KR102011815B1 - 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. Since the pharmaceutical composition has a remarkable effect in reducing acid concentration accumulated in an organism, it is expected to be widely used in medical and health fields. The present invention is the pharmaceutical composition for preventing or treating lactic acidosis, which contains diethylaminobenzaldehyde (DEAB) or 3-hydroxykynurenine (3-hydroxy-DL-kynurenine) 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 means a lower pH (higher hydrogen ion concentration) based on pH 7.4 ± 0.05 of arterial blood of a normal person. It is divided into "respiratory acidosis" and "metabolic acidosis", and metabolic acidosis includes diabetic ketoacidosis, lactic acidosis, or poisoning of toxic substances such as salicylic acid, methanol, and ethylene glycol. Among them, lactic acidosis is produced by the accumulation of a large amount of lactic acid in the body and the acid equilibrium is broken and acidosis occurs. Lactic acid is defined as a state of more than 45 mg / ㎗ and a ph of 7.25 or less. Cells produce energy by metabolizing glucose in the presence of oxygen. Lactate is produced when glucose metabolism occurs in the absence of oxygen. Therefore, lactic acidosis occurs mainly in the state of reduced oxygenation in the body such as hypoxic shock, decreased blood volume, left ventricular dysfunction, and localized effects of drugs and toxins (ethanol and methanol) or increased energy metabolism as in tumors. Lactate in tissues increases even in the state. 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 it.

However, in addition to supplying sufficient oxygen for the treatment of lactic acid, there is no alternative that can adjust the concentration of lactic acid with a medicament, and there is a need for developing a therapeutic agent for preventing or treating lactic acidosis.

Therefore, the present invention has been made to solve the problems of the prior art, and relates to a pharmaceutical composition for the prevention or treatment of acidosis. Since the pharmaceutical composition of the present invention has a remarkable effect in reducing the acid concentration accumulated in the organism, it is expected to be widely used in the medical and health fields.
(Previous Document) De Paepe P, et al., Disulfiram inhibition of cyanide formation after acetonitrile poisoning; Clin Toxicol (Phila), 2016. 54 (1): 56-60.

The present invention has been made to solve the problems of the prior art, and relates to a pharmaceutical composition for the prevention or treatment of acidosis.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is 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 are set forth, such as specific forms, compositions, processes and the like. 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" means a state having a lower pH (higher hydrogen ion concentration) based on arterial blood pH 7.4 ± 0.05 of a normal person. Depending on the cause, "respiratory acidosis" in which the oxygen supply to the tissue is reduced due to insufficient oxygen absorption or reduced blood flow in the lungs, and the amount of lactic acid in the blood or topically increased regardless of the decrease 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 three mechanisms: acid load, loss of alkali, or impaired excretion of the kidneys. In the case of increased acid, 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 equilibrium that is broken and acidosis occurs. Lactic acid exceeds 45 mg / ㎗ and pH 7.45 It is defined as the following state. Cells produce energy by metabolizing glucose in the presence of oxygen. Lactate is produced when glucose metabolism occurs in the absence of oxygen. Therefore, lactic acidosis occurs mainly in the state of reduced oxygenation in the body such as hypoxic shock, decreased blood volume, left ventricular dysfunction, and localized effects of drugs and toxins (ethanol and methanol) or increased energy metabolism as in tumors. Lactate in tissues increases even in the state. 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 it. The causes of lactic acidosis include liver disease, kidney disease, diabetes, leukemia, acquired immunodeficiency syndrome (AIDS), glycogen accumulation disease, drugs and toxins, severe infections (systemic pneumonia and meningosis), tumors, muscular dystrophy and normal ATP. There are several genetic metabolic 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 / or ameliorate a desired disease. Treatment for the purposes of the present invention includes the activity of ameliorating the symptoms of acidosis by eliminating the cause of the occurrence of acidosis in the condition in which the acidosis has developed, or by reducing the acid concentration produced when the cause is impossible to eliminate.

In one embodiment of the present invention, "pharmaceutical composition" means a composition to be 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 in the present invention and a pharmaceutically acceptable carrier, excipient or diluent. In addition, the pharmaceutical composition according to the present invention contains 0.1 to 50% by weight of the active ingredient of the present invention based on 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.

In one embodiment of the invention “administration” means introducing the composition of the invention to the patient in any suitable way, the route of administration of the composition of the invention via any general route as long as it can reach the target tissue. May be administered. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, pulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intradural administration, but are not limited thereto. Do not. In the present invention, the effective amount is defined as the type of disease, the severity of the disease, the type and amount of the active ingredient and other ingredients contained in the composition, the type and formulation of the patient and the age, body weight, general health condition, sex and diet, time of administration, route of administration And various factors, including the rate of secretion of the composition, the duration of treatment, and the drugs used concurrently. In adults, the therapeutic pharmaceutical composition can be administered once in the body in an amount of 50ml ~ 500ml, 0.1ng / kg-10mg / kg for a compound, 0.1ng / kg-10mg for a monoclonal antibody. It may be administered at a dose of / kg. Dosing interval may be 1 to 12 times a day, if 12 times a day may be administered once every two hours. In addition, the pharmaceutical composition of the present invention may be administered alone or in combination with other therapies known in the art for the treatment of cancer stem cells of interest, such as chemotherapeutic agents, radiation and surgery. The pharmaceutical compositions of the present invention may also be administered in admixture with other therapies designed to enhance immune responses, for example adjuvant or cytokines (or nucleic acids encoding cytokines), as is well known in the art. Other standard delivery methods may be used, such as biolistic delivery or ex vivo treatment. In vitro treatment, for example, antigen presenting cells (APCs), dendritic cells, peripheral blood mononuclear cells, or bone marrow cells can be obtained from a patient or appropriate donor and then activated in vitro with the 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, for example 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 when taken for long periods of time. 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. Herein, when the food composition is prepared in the form of a beverage, there is no particular limitation other than the food composition in the proportion indicated, and may include 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 flavourant include natural flavourant (tautin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition is a variety of nutrients, 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 colloidal 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, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, digizin, pargyline, Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydride Pharmaceutical composition for the prevention or treatment of acidosis comprising any one or more selected from the group consisting of 3-hydroxy-DL-kynurenine as an active ingredient To provide.

The pharmaceutical composition is preferably molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, benomyl (benomyl), cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daizin, 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-kynurenine It is to include any one or more as an active ingredient.

The pharmaceutical composition is more preferably benoyl (benomyl), cis-platinum (cis-diamminedichloridoplatinum (CDDP), chlorpropamide (dialzin), parziline (pargyline), phospho (enol) pyruvate monosodium Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxykynurenine (3-hydroxy- DL-kynurenine) is one or more selected from the group consisting of as an active ingredient.

In addition, the pharmaceutical composition is more preferably any one selected from the group consisting of diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxy-kynurenine (3-hydroxy-DL-kynurenine) It 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, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, digizin, pargyline, Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydride Preparation of food for preventing or improving acidosis comprising any one or more selected from the group consisting of 3-hydroxy-DL-kynurenine as an active ingredient Provide water.

The food composition is preferably molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, benomyl (benomyl), cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daizin, 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-kynurenine It is to include any one or more as an active ingredient.

The food composition is more preferably benoyl (benomyl), cis-platinum (cis-diamminedichloridoplatinum (CDDP), chlorpropamide (dipropzin), digizin (pargyline), phospho (enol) pyruvate monosodium Phospho (enol) pyruvic acid monosodium salt hydrate, kynurenic acid, Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxykynurenine (3-hydroxy- DL-kynurenine) is one or more selected from the group consisting of as an active ingredient.

In addition, the food composition is more preferably any one selected from the group consisting of Diethylaminobenzaldehyde (DEAB), disulfiram, and 3-hydroxy-kynurenine (3-hydroxy-DL-kynurenine) It 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 preventing or treating acidosis. Since the pharmaceutical composition of the present invention has a remarkable effect in reducing acid concentration accumulated in an organism, it is expected to be widely used in medicine and health.

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

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating 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 Materials for Acidosis Treatment

The inventors of the present invention screened various candidate substances in order to develop an acidosis therapeutic substance, resulting in the substances of Table 1 below.

No. Substance 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 Dizinn 8 Diethylaminobenzaldehyde (DEAB) 9 Disulfiram 10 Molinate 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: Confirmation of the acid concentration reduction effect of the candidate substance for treating acidosis

The lactic acid concentration reduction effect of the candidate substances described in Table 1 was confirmed.

To this end, A549 cancer cells (adenocarcinomic human alveolar basal epithelial cells; cat. Incubated in a 5 ° C. ₂ ° C. environment and passaged every 3 days. Lactic acid is produced in large amounts when glycolysis is activated in hypoxia, and cancer cells are known to produce large amounts of lactic acid because the cells are excessively dense and have very active energy consumption.

The cells were seeded in a 24-well plate at a concentration of 3 × 10 ⁵ cells / well, incubated overnight, and then, each of the candidate substances in Table 1 was dissolved in DMSO (Dimethyl Sulfoxide), treated at 50 uM, and added for 24 hours. Incubated with The negative control group of the candidates was not treated with anything, and the positive control group was treated with sodium oxalate (sodium oxamate), which is conventionally known as a lactic acid therapy, at the same concentration (50 uM), or 10-fold concentration (50 mM). Subsequently, 50 μl of the diluted solution diluted with Dulbecco's Phosphate-Buffered Saline (DPBS) and 50 μl of Lactate assay reaction buffer (Promega, Madison, WI, USA) were mixed and placed in a 96-well plate at room temperature. After reacting for 1 hour, luminescence was measured with a spectrophotometer (Synergy HTX Multi-Reader, BioTek). At the same time, the number of cells in each sample was measured by a cell viability analysis kit (Cell Counting Kit-8), and calculated to compare the same cell number in each sample as compared to the number of cells in the negative control group. All experiments were repeated three times and the average is shown in FIG. 1.

As a result of the experiment, there was a difference in degree, and all the candidate substances for treating lactic acidosis to be screened by the present invention were shown to have an effect of reducing lactate concentration. More specifically, the group consisting of citral, CVT-10216, cyanamide, and retinoic acid, compared with the positive control group treated with the same concentration (50 uM sodium oxalate), had a lactic acid reduction effect of about 5% , N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, and phenylglyoxane group had a lactic acid reduction effect of about 10%, benomil, cisplatin, chlorpropamide, dizin, parziline, 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%. It has been shown to have a lactic acid reduction effect of%.

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, 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 equivalents thereof.

Claims (12)

Diethylaminobenzaldehyde (DEAB), or 3-hydroxy-kynurenine (3-hydroxy-DL-kynurenine) comprising as an active ingredient, lactic acidosis prevention or treatment pharmaceutical composition.
delete delete delete delete delete Diethylaminobenzaldehyde (DEAB), or 3-hydroxy-kynurenine (3-hydroxy-DL-kynurenine) comprising as an active ingredient, lactic acidosis prevention or food composition for improvement.
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