidosis is preferably metabolic acidosis or respiratory acidosis, and more preferably lactic acidosis, but is not limited thereto.

In another embodiment of the invention, citral, CVT-10216 (3-[[[3- [4-[(Methylsulfonyl) amino] phenyl] -4-oxo-4H-1-benzopyran-7-yl ] oxy] methyl] -benzoic acid), cyanamide, retinoic acid, molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-Acetyl- N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, benomyl, cisplatin (cis-diamminedichloridoplatinum; CDDP), chlorpropamide, daidzin, pargyline, Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydr Food composition for preventing or improving acidosis, including any one or more selected from the group consisting of hydroxykinenerine (3-hydroxy-DL-kynurenine) as an active ingredient Provide water.

The food composition is preferably morphinate (N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide), phenylglyoxal, Benomyl (benomyl), cis-diamminedichloridoplatinum (CDDP), chlorpropamide, diidzin, pargyline, phospho (enol) pyruvic acid monosodium salt hydrate (phospho (enol) pyruvic acid selected from the group consisting of monosodium salt hydrate, kynurenic acid, diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxy-DL-kynurenine It is to include any one or more of the active ingredients.

The food composition is more preferably benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daidzin, pargyline, phospho (enol) pyruvic monosodium Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxykynurenine (3-hydroxy- DL-kynurenine) is to include any one or more selected from the group consisting of.

In addition, the food composition is more preferably diethylaminobenzaldehyde (Diethylaminobenzaldehyde; DEAB), disulfiram (disulfiram), and 3-hydroxykynurenine (3-hydroxy-DL-kynurenine) any one selected from the group consisting of This is to include the above as an active ingredient.

In the above, the acidosis is preferably metabolic acidosis or respiratory acidosis, and more preferably lactic acidosis, but is not limited thereto.

Hereinafter, the present invention will be described in detail step by step.

The present invention relates to a pharmaceutical composition for the prevention or treatment of acidosis, and the pharmaceutical composition of the present invention has a remarkable effect on reducing the concentration of acid accumulated in an organism, and thus is expected to be greatly used in the medical and health fields.

1 is a result of evaluating the effect of reducing acidosis of candidate substances for treatment of acidosis according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These examples are only intended to illustrate the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example 1: Screening of candidate substances for treatment of acidosis

The inventors of the present invention screened various candidate substances to develop an acid treatment substance, and derived the substances in Table 1 below.

No. Substance name One Benomyl 2 Cisplatin (cis-diamminedichloridoplatinum; CDDP) 3 Chlorpropamide 4 Citral 5 CVT-10216 (3-[[[3- [4-[(Methylsulfonyl) amino] phenyl] -4-oxo-4H-1-benzopyran-7-yl] oxy] methyl] -benzoic acid) 6 Cyanamide 7 Daidzin 8 Diethylaminobenzaldehyde (DEAB) 9 Disulfiram 10 Morinate 11 N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide 12 Pargyline 13 Phospho (enol) pyruvic acid monosodium salt hydrate 14 Phenylglyoxal 15 Retinoic acid 16 Kynurenic acid 17 3-hydroxy-DL-kynurenine

Example 2: Confirm the effect of reducing the acid concentration of the candidate substance for treating acidosis

The effect of reducing the lactic acid concentration of the candidate substances listed in Table 1 was confirmed.

To this end, first, A549 cancer cells (adenocarcinomic human alveolar basal epithelial cells; cat.CCL-185) obtained from the American Cell Line Bank (ATCC) were cultured in RPMI 1640 with 10% fetal calf serum and 1% antibiotic-fungal agent. Cultivated in ° C, 5% CO ₂ environment, and passaged every 3 days. Lactic acid is produced in large quantities when glycolysis is activated in hypoxia, and cancer cells are known to produce large amounts of lactic acid because cells are concentrated in excess and have very active energy consumption activities.

The cells were seeded in a 24-well plate at a concentration of 3 × 10 ⁵ cells / well, and after incubation overnight, each of the candidate substances in Table 1 was dissolved in DMSO (Dimethyl Sulfoxide) and treated at a concentration of 50 uM, and added for 24 hours. Incubated with. Nothing was treated with the negative control of the candidate substances, and as the positive control, sodium oxamate, which is conventionally known as a treatment for lactic acidosis, was treated with the same concentration (50 uM) or 10 times the concentration (50 mM). Thereafter, the cell culture solution was mixed with 50 μl of a diluted solution diluted with DPBS (Dulbecco's Phosphate-Buffered Saline) and 50 μl of a lactic acid assay reaction buffer (Lactate assay reaction buffer, Promega, Madison, WI, USA) into a 96-well plate, and at room temperature. After reacting for 1 hour, luminescence was measured with a spectrophotometer (Synergy HTX Multi-Reader, BioTek). At the same time, the cell number of each sample was measured with a cell viability analysis kit (Cell Counting Kit-8), and calculated so that the lactic acid measured value compared to the same cell number in each sample could be compared against the number of cells in the negative control. All experiments were repeated 3 times, and the average is shown in FIG. 1.

As a result of the experiment, it was found that there are only differences in the degree, and all the candidate substances for the treatment of lactic acidosis to be screened by the present invention have an effect of reducing the lactic acid concentration. More specifically, compared to the positive control treated with the same concentration (sodium oxalate 50 uM), the group consisting of citral, CVT-10216, cyanamide, and retinoic acid had a lactic acid reduction effect of about 5%, and morinate , N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, and the group consisting of phenylglyoxane had a lactic acid reduction effect of about 10%, benomyl, cisplatin, chlorpropamide, diazine, parzylline, The group consisting of phospho (enol) pyruvic acid monosodium salt hydrate, and kynurenic acid had a lactic acid reduction effect of about 15%, and the group consisting of diethylaminobenzaldehyde, disulfiram, and 3-hydroxykynurenine was about 20. % Of lactic acid.

Since the specific parts of the present invention have been described in detail above, it is clear that for those skilled in the art, these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (2)

Pargyline (pargyline), or kynurenic acid (kynurenic acid) containing as an active ingredient, lactic acidosis prevention or treatment pharmaceutical composition.
A food composition for preventing or improving lactic acidosis, comprising pargyline or kynurenic acid as an active ingredient.

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