KR20210101186A - A pharmaceutical composition for co-administration with acidosis inducing agent - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for combined administration of an acidosis-inducing medicine. Acidosis is a problem which occurs due to the breakdown of acid-base equilibrium as a large amount of acid is produced and accumulated in the body, and there is a problem that acidosis often occurs as a side effect in drugs for the treatment of various diseases. The pharmaceutical composition of the present invention maintains original purpose of administration of the acidosis-inducing medicine, and also has a significant effect on reducing the concentration of acid accumulated in an organism due to the administration of the acidosis-inducing medicine, thereby being expected to be widely used in medicine and hygiene fields.

Description

A pharmaceutical composition for co-administration with acidosis inducing agent

The present invention relates to a pharmaceutical composition for concurrent administration of an acidosis-inducing agent.

Acidosis refers to a state in which the pH is lower than that of normal arterial blood pH 7.4±0.05 (a state in which the hydrogen ion concentration is high). It is largely divided into "respiratory acidosis" and "metabolic acidosis", and the 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 defined as a state in which lactic acid exceeds 45 mg/dL, as a large amount of lactic acid is produced and accumulated in the body, causing acidosis to break the acid-base balance. Cells metabolize glucose in the presence of oxygen to produce energy, and when glucose metabolism occurs in the absence of oxygen, lactic acid is produced. If lactic acidosis continues and acid-base balance is disrupted, symptoms of muscle weakness, hyperventilation, nausea, vomiting, sweating, or coma appear, and in severe cases, life may be lost. It is important to maintain However, lactic acidosis is a problem in many cases as a side effect of drugs for the treatment of various diseases. For example, metformin, an antidiabetic drug, is a very effective antidiabetic drug, but gastrointestinal hypothyroidism and lactic acidosis are known as the most important side effects of metformin.

Accordingly, the present invention has been devised to solve the problems of the prior art, and relates to a pharmaceutical composition for concurrent administration of an acidosis-inducing agent. The pharmaceutical composition of the present invention not only maintains the original administration purpose of the acidosis-inducing agent, but also has a remarkable effect in reducing the acid concentration accumulated in the organism due to the administration of the acidosis-inducing agent, so it will be widely used in medicine and health. It is expected.

The present invention has been devised to solve the problems in the prior art as described above, and relates to a pharmaceutical composition for co-administration of an acidosis-inducing agent.

However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, various specific details are set forth, such as specific forms, compositions and processes, and the like, for a thorough understanding of the present invention. 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 specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an 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, references to "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, the particular features, forms, compositions, or properties may be combined in any suitable manner in one or more embodiments.

Unless otherwise defined in the specification, 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 that of normal arterial blood pH 7.4±0.05 (a state in which the hydrogen ion concentration is high). Depending on the cause, "respiratory acidosis", in which oxygen supply to tissues is reduced due to insufficient oxygen absorption in the lungs or reduced blood flow, and in which the amount of lactic acid in the blood or locally increases regardless of the decrease in oxygen Classified as "metabolic acidosis". 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, alkali loss, or impaired renal acid excretion. poisoning of toxic substances, etc.

In one embodiment of the present invention, “lactic acidosis” is a type of acidosis, and acidosis occurs when a large amount of lactic acid is produced and accumulated in the body, and the acid-base balance is broken. It is defined as the following state. Cells metabolize glucose in the presence of oxygen to produce energy, and when glucose metabolism occurs in the absence of oxygen, lactic acid is produced. If lactic acidosis continues and acid-base equilibrium is disrupted, symptoms of muscle weakness, hyperventilation, nausea, vomiting, sweating, or coma appear, and in severe cases, life may be lost. It is important to maintain The causes of lactic acidosis include liver disease, kidney disease, neurological disease, mental disease, diabetes, leukemia, acquired immunodeficiency syndrome (AIDS), glycogen storage disease, drugs and poisons, severe infections (systemic sepsis and meningitis), Tumors, muscular dystrophy and several genetic metabolic and mitochondrial diseases that affect normal ATP production, and strenuous exercise.

In one embodiment of the present invention, “a drug that induces lactic acidosis” refers to a drug that induces lactic acidosis in the body as a side effect other than the intended purpose of administration. For example, metformin, a diabetes treatment agent, is a very effective treatment for diabetes. As a side effect of the effect, it causes gastrointestinal hypotension and lactic acidosis.Lactate acidosis caused by the above drugs causes a great loss in the health/pharmaceutical industry in that it makes it difficult to freely use the drug for its intended purpose, so the lactic acid It is required to develop a drug that can suppress the side effects of lactic acidosis by co-administration with an acidosis-inducing agent.

In one embodiment of the present invention, “treatment” refers to a series of activities performed for alleviation and/or amelioration of a desired disease. For the purpose of the present invention, treatment includes an activity of improving the symptoms of acidosis by removing the cause of the occurrence of acidosis caused by the administration of an acidosis-inducing agent, or reducing the concentration of the generated acid when the cause cannot be eliminated.

In one embodiment of the present invention, "pharmaceutical composition" refers to 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 caused by the administration of an acidosis-inducing agent, 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 with respect to the total weight of the composition. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, 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 present invention, "administration" means introducing the composition of the present invention to a patient by any suitable method, and the administration route of the composition of the present invention is through 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, intrapulmonary administration, rectal administration, intraperitoneal administration, intraperitoneal administration, intrathecal administration may be made, but is not limited thereto does not In the present invention, the effective amount refers to the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of formulation and the age, weight, general health status, sex and diet, administration time, route of administration of the patient. And it can be adjusted according to various factors, including the secretion rate of the composition, the duration of treatment, and drugs used concurrently. For adults, the therapeutic pharmaceutical composition can be administered into the body in an amount of 50ml to 500ml at a time, 0.1ng/kg-10mg/kg in the case of a compound, 0.1ng/kg-10mg in the case of a monoclonal antibody It can be administered at a dose of /kg. The administration interval may be 1 to 12 times a day, and if 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 with other therapies known in the art, for example, 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 admixture 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 may be used, such as biolistic delivery or ex vivo treatment. In ex vivo treatment, for example, antigen-presenting cells (APCs), dendritic cells, peripheral blood mononuclear cells, or bone marrow cells can be obtained from a patient or an appropriate donor and activated in vitro with the present 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 indications for the purpose of the present invention. For example, it may be prepared in the form of beverage, gum, tea, vitamin complex, powder, granule, tablet, capsule, confectionery, rice cake, bread, and the like. Since the food composition of the present invention is improved from the existing food intake with little toxicity and side effects, it can be safely used even when taken for a long period of time for the purpose of prevention. When the composition of the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 100% of the total weight. Here, when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, and common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol are included. can do. Examples of the flavoring agent include natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). Others of the present invention of various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, It may contain stabilizer, preservative, glycerin, alcohol, carbonation agent used in carbonated beverage, etc. These components can be used independently or in combination.The proportion of these additives is usually per 100 parts by weight of the composition of the present invention. It is generally selected in the range of 0.1 to 100 parts by weight, but is not limited thereto.

In one embodiment of the present invention, there is provided a pharmaceutical composition for co-administration of an acidosis-inducing agent comprising an aldehyde dehydrogenase as an active ingredient, wherein the aldehyde dehydrogenase is 3-hydroxy-DL-kynurenine. , benomyl, cisplatin (cis-diamminedichloridoplatinum; CDDP), chlorpropamide, citral, CVT-10216(3-[[[3-[4-[(methylsulfonyl)amino]phenyl) ]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, or 3-[[[3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H- chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, gossypol, kynurenic acid, molinate, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, phenylglyoxal, retinoic acid (retinoic acid), N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), and sodium oxalate (sodium oxamate) any one or more selected from the group consisting of It provides a pharmaceutical composition for co-administration of an acidosis-inducing agent, characterized in that the acidosis-inducing agent is liver disease, kidney disease, neurological disease, mental disease, diabetes, leukemia, acquired immunodeficiency syndrome (AIDS), glycogen storage disease, infection , for the treatment of tumors, muscular dystrophy, genetic metabolic disorders, mitochondrial disorders, acute dyskinesia, or poison poisoning. It provides a pharmaceutical composition for the combined administration of an acidosis-inducing agent to be administered to, wherein the acidosis-inducing agent is metformin, phenformin, isoniazid, berberine, and linezolid linezolid) provides a pharmaceutical composition for concurrent administration of an acidosis-inducing agent, characterized in that it is any one or more selected from the group consisting of, wherein the acidosis is a pharmaceutical composition for concurrent administration of an acidosis-inducing agent wherein the arterial blood pH is 7.35 or less to provide.

In another embodiment of the present invention, there is provided a food composition for co-administration of an acidosis-inducing agent comprising an aldehyde dehydrogenase as an active ingredient, wherein the aldehyde dehydrogenase is 3-hydroxy-DL-kynurenine , benomyl, cisplatin (cis-diamminedichloridoplatinum; CDDP), chlorpropamide, citral, CVT-10216(3-[[[3-[4-[(methylsulfonyl)amino]phenyl) ]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, or 3-[[[3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H- chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylaminobenzaldehyde (DEAB), disulfiram, gossypol, kynurenic acid, molinate, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, phenylglyoxal, retinoic acid (retinoic acid), N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide), and sodium oxalate (sodium oxamate) any one or more selected from the group consisting of It provides a food composition for co-administration of an acidosis-inducing agent, characterized in that the acidosis-inducing agent is liver disease, kidney disease, neurological disease, mental disease, diabetes, leukemia, acquired immunodeficiency syndrome (AIDS), glycogen storage disease, infection , for the treatment of tumors, muscular dystrophy, genetic metabolic disorders, mitochondrial disorders, acute dyskinesia, or poison poisoning. It provides a food composition for the co-administration of an acidosis-inducing agent that is administered to linezolid) provides a food composition for concurrent administration of an acidosis-inducing agent, characterized in that at least one selected from the group consisting of acidosis-inducing agent, wherein the acidosis is arterial blood pH of 7.35 or less. to provide.

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, wherein the pharmaceutical composition of the present invention not only maintains the original purpose of administration of the acidosis-inducing agent, but also reduces the concentration of acid accumulated in the organism due to the administration of the acidosis-inducing agent. It is expected to be widely used in the fields of medicine and health because it has a remarkable effect on

1 is a result confirming the effect of co-administration of metformin as an acidosis-inducing substance and a candidate substance for the treatment of acidosis using A549 cells according to an embodiment of the present invention.
2 is a result confirming the effect of co-administration of isoniazid as an acidosis-inducing substance and a candidate substance for the treatment of acidosis using A549 cells according to an embodiment of the present invention.
3A and 3B are results of confirming the effect of co-administration of berberine as an acidosis-inducing substance and a candidate substance for acidosis treatment using A549 cells according to an embodiment of the present invention.
4A and 4B are results of confirming the effect of co-administration of berberine as an acidosis-inducing substance and a candidate substance for the treatment of acidosis using L132 cells according to an embodiment of the present invention.
5A and 5B are results confirming the effect of co-administration of linezolid as an acidosis-inducing substance and a candidate substance for the treatment of acidosis using A549 cells, according to an embodiment of the present invention.
6A and 6B are results of confirming the effect of co-administration of linezolid as an acidosis-inducing substance and a candidate substance for the treatment of acidosis using L132 cells, according to an embodiment of the present invention.
7A and 7B are results of confirming the effect of co-administration of phenformin as an acidosis-inducing substance and a candidate substance for acidosis treatment using A549 cells, according to an embodiment of the present invention.
8A and 8B are results of confirming the effect of co-administration of phenformin as an acidosis-inducing substance and a candidate substance for the treatment of acidosis using L132 cells, according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill 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 the treatment of acidosis

As a result of screening various aldehyde dehydrogenase (ALDH inhibitors) candidate substances to develop acidosis therapeutic substances, the inventors of the present invention derived substances shown in Table 1 below.

No. substance name One 3-hydroxykynurenine (3-hydroxy-DL-kynurenine; 3-HDK) 2 benomyl 3 cis-diamminedichloridoplatinum (CDDP) 4 chlorpropamide 5 citral 6 CVT-10216(3-[[[3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, or 3-[[ [3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid) 7 cyanamide 8 Daidzin 9 diethylaminobenzaldehyde (DEAB) 10 disulfiram 11 gossypol 12 kynurenic acid 13 molinate 14 Pargyline 15 Phospho (enol) pyruvic acid monosodium salt hydrate 16 phenylglyoxal 17 retinoic acid 18 N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide) 19 sodium oxalate

Example 2: Confirmation of the effect of co-administration of an acidosis-inducing substance and a candidate substance for the treatment of acidosis

Examples of lactic acidosis inducing substances include biguanides, metformin, or phenformin, as a treatment for diabetes, isoniazid, as an anti-tuberculosis or anti-depressant, berberine as an antiviral, antifungal, or antibiotic , or linezolid was used as an oxazolidinone-based antibiotic. These drugs are drugs for which lactic acidosis is known as a side effect other than the original pharmaceutical use.

In order to confirm the effect of co-administration of the lactic acidosis-inducing substance and the candidate substance for the treatment of lactic acidosis described in Example 1, A549 cells (cancer cells) or L132 (normal cells) were each 1×10 ^{4 in 96 or 24-well plates.} , or 3×10 ⁵ cells/well, seeded and cultured overnight, the lactic acidosis-inducing substance and a candidate substance for the treatment of acidosis were co-administered, and further cultured for 24 hours. The administration concentration of the candidate substance for the treatment of acidosis was unified at 50 μM, and the administration concentration of the lactic acidosis-inducing substance was 1 to 100 μM for metformin, 1 to 500 μM for isoniazid, 10 μM for berberine, 200 μM for linezolid, and Fenfort. In the case of min, 100 μM was administered. All substances were dissolved in DMSO (Dimethyl Sulfoxide, Sigma-Aldrich Corporation, St. Louis, MO, USA), and the concomitant substances were administered simultaneously. After that, 50 μl of the cell culture solution diluted with DPBS (Dulbecco's Phosphate-Buffered Saline, Wellgene, Korea) and 50 μl of lactate assay reaction buffer (Lactate assay reaction buffer, Promega, Madison, WI, USA) were mixed and put in a 96-well plate. After reacting at room temperature for 1 hour, luminescence was measured with a spectrophotometer (Synergy HTX Multi-Reader, BioTek, Winooski, Vermont, US). At the same time, the number of cells in each sample was measured with a cell viability analysis kit (Cell Counting Kit-8, Dojindo molecular technologies, Kumamoto, Japan), and the lactate measurement value compared to the same number of cells in each sample was compared with the number of cells in the negative control group. calculated to be possible. The experimental results are shown in FIGS. 1 to 8, and Tables 2 to 7 below.

Cell: A549 Luminescence intensity (%) PC Contrast
lactic acid
shame(%) PC Contrast
lactic acid
Decrease rate (%) Berberine (10 μM) - + Control
(negative control; NC) 100.00 ± 0.24 - - - Lactic acidosis inducers
(positive control; PC) - 133.35 ± 3.66 ^*** 100.00 0.00 3-hydroxy-DL-kynurenine 91.52 ± 1.46 ^*** 123.42 ± 7.78 92.55 7.45 Benomyl 87.71 ± 1.21 ^*** 118.08 ± 2.36 ^## 88.55 11.45 CDDP 75.98 ± 2.34 ^*** 98.94 ± 3.52 ^### 74.20 25.80 Chlorpropamide 96.97 ± 1.24 ^* 120.93 ± 2.88 ^# 90.69 9.31 Citral 100.48 ± 0.81 127.58 ± 3.61 95.67 4.33 CVT-10216 96.46 ± 1.04 ^** 127.73 ± 4.05 95.79 4.21 Cyanamide 97.02 ± 0.81 ^** 128.76 ± 4.45 96.56 3.44 Daidzin 97.42 ± 1.10 ^* 123.33 ± 2.62 ^# 92.49 7.51 DEAB 96.72 ± 0.78 ^*** 122.62 ± 4.07 91.95 8.05 Disulfiram 86.10 ± 1.66 ^*** 100.91 ± 3.69 ^### 75.67 24.33 Gossypol 87.59 ± 1.87 ^*** 83.52 ± 1.73 ^### 62.63 37.37 Kynurenic acid 93.86 ± 1.10 ^*** 135.85 ± 9.82 101.87 -1.87 Molinate 109.57 ± 1.91 141.06 ± 5.84 105.78 -5.78 Pargyline 95.68 ± 0.70 ^*** 135.87 ± 5.30 101.89 -1.89 Phospho(enol)pyruvic acid monosodium salt hydrate 100.07 ± 1.80 120.11 ± 4.90 90.07 9.93 Phenylglyoxal 97.26 ± 1.03 ^* 120.26 ± 2.93 ^## 90.18 9.82
^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 (vs. Control)
^# p < 0.05, ^## p < 0.01, ^### p < 0.001 (vs. lactic acidosis inducers)
Data are presented as the mean ± standard error of the mean (SEM). Statistical significance was evaluated with Student's t- test. A p value of < 0.05 was considered statistically significant (n = 10 ≤ 46).

Cell: A549 Luminescence intensity (%) PC Contrast
lactic acid
shame(%) PC Contrast
lactic acid
Decrease rate (%) Linezolid (200 μM) - + Control
(negative control; NC) 100.00 ± 0.24 - - - Lactic acidosis inducers
(positive control; PC) - 138.85 ± 2.60 ^*** 100.00 0.00 3-hydroxy-DL-kynurenine 91.52 ± 1.46 ^*** 116.19 ± 2.54 ^### 83.68 16.32 Benomyl 87.71 ± 1.21 ^*** 117.08 ± 3.87 ^### 84.32 15.68 CDDP 75.98 ± 2.34 ^*** 108.81 ± 4.46 ^### 78.37 21.63 Chlorpropamide 96.97 ± 1.24 ^* 120.54 ± 3.88 ^### 86.81 13.19 Citral 100.48 ± 0.81 143.30 ± 5.38 103.20 -3.20 CVT-10216 96.46 ± 1.04 ^** 129.03 ± 3.60 ^# 92.93 7.07 Cyanamide 97.02 ± 0.81 ^** 121.85 ± 2.71 ^### 87.76 12.24 Daidzin 97.42 ± 1.10 ^* 114.48 ± 2.81 ^### 82.45 17.55 DEAB 96.72 ± 0.78 ^*** 121.72 ± 4.16 ^### 87.66 12.34 Disulfiram 86.10 ± 1.66 ^*** 112.37 ± 6.99 ^## 80.93 19.07 Gossypol 87.59 ± 1.87 ^*** 94.22 ± 2.91 ^### 67.86 32.14 Kynurenic acid 93.86 ± 1.10 ^*** 127.10 ± 4.28 ^# 91.54 8.46 Molinate 109.57 ± 1.91 147.02 ± 8.95 105.88 -5.88 Pargyline 95.68 ± 0.70 ^*** 136.40 ± 5.27 98.24 1.76 Phospho(enol)pyruvic acid monosodium salt hydrate 100.07 ± 1.80 129.07 ± 6.22 92.96 7.04 Phenylglyoxal 97.26 ± 1.03 ^* 114.89 ± 4.77 ^### 82.74 17.26
^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 (vs. Control)
^# p < 0.05, ^## p < 0.01, ^### p < 0.001 (vs. lactic acidosis inducers)
Data are presented as the mean ± standard error of the mean (SEM). Statistical significance was evaluated with Student's t- test. A p value of < 0.05 was considered statistically significant (n = 10 ≤ 46).

Cell: A549 Luminescence intensity (%) PC Contrast
lactic acid
shame(%) PC Contrast
lactic acid
Decrease rate (%) Phenformin (100 μM) - + Control
(negative control; NC) 100.00 ± 0.24 - - - Lactic acidosis inducers
(positive control; PC) - 137.16 ± 2.67 ^*** 100.00 0.00 3-hydroxy-DL-kynurenine 91.52 ± 1.46 ^*** 125.28 ± 2.51 ^## 91.34 8.66 Benomyl 87.71 ± 1.21 ^*** 127.20 ± 4.47 ^# 92.74 7.26 CDDP 75.98 ± 2.34 ^*** 109.77 ± 4.37 ^### 80.03 19.97 Chlorpropamide 96.97 ± 1.24 ^* 130.12 ± 2.45 94.87 5.13 Citral 100.48 ± 0.81 128.66 ± 3.38 93.80 6.20 CVT-10216 96.46 ± 1.04 ^** 126.37 ± 2.97 ^# 92.13 7.87 Cyanamide 97.02 ± 0.81 ^** 135.56 ± 2.80 98.83 1.17 Daidzin 97.42 ± 1.10 ^* 136.83 ± 0.93 99.76 0.24 DEAB 96.72 ± 0.78 ^*** 129.31 ± 3.07 94.28 5.72 Disulfiram 86.10 ± 1.66 ^*** 124.58 ± 5.45 ^# 90.83 9.17 Gossypol 87.59 ± 1.87 ^*** 92.23 ± 4.44 ^### 67.24 32.76 Kynurenic acid 93.86 ± 1.10 ^*** 126.98 ± 2.42 ^## 92.58 7.42 Molinate 109.57 ± 1.91 125.00 ± 3.24 ^## 91.13 8.87 Pargyline 95.68 ± 0.70 ^*** 131.11 ± 4.42 95.59 4.41 Phospho(enol)pyruvic acid monosodium salt hydrate 100.07 ± 1.80 130.18 ± 1.81 ^# 94.91 5.09 Phenylglyoxal 97.26 ± 1.03 ^* 122.91 ± 3.16 ^## 89.61 10.39
^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 (vs. Control)
^# p < 0.05, ^## p < 0.01, ^### p < 0.001 (vs. lactic acidosis inducers)
Data are presented as the mean ± standard error of the mean (SEM). Statistical significance was evaluated with Student's t- test. A p value of < 0.05 was considered statistically significant (n = 10 ≤ 46).

Cell: L132 Luminescence intensity (%) PC Contrast
lactic acid
shame(%) PC Contrast
lactic acid
Decrease rate (%) Berberine (10 μM) - + Control
(negative control; NC) 100.00 ± 0.29 - - - Lactic acidosis inducers
(positive control; PC) - 180.47 ± 4.06 ^*** 100.00 0.00 3-hydroxy-DL-kynurenine 87.48 ± 1.65 ^*** 157.57 ± 6.63 ^## 87.31 12.69 Benomyl 85.37 ± 1.55 ^*** 154.09 ± 5.00 ^### 85.38 14.62 CDDP 76.97 ± 2.13 ^*** 128.90 ± 3.32 ^### 71.42 28.58 Chlorpropamide 92.44 ± 1.05 ^*** 184.77 ± 3.41 102.38 -2.38 Citral 102.44 ± 0.98 184.14 ± 5.78 102.03 -2.03 CVT-10216 97.70 ± 1.10 ^* 186.15 ± 4.42 103.15 -3.15 Cyanamide 92.07 ± 1.56 ^*** 180.22 ± 3.21 99.86 0.14 Daidzin 91.95 ± 1.14 ^*** 173.14 ± 6.14 95.94 4.06 DEAB 93.41 ± 2.71 ^* 191.48 ± 4.00 106.10 -6.10 Disulfiram 93.39 ± 2.64 ^* 124.82 ± 5.30 ^### 69.16 30.84 Gossypol 84.30 ± 2.90 ^*** 91.96 ± 8.20 ^### 50.96 49.04 Kynurenic acid 93.70 ± 1.30 ^*** 163.49 ± 3.85 ^## 90.59 9.41 Molinate 154.71 ± 3.38 189.56 ± 5.84 105.04 -5.04 Pargyline 96.12 ± 1.32 ^** 183.29 ± 5.41 101.56 -1.56 Phospho(enol)pyruvic acid monosodium salt hydrate 94.55 ± 1.37 ^*** 167.93 ± 6.59 93.05 6.95 Phenylglyoxal 93.72 ± 1.34 ^*** 162.53 ± 7.06 ^# 90.06 9.94
^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 (vs. Control)
^# p < 0.05, ^## p < 0.01, ^### p < 0.001 (vs. lactic acidosis inducers)
Data are presented as the mean ± standard error of the mean (SEM). Statistical significance was evaluated with Student's t- test. A p value of < 0.05 was considered statistically significant (n = 10 ≤ 46).

Cell: L132 Luminescence intensity (%) PC Contrast
lactic acid
shame(%) PC Contrast
lactic acid
Decrease rate (%) Linezolid (200 μM) - + Control
(negative control; NC) 100.00 ± 0.29 - - - Lactic acidosis inducers
(positive control; PC) - 134.13 ± 2.76 ^*** 100.00 0.00 3-hydroxy-DL-kynurenine 87.48 ± 1.65 ^*** 115.88 ± 5.40 ^## 86.39 13.61 Benomyl 85.37 ± 1.55 ^*** 113.78 ± 4.63 ^### 84.83 15.17 CDDP 76.97 ± 2.13 ^*** 91.59 ± 9.73 ^### 68.28 31.72 Chlorpropamide 92.44 ± 1.05 ^*** 120.87 ± 2.06 ^### 90.11 9.89 Citral 102.44 ± 0.98 136.84 ± 6.03 102.02 -2.02 CVT-10216 97.70 ± 1.10 ^* 134.51 ± 5.70 100.28 -0.28 Cyanamide 92.07 ± 1.56 ^*** 119.36 ± 1.28 ^### 88.99 11.01 Daidzin 91.95 ± 1.14 ^*** 117.76 ± 2.20 ^### 87.80 12.20 DEAB 93.41 ± 2.71 ^* 141.12 ± 6.19 105.21 -5.21 Disulfiram 93.39 ± 2.64 ^* 116.91 ± 5.09 ^## 87.16 12.84 Gossypol 84.30 ± 2.90 ^*** 91.00 ± 4.58 ^### 67.84 32.16 Kynurenic acid 93.70 ± 1.30 ^*** 125.45 ± 4.95 93.53 6.47 Molinate 154.71 ± 3.3 168.58 ± 7.49 125.68 -25.68 Pargyline 96.12 ± 1.32 ^** 118.97 ± 2.06 ^### 88.70 11.30 Phospho(enol)pyruvic acid monosodium salt hydrate 94.55 ± 1.37 ^*** 119.78 ± 3.96 ^## 89.30 10.70 Phenylglyoxal 93.72 ± 1.34 ^*** 119.23 ± 6.15 ^# 88.89 11.11
^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 (vs. Control)
^# p < 0.05, ^## p < 0.01, ^### p < 0.001 (vs. lactic acidosis inducers)
Data are presented as the mean ± standard error of the mean (SEM). Statistical significance was evaluated with Student's t- test. A p value of < 0.05 was considered statistically significant (n = 10 ≤ 46).

Cell: L132 Luminescence intensity (%) PC Contrast
lactic acid
shame(%) PC Contrast
lactic acid
Decrease rate (%) Phenformin (100 μM) - + Control
(negative control; NC) 100.00 ± 0.29 - - - Lactic acidosis inducers
(positive control; PC) - 197.99 ± 4.82 ^*** 100.00 0.00 3-hydroxy-DL-kynurenine 87.48 ± 1.65 ^*** 181.68 ± 5.51 91.76 8.24 Benomyl 85.37 ± 1.55 ^*** 184.19 ± 5.25 93.03 6.97 CDDP 76.97 ± 2.13 ^*** 166.27 ± 8.17 ^### 83.98 16.02 Chlorpropamide 92.44 ± 1.05 ^*** 191.42 ± 4.96 96.68 3.32 Citral 102.44 ± 0.98 197.14 ± 5.12 99.57 0.43 CVT-10216 97.70 ± 1.10 ^* 196.43 ± 5.54 99.21 0.79 Cyanamide 92.07 ± 1.56 ^*** 194.40 ± 5.56 98.19 1.81 Daidzin 91.95 ± 1.14 ^*** 194.40 ± 4.24 98.19 1.81 DEAB 93.41 ± 2.71 ^* 183.71 ± 5.42 92.79 7.21 Disulfiram 93.39 ± 2.64 ^* 154.84 ± 5.42 ^### 78.21 21.79 Gossypol 84.30 ± 2.90 ^*** 102.12 ± 2.97 ^### 51.58 48.42 Kynurenic acid 93.70 ± 1.30 ^*** 181.56 ± 5.82 91.70 8.30 Molinate 154.71 ± 3.38 196.32 ± 5.38 99.16 0.84 Pargyline 96.12 ± 1.32 ^** 199.74 ± 5.94 100.88 -0.88 Phospho(enol)pyruvic acid monosodium salt hydrate 94.55 ± 1.37 ^*** 181.06 ± 15.09 91.45 8.55 Phenylglyoxal 93.72 ± 1.34 ^*** 190.30 ± 6.09 96.12 3.88
^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 (vs. Control)
^# p < 0.05, ^## p < 0.01, ^### p < 0.001 (vs. lactic acidosis inducers)
Data are presented as the mean ± standard error of the mean (SEM). Statistical significance was evaluated with Student's t- test. A p value of < 0.05 was considered statistically significant (n = 10 ≤ 46).

From the above results, even if it is a candidate substance for the treatment of acidosis that has a similar effect on reducing lactic acid when administered alone, the effect is very different when administered in combination with a lactic acidosis-inducing substance, and it can be seen that the effect is also different depending on the type of lactic acidosis-inducing substance . For example, when DEAB or disulfiram, a candidate substance for the treatment of acidosis, was administered alone to L132 cells, the lactic acid level was 93.41±2.71 and 93.39±2.64, respectively, compared to the negative control group. When administered, the rate of decrease in lactate level was significantly different, increasing by 5.21% and decreasing by 12.84%, respectively, compared to the positive control group.

As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (10)

A pharmaceutical composition for concurrent administration of an acidosis-inducing agent, comprising an aldehyde dehydrogenase as an active ingredient.
The method of claim 1,
The aldehyde dehydrogenase is 3-hydroxykynurenine (3-hydroxy-DL-kynurenine), benomyl (benomyl), cisplatin ( cis- diamminedichloridoplatinum; CDDP), chlorpropamide (chlorpropamide), citral (citral), CVT -10216(3-[[[3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, or 3-[[[ 3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylamino Benzaldehyde (diethylaminobenzaldehyde; DEAB), disulfiram, gossypol, kynurenic acid, molinate, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate ( phospho(enol)pyruvic acid monosodium salt hydrate), phenylglyoxal, retinoic acid, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-Acetyl-N-acetoxy-4) -chlorobenzenesulfonamide), and sodium oxalate (sodium oxamate), characterized in that any one or more selected from the group consisting of, a pharmaceutical composition for co-administration of an acidosis-inducing agent.
The method of claim 1,
The acidosis-inducing agent is liver disease, kidney disease, neurological disease, mental disease, diabetes, leukemia, acquired immunodeficiency syndrome (AIDS), glycogen storage disease, infection, tumor, muscular dystrophy, genetic metabolic disease, mitochondrial disease, acute movement disorder, Or, a pharmaceutical composition for concurrent administration of an acidosis-inducing agent, which is administered for the treatment of poison poisoning.
4. The method of claim 3,
The acidosis inducing agent is metformin (metformin), phenformin (phenformin), isoniazid (isoniazid), berberine (berberine), and acidosis inducing agent, characterized in that at least one selected from the group consisting of linezolid (linezolid) A pharmaceutical composition for concomitant administration of drugs.
The method of claim 1,
The acidosis is an arterial blood pH of 7.35 or less, a pharmaceutical composition for co-administration of an acidosis-inducing agent.
A food composition for co-administration of an acidosis-inducing agent comprising an aldehyde dehydrogenase as an active ingredient.
7. The method of claim 6,
The aldehyde dehydrogenase is 3-hydroxy-DL-kynurenine, benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, citral, CVT. -10216(3-[[[3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid, or 3-[[[ 3-[4-[(methylsulfonyl)amino]phenyl]-4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid), cyanamide, daidzin, diethylamino Benzaldehyde (diethylaminobenzaldehyde; DEAB), disulfiram, gossypol, kynurenic acid, molinate, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate ( phospho(enol)pyruvic acid monosodium salt hydrate), phenylglyoxal, retinoic acid, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide (N-Acetyl-N-acetoxy-4) -chlorobenzenesulfonamide), and sodium oxalate (sodium oxamate), characterized in that any one or more selected from the group consisting of, a food composition for co-administration of an acidosis-inducing agent.
7. The method of claim 6,
The acidosis-inducing agent is liver disease, kidney disease, neurological disease, mental disease, diabetes, leukemia, acquired immunodeficiency syndrome (AIDS), glycogen storage disease, infection, tumor, muscular dystrophy, genetic metabolic disease, mitochondrial disease, acute movement disorder, Or, a food composition for co-administration of an acidosis-inducing agent, which is administered for the treatment of poison poisoning.
9. The method of claim 8,
The acidosis inducing agent is metformin (metformin), phenformin (phenformin), isoniazid (isoniazid), berberine (berberine), and acidosis inducing agent, characterized in that at least one selected from the group consisting of linezolid (linezolid) A food composition for concomitant administration of pharmaceuticals.
7. The method of claim 6,
The acidosis is an arterial blood pH of 7.35 or less, a food composition for co-administration of an acidosis-inducing agent.

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