PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATMENT OF ACIDOSIS

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating acidosis. The pharmaceutical composition has a remarkable effect in decreasing the concentration of acid accumulated in an organism and thus is expected to be widely used in the fields of medicine and health.

Claims

1-18. (canceled)

19. A method for preventing or treating acidosis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one active ingredient selected from the group consisting of diethylaminobenzaldehyde (DEAB), disulfiram, 3-hydroxy-DL-kynurenine, benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daidzin, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, kynurenic acid, molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, 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, and retinoic acid.

20. The method of claim 19, wherein the acidosis is metabolic acidosis or respiratory acidosis.

21. The method of claim 20, wherein the metabolic acidosis is lactic acidosis, diabetic ketoacidosis, or poisoning by a toxic substance.

22. The method of claim 21, wherein the toxic substance is salicylic acid, methanol, or ethylene glycol.

23. The method of claim 21, wherein the metabolic acidosis is lactic acidosis.

24. The method of claim 19, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

25. The method of claim 24, wherein the pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil.

26. The method of claim 19, wherein the at least one active ingredient is present in the pharmaceutical composition in an amount of about 0.1% to about 50% by weight.

27. The method of claim 19, wherein the at least one active ingredient is administered to the subject at a dose of about 0.1 ng/kg to about 10 mg/kg of body weight.

28. The method of claim 19, wherein the pharmaceutical composition is administered 1 to 12 times a day.

29. The method of claim 19, wherein the pharmaceutical composition is administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, intranasally, rectally, intraperitoneally, intrathecally, via intrapulmonary administration, or via intracavitary administration.

30. A method for decreasing acid accumulation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one active ingredient selected from the group consisting of diethylaminobenzaldehyde (DEAB), disulfiram, 3-hydroxy-DL-kynurenine, benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daidzin, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, kynurenic acid, molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, 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, and retinoic acid.

31. The method of claim 30, wherein the acid accumulation is lactic acid accumulation.

32. The method of claim 31, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

33. The method of claim 32, wherein the pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil.

34. The method of claim 30, wherein the at least one active ingredient is present in the pharmaceutical composition in an amount of about 0.1% to about 50% by weight.

35. The method of claim 30, wherein the at least one active ingredient is administered to the subject at a dose of about 0.1 ng/kg to about 10 mg/kg of body weight.

36. The method of claim 30, wherein the pharmaceutical composition is administered 1 to 12 times a day.

37. The method of claim 30, wherein the pharmaceutical composition is administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, intranasally, rectally, intraperitoneally, intrathecally, via intrapulmonary administration, or via intracavitary administration.

38. A method for maintaining acid-base balance in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one active ingredient selected from the group consisting of diethylaminobenzaldehyde (DEAB), disulfiram, 3-hydroxy-DL-kynurenine, benomyl, cis-diamminedichloridoplatinum (CDDP), chlorpropamide, daidzin, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, kynurenic acid, molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, phenylglyoxal, 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, and retinoic acid.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0031] FIG. 1 illustrates results obtained by evaluating the acidosis-decreasing effect of candidate substances for acidosis treatment, according to an embodiment of the present invention.

DETAILED DESCRIPTION OF INVENTION

[0032] It was checked whether the candidate substances for lactic acidosis treatment, which were screened in the present invention, have a lactic acid concentration-decreasing effect. As a result, it was found that all candidate substances had a lactic acid concentration-decreasing effect. More specifically, in a case of being compared with the positive control (50 μM sodium oxamate) in which the same concentration as the candidate substances is used, it was found that the group consisting of citral, CVT-10216, cyanamide, and retinoic acid had a lactic acid concentration-decreasing effect of about 5%; the group consisting of molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, and phenylglyoxane had a lactic acid concentration-decreasing effect of about 10%; the group consisting of benomyl, cis-diamminedichloridoplatinum, chlorpropamide, daidzin, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, and kynurenic acid had a lactic acid concentration-decreasing effect of about 15%; and the group consisting of diethylaminobenzaldehyde, disulfiram, and 3-hydroxy-DL-kynurenine had a lactic acid concentration-decreasing effect of about 20%.

[0033] Hereinafter, the present invention will be described in more detail by way of examples. These examples are only for describing the present invention in more detail, and it will be apparent to those skilled in the art that according to the gist of the present invention, the scope of the present invention is not limited by these examples.

Example 1: Screening of Candidate Substances for Acidosis Treatment

[0034] As a result of screening various candidate substances to develop substances for treating acidosis, the present inventors discovered the substances as shown in Table 1 below.

TABLE-US-00001 TABLE 1 No. Name of substance 1 Benomyl 2 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, or 3-[[[3-[4-[(methylsulfonyl)amino]phenyl]- 4-oxo-4H-chromen-7-yl]oxy]methyl]benzoic acid) 6 Cyanamide 7 Daidzin 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: Checking of the Acid Concentration-Decreasing Effect of Candidate Substances for Acidosis Treatment

[0035] A lactic acid concentration-decreasing effect of the candidate substances as shown in Table 1 was checked.

[0036] To this end, first, A549 cancer cells (adenocarcinomic human alveolar basal epithelial cells, Cat #CCL-185) obtained from the American Type Culture Collection (ATCC) were cultured in RPMI 1640 culture medium containing 10% fetal bovine serum and 1% antibiotic-antimycotic agent under an environment at 37° C. and 5% CO.sub.2, and passages were performed every 3 days. Lactic acid is produced in large amounts when glycolysis is activated in hypoxia. Cancer cells, which are densely packed with cells, are very active in energy-consuming activities, and thus are known to produce lactic acid in large amounts.

[0037] The cells were seeded in 24-well plates at a concentration of 3×10.sup.5 cells/well, and incubation was performed overnight. Then, each plate was treated with each of the candidate substances (at a concentration of 50 μM) as shown in Table 1 which had been dissolved in dimethyl sulfoxide (DMSO). Incubation was further performed for 24 hours. For the negative control for the candidate substances, no treatment was performed; and for the positive control, treatment with sodium oxamate, which is conventionally known as a therapeutic agent for lactic acidosis, was performed at the same concentration (50 μM) or the 10-fold higher concentration (50 mM). Subsequently, 50 μl of the cell culture solution obtained by being diluted with Dulbecco's Phosphate-Buffered Saline (DPBS), and 50 μl of the lactate assay reaction buffer (Promega, Madison, Wis., USA) were mixed and the mixture was added in a 96-well plate. Reaction was allowed to proceed at room temperature for 1 hour. Then, luminescence was measured with a spectrophotometer (Synergy HTX Multi-Reader, BioTek). At the same time, the number of cells in each sample was measured with a cell viability analysis kit (Cell Counting Kit-8), and calculation was performed so that the lactic acid measurement value in each sample could be compared with that in the negative control for the same number of cells. All experiments were repeated 3 times, and the averages are shown in FIG. 1.

[0038] As a result of the experiments, it was found that all candidate substances for lactic acidosis treatment, which were screened in the present invention, had a lactic acid concentration-decreasing effect with only a difference in degree. More specifically, in a case of being compared with the positive control (50 μM sodium oxamate) in which the same concentration as the candidate substances is used, it was found that the group consisting of citral, CVT-10216, cyanamide, and retinoic acid had a lactic acid concentration-decreasing effect of about 5%; the group consisting of molinate, N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, and phenylglyoxane had a lactic acid concentration-decreasing effect of about 10%; the group consisting of benomyl, cis-diamminedichloridoplatinum, chlorpropamide, daidzin, pargyline, phospho(enol)pyruvic acid monosodium salt hydrate, and kynurenic acid had a lactic acid concentration-decreasing effect of about 15%; and the group consisting of diethylaminobenzaldehyde, disulfiram, and 3-hydroxy-DL-kynurenine had a lactic acid concentration-decreasing effect of about 20%.

[0039] Although specific parts of the present invention have been described in detail, it is obvious to those skilled in the art that such a specific description 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.

INDUSTRIAL APPLICABILITY

[0040] Lactic acidosis occurs mostly in a condition of decreased oxygenation in the body, such as hypoxic shock, decreased blood volume, and left ventricle failure; and lactic acid in tissues increases locally even under influence of drugs and toxins (ethanol and methanol) or under increased energy metabolism such as in tumors. In a case where lactic acidosis continues and acid-base balance is disrupted, symptoms such as muscle weakness, hyperventilation, nausea, vomiting, sweating, or coma may appear and these symptoms may lead to death in severe cases. Therefore, it is important to maintain the acid-base balance by decreasing the concentration of lactic acid that has been over-accumulated in the body.

[0041] The pharmaceutical composition of the present invention has a remarkable effect in decreasing the concentration of acid accumulated in an organism and thus is expected to be widely used in the fields of medicine and health.