Prophylactic or therapeutic agent for acute kidney injury induced by anticancer agent

Abstract

Disclosed are: a prophylactic or therapeutic agent for acute kidney injury induced by an anti-cancer agent, the prophylactic or therapeutic agent containing at least one substance selected from the group consisting of the following substances; and a method for determining whether or not the prophylactic or therapeutic agent can be administered, using the prophylactic or therapeutic agent, and / or using the prophylactic or therapeutic agent on the basis of the concentration of GDF-15 in blood. The substance is glutathione trisulfide and a pharmacologically acceptable salt of the glutathione trisulfide; at least one cyclodextrin inclusion compound selected from the group consisting of thioctic acid trisulfides, derivatives thereof, and pharmacologically acceptable salts thereof; lipoic acid trisulfides and derivatives thereof; as well as pantethine trisulfides and pharmacologically acceptable salts thereof.

Description

Technical Field

[0001] The present invention relates to a preventive or therapeutic agent for acute kidney injury induced by an anticancer agent. Background Art

[0002] Acute kidney injury is dreaded because it severely impairs the QOL of patients and shows a very high mortality rate. Acute kidney injury is considered to be a state in which multiple causes act together and result in severe renal failure. Its causes can be manifested as various stresses applied to the organism. In recent years, Growth Differentiation Factor-15 (GDF-15) has attracted attention as a stress marker that sensitively responds to the state after such various stresses are imposed on the organism (Non-Patent Document 1). For ischemic kidney injury, it has also been reported that GDF-15 rapidly increases after ischemia-reperfusion (Non-Patent Document 2). In addition, it has been reported that the concentration of GDF-15 in the blood becomes a predictive marker for poor prognosis of kidney injury (Non-Patent Document 3).

[0003] Anticancer agents are known to be one of the causes of acute kidney injury. Among anticancer agents, there are anticancer agents that directly damage tubular cells and cause acute tubular necrosis (ATN). As representative agents that cause ATN, cisplatin, ifosfamide, azacitidine, imatinib, etc. are known. For example, cisplatin is one of the most frequently used platinum preparations for cancer treatment, but there is a major clinical problem that acute kidney injury caused by ATN occurs in about 20 to 30% of patients who have been administered cisplatin.

[0004] Cisplatin is thought to be actively taken into cells by an organic cation transporter (OCT (organic cation transporter)) present on the basolateral side of the proximal renal tubular basement membrane, resulting in necrosis of the proximal renal tubules. For kidney injury caused by anticancer agents such as cisplatin, prevention is the most important. For prevention, it is recommended to sufficiently (more than 3 liters per day according to the guidelines) perform fluid replacement mainly with physiological saline. The use of diuretics that have been widely used and whose safety has been confirmed may also be considered, but from the viewpoint of preventing kidney injury, it is only "weakly recommended (advised to use)" in the guidelines (Non-Patent Document 4).

[0005] It has been reported that specific glutathione monoalkyl esters are effective against the side effect of renal function damage caused by cisplatin administration (Patent Document 1). However, Patent Document 1 only states that when glutathione monoisopropyl ester sulfate is intraperitoneally administered at a dose of 300 mg / kg, it alleviates the body weight suppression and the increase in serum urea nitrogen caused by cisplatin. Administering a large amount of the drug parenterally as in Patent Document 1 would impose a significant burden on patients, and thus it is not recommended in the current guidelines.

[0006] In addition, it has been reported that Na2S4, an inorganic polysulfide, is effective against cisplatin-induced kidney injury (Non-Patent Document 5). When the administration amount of Na2S4 is 5.6 mg / kg, the effect is good, but the administration route is intraperitoneal administration, which is expected to impose a large burden on patients.

[0007] On the other hand, the beneficial effects of organic polysulfides on the human body have received attention. It has been reported that organic polysulfides may have physiological functions such as anti-aging (for example, Non-Patent Documents 6 and 7). There are also reports that substances related to mitochondrial functions such as mitochondrial energy production exist in organic polysulfides (Non-Patent Document 8). As organic polysulfides, for example, glutathione trisulfide (hereinafter also referred to as GSSSG) (Patent Document 2), pantethine trisulfide (Patent Document 3), lipoic acid trisulfide (Patent Document 4), etc. are known. These organic polysulfides can be produced by, for example, the methods described in Patent Documents 2 and 5. Regarding GSSSG, it has also been reported that the anti-inflammatory effect is enhanced by combining it with other drugs (Patent Document 6).

[0008] Prior Art Documents

[0009] Patent Documents

[0010] Patent Document 1: Japanese Unexamined Patent Application Publication No. 63-284132

[0011] Patent Document 2: International Publication No. 2018 / 117186

[0012] Patent Document 3: International Publication No. 2022 / 045052

[0013] Patent Document 4: International Publication No. 2022 / 045212

[0014] Patent Document 5: International Publication No. 2021 / 200487

[0015] Patent Document 6: International Publication No. 2022 / 168975

[0016] Non-Patent Documents

[0017] Non-Patent Document 1: Y. Fujita, et al., Geriatr. Gerontol. Int, 2016, Mar; 16, Suppl, 1: 17-29.

[0018] Non-Patent Document 2: J. Liu, et al., J. Am. Soc. Nephrol, 2020, Apr; 31(4): 701-715.

[0019] Non-Patent Document 3: J-H. Lim, et al., J. Clin Med, 2021, Aug, 18; 10(16): 3660.

[0020] Non-Patent Document 4: Y. Matsubara, M. Yanagida, "Anticancer drugs and acute kidney injury", Nihon Naika Gakkai Zasshi, 107: 865-871, 2018

[0021] Non-Patent Document 5: X. Cao, et al.,. Redox Biology, Volume 15, May 2018: 513-521

[0022] Non-Patent Document 6: T. Ida, et al.,. PNAS, May 27, 2014, 111(21) 7606-7611 Non-Patent Document 7: T. Akaike, et al,,, Nature Communications, 2017, Oct 27; 8(1): 1177

[0023] Non-Patent Document 8: S. Fujii, et al., Br. J. Pharmacol, 2019, Feb; 176(4): 607-615. Summary of the Invention

[0024] Problems to be Solved by the Invention

[0025] An object of the present invention is to provide a prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent that can exhibit a prophylactic or therapeutic effect at a low dose and can be administered orally or parenterally.

[0026] Means for Solving the Problems

[0027] The present inventors found that in a cisplatin-induced cytotoxicity test using renal tubular cells (in vitro), the organic trisulfide has a cell death inhibitory effect about 1000 times stronger than that of the inorganic polysulfide Na2S4. The present inventors studied the effect of GSSSG in an animal model of cisplatin-induced acute kidney injury. As a result, it was considered that the increase in blood urea nitrogen (UN) concentration and blood creatinine (CRE) concentration was inhibited in the administration group. In addition, it was found that measuring the concentration of GDF-15 in blood may be useful in selecting whether the following substances can be administered, the usage and / or dosage, the substances being: a compound represented by the following formula (1) (hereinafter also referred to as "compound (1)"); a compound represented by the following formula (2) (hereinafter also referred to as "compound (2)"); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of compound (2), compound (1), and compound (2); and pantethine trisulfide and its pharmacologically acceptable salt.

[0028]

[0029] [In the formula, R 1 and R 2 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5. ]

[0030]

[0031] [In the formula, R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R11 an alkyl group having 2 to 6 carbon atoms or -(CH2CH2O) of more than 1 substituent in the group formed n R 8 ,R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 11 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.]

[0032] Based on these findings, the present inventors have completed the present invention including the following [1] to

[15] .

[0033] [1] A prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent, which contains at least one selected from the group consisting of the following substances (hereinafter sometimes collectively referred to as "trisulfides"): GSSSG and its pharmaceutically acceptable salts; compound (1); compound (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmaceutically acceptable salt of compound (2), compound (1), and compound (2); and pantethine trisulfide and its pharmaceutically acceptable salts.

[0034] [1a] A prophylactic or therapeutic agent for acute kidney injury containing the above trisulfides, which is administered in combination with an anticancer agent.

[0035] [1b] An anticancer agent, which is administered in combination with the above trisulfides.

[0036] [2] A method for preventing or treating acute kidney injury induced by an anticancer agent, wherein the above trisulfides are administered to a patient in need thereof.

[0037] [2a] A method for treating cancer, wherein an anticancer agent and the above trisulfides are administered to a patient in need thereof.

[0038] [3] The above trisulfides, which are used for preventing or treating acute kidney injury induced by an anticancer agent.

[0039] [3a] The above trisulfides, which are used for preventing or treating acute kidney injury and are administered in combination with an anticancer agent.

[0040] [3b] An anticancer agent, which is used for treating cancer and is administered in combination with the above trisulfides.

[0041] [3c] A combination of the above trisulfides and an anticancer agent, which is used for treating cancer.

[0042] [4] Use of the above-mentioned trisulfides in the manufacture of a prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent.

[0043] [4a] Use of the above-mentioned trisulfides in the manufacture of a prophylactic or therapeutic agent for acute kidney injury to be administered in combination with an anticancer agent.

[0044] [4b] A combination of the above-mentioned trisulfides and an anticancer agent, which is used for cancer treatment.

[0045] [5] The prophylactic or therapeutic agent, prophylactic or therapeutic method, the above-mentioned trisulfides for the above-mentioned use, or the application according to any one of [1] to [4b], wherein the above-mentioned trisulfides are at least one selected from the group consisting of GSSSG and its pharmacologically acceptable salts, compound (1), compound (2), and pantethine trisulfide and its pharmacologically acceptable salts.

[0046] [6] The prophylactic or therapeutic agent, prophylactic or therapeutic method, the above-mentioned trisulfides for the above-mentioned use, or the application according to any one of [1] to [5], wherein the acute kidney injury induced by the above-mentioned anticancer agent is acute kidney injury caused by acute tubular necrosis induced by the above-mentioned anticancer agent.

[0047] [7] The prophylactic or therapeutic agent, prophylactic or therapeutic method, the above-mentioned trisulfides for the above-mentioned use, or the application according to any one of [1] to [6], wherein the above-mentioned anticancer agent is at least one selected from the group consisting of cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, methotrexate, pemetrexed, gemcitabine, pentostatin, and mitomycin C.

[0048] [8] The prophylactic or therapeutic agent, prophylactic or therapeutic method, the above-mentioned trisulfides for the above-mentioned use, or the application according to any one of [1] to [7], wherein the above-mentioned anticancer agent is at least one selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.

[0049] [9]A method for predicting or determining the administrability, usage, or dosage of at least one selected from the group consisting of: compound (1); compound (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of compound (2), compound (1), and compound (2); and pantethine trisulfide and its pharmacologically acceptable salts, for an object, the method comprising: a measurement step of measuring the blood GDF-15 concentration of the object; and a prediction or determination step of predicting or determining at least one of the administrability, usage, and dosage of at least one selected from the group consisting of: compound (1); compound (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of compound (2), compound (1), and compound (2); and pantethine trisulfide and its pharmacologically acceptable salts, based on the blood GDF-15 concentration.

[0050]

[10] The method according to [9], wherein the prediction or determination step includes: a step of estimating the blood urea nitrogen concentration and / or the serum creatinine concentration of the object based on the blood GDF-15 concentration; and a step of predicting or determining at least one of the administrability, usage, and dosage of at least one selected from the group consisting of: compound (1); compound (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of compound (2), compound (1), and compound (2); and pantethine trisulfide and its pharmacologically acceptable salts, based on the blood urea nitrogen concentration and / or the serum creatinine concentration.

[0051]

[11] A method for predicting or determining the administrability, usage, or dosage of the above-mentioned trisulfides for a patient with acute kidney injury induced by an anticancer agent, the method comprising: a measurement step of measuring the blood GDF-15 concentration of a patient with acute kidney injury induced by an anticancer agent; and a prediction or determination step of predicting or determining at least one of the administrability, usage, and dosage of the above-mentioned trisulfides for the patient based on the blood GDF-15 concentration.

[0052]

[12] A method for preparing a prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent containing the above-mentioned trisulfides, the method comprising: a measurement step of measuring the blood GDF-15 concentration of an object; and a prediction or determination step of predicting or determining the content of the above-mentioned trisulfides in the prophylactic or therapeutic agent based on the blood GDF-15 concentration.

[0053]

[13] A method for determining an index for prognosis determination and / or diagnosis of acute kidney injury induced by an anticancer agent in vitro, which comprises a measurement step of measuring the concentration of GDF-15 as the above-mentioned index in a sample obtained from a subject.

[0054]

[14] A method for predicting or determining at least one of whether the above-mentioned trisulfide can be administered, the usage, and the dosage to a patient with acute kidney injury induced by an anticancer agent, which comprises a measurement step of measuring the concentration of GDF-15 in the blood of the above-mentioned patient.

[0055]

[15] A method for providing the concentration of GDF-15 in the blood of the above-mentioned patient in order to predict or determine at least one of whether the above-mentioned trisulfide can be administered, the usage, and the dosage to a patient with acute kidney injury induced by an anticancer agent, which comprises a measurement step of measuring the concentration of GDF-15 in the blood of the above-mentioned patient.

[0056] Advantages of the Invention

[0057] According to the present invention, a prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent, which can exhibit a prophylactic or therapeutic effect at a low dosage and can be administered orally or parenterally, can be provided. In addition, a method for selecting at least one of whether the above-mentioned prophylactic or therapeutic agent can be administered, the usage, and the dosage by using the concentration of growth differentiation factor-15 (GDF-15) in the blood when preventing or treating acute kidney injury induced by an anticancer agent can be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 It is a graph showing the relationship between the respective concentrations of GSSSG and Na2S4 in Example 1 and the cell death inhibitory effect.

[0059] Figure 2 It is an image showing live cells (middle) and dead cells (lower) when the concentrations of GSSSG and Na2S4 in Example 1 are 0.1 μM, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0060] The content of the present invention will be described in detail below, but the present invention is not limited to the following embodiments.

[0061] The prophylactic or therapeutic agent, prophylactic or therapeutic method of the present invention, and other methods described in this specification can be administered or applied to humans.

[0062] One embodiment of the present invention relates to a prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent, which contains the above-mentioned trisulfides (at least one selected from the group consisting of the following substances: GSSSG and its pharmacologically acceptable salts; compound (1); compound (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of compound (2), compound (1) and compound (2); and pantethine trisulfide and its pharmacologically acceptable salts).

[0063] The above-mentioned trisulfides may be at least one selected from the group consisting of the following substances: compound (1); compound (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of compound (2), compound (1) and compound (2); and pantethine trisulfide and its pharmacologically acceptable salts, or may be at least one selected from the group consisting of compound (1), compound (2), and pantethine trisulfide and its pharmacologically acceptable salts.

[0064] In formula (1), R 1 or R 2 is an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 is composed of, or -(CH2CH2O) n R 8 When this is the case, the hydrophilicity of compound (1) is further improved, and it is considered that, for example, the drug absorbability upon oral administration is improved.

[0065] In formula (1), R 1 and R 2 may be a hydrogen atom, an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. These alkyl groups may have one or more substituents selected from the group consisting of a carboxyl group, and substituents represented by -OR 5 such as a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group. In formula (1), R 1 and R 2 may be an alkyl group such as an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, and these alkyl groups may have one or more substituents selected from the group consisting of substituents represented by -NR 6 R 7 such as an amino group or a dimethylamino group, and -N + H3, -N + (CH3)3, -N +One or more substituents selected from the group consisting of substituents represented by (C2H6)3, etc. and -N + R 9 R 10 R 11 One or more substituents selected from the group consisting of substituents represented by R 1 and R 2 may have one or two substituents such as an amino group and a carboxyl group. R 1 and R 2 may be a group represented by, for example, the following formula (10) or (11) (wherein, * represents a bonding site). R 1 and R 2 may be a group represented by bis(2-ethoxyethyl) ether, etc. and -(CH2CH2O) n R 8 As a specific example of the compound represented by the following formula (1), for example, a compound in which R 1 and R 2 are both hydrogen atoms, a compound in which R 1 is a hydrogen atom and R 2 is a group represented by the following formula (10), a compound in which R 1 is a hydrogen atom and R 2 is a group represented by the following formula (11).

[0066]

[0067] The compounds in the present specification may have optical isomers and racemates, but the present invention is not limited to any of them, and may be a racemate, any of the optically active forms, or a mixture containing the optically active forms at any ratio.

[0068] In formula (2), R 3 may be, for example, an alkyl group such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc., and these alkyl groups may have a substituent represented by -OR 5 The substituent represented by -OR 5 may be a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, etc. In formula (2), R 3 may be an alkyl group such as an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc., and these alkyl groups have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 The substituent represented by -NR 6 R 7 may be an amino group, a dimethylamino group, etc. The substituent represented by -N + R 9 R10 R 11 The substituent represented can be -N + H3, -N + (CH3)3, -N + (C2H6)3, etc. In formula (2), R 3 can be a group represented by -(CH2CH2O) n R 8 The group represented by -(CH2CH2O) n R 8 The group represented can be bis(2-ethoxyethyl) ether, etc. In formula (2), R 3 can be a group represented by, for example, the following formula (30) or (31) (in the formula, * represents a bonding site).

[0069] As a specific example of the compound represented by formula (2), for example, a compound in which R 3 is the group represented by the following formula (30), a compound in which R 3 is the group represented by the following formula (31) can be cited.

[0070]

[0071] The compound represented by formula (2) has good hydrophilicity, and it is considered that, for example, the drug absorbability during oral ingestion is improved.

[0072] The pharmacologically acceptable salt of compound (2), compound (1) and compound (2) can be produced, for example, by the method described in Patent Document 4.

[0073] The cyclodextrin clathrate compound selected from at least one of the group consisting of the pharmacologically acceptable salt of compound (2), compound (1) and compound (2) is obtained by clathrating at least one of the group consisting of the pharmacologically acceptable salt of compound (2), compound (1) and compound (2) with cyclodextrin or its derivative.

[0074] The cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or their derivatives. Herein, the derivative of cyclodextrin refers to a substance formed by substituting a hydrogen atom of at least one hydroxyl group possessed by each cyclodextrin with an alkyl group or a sugar which may have a substituent. Examples of the derivative of cyclodextrin include, for example, methyl-α-cyclodextrin, methyl-β-cyclodextrin, methyl-γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, glucosyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin and the like.

[0075] The cyclodextrin clathrate of at least one selected from the group consisting of the pharmacologically acceptable salt of compound (2), compound (1) and compound (2) can be produced, for example, by the method described in Patent Document 4.

[0076] Pantethine trisulfide is a compound represented by the following formula (3).

[0077]

[0078] Pantethine trisulfide and its pharmacologically acceptable salt can be produced, for example, by the method described in Patent Document 3.

[0079] In one embodiment of the present invention, examples of the pharmacologically acceptable salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid; salts with alkali metals such as sodium, potassium; salts with alkaline earth metals such as calcium, magnesium; ammonium salts; salts with amino acids such as arginine and the like.

[0080] In one embodiment of the present invention, the above-mentioned trisulfides may sometimes exist in polymorphic forms, but are not limited to any one of them, and may be a single substance of any crystal form or a mixture. In addition, the above-mentioned trisulfides in one embodiment of the present invention also include amorphous substances. The above-mentioned trisulfides in one embodiment of the present invention include anhydrous substances and solvates (especially hydrates).

[0081] In one embodiment of the present invention, the prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent can be formulated into, for example, tablets, capsules, powders, granules, liquids or syrups for oral administration. The prophylactic or therapeutic agent of one embodiment of the present invention can also be formulated into, for example, injections, infusions or suppositories for parenteral administration. However, by being able to be orally administered, the burden on the subject to be administered (e.g., cancer patients) can be reduced. The prophylactic or therapeutic agent of one embodiment of the present invention can be formulated into these dosage forms by known pharmaceutical technologies. In the case of solid agents, pharmacologically acceptable excipients such as starch, lactose, refined sugar, glucose, crystalline cellulose, carboxymethyl cellulose, carboxymethylcellulose, carboxyethyl cellulose, calcium phosphate, magnesium stearate, gum arabic, etc. can be incorporated during formulation, and lubricants, binders, disintegrants, coating agents, coloring agents, etc. can be incorporated as needed. In addition, in the case of liquids, stabilizers, solubilizers, suspending agents, emulsifiers, buffers, preservatives, etc. can be incorporated.

[0082] In one embodiment of the present invention, the dosage of the prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent is a therapeutically effective amount, which varies depending on symptoms, age, administration method, dosage form, etc. Generally, for adults, 0.5 to 2000 mg of the above compound can be administered per day, preferably 1 to 800 mg once a day or divided into several times, or continuously administered by intravenous drip every day. It is considered that when the dosage of the prophylactic or therapeutic agent of one embodiment of the present invention is within this range, the prophylactic effect or therapeutic effect on acute kidney injury induced by an anticancer agent is improved.

[0083] The acute kidney injury induced by an anticancer agent can be acute kidney injury caused by acute tubular necrosis induced by an anticancer agent. Examples of anticancer agents that can cause acute kidney injury caused by acute tubular necrosis or acute kidney injury include cytotoxic anticancer agents, molecularly targeted drugs, bisphosphonate preparations, interferon preparations, etc.

[0084] Examples of cytotoxic anticancer agents that cause acute kidney injury due to acute tubular necrosis or acute kidney injury include: platinum preparations such as cisplatin, carboplatin, and oxaliplatin; alkylating agents such as cyclophosphamide and ifosfamide; antimetabolites such as methotrexate, pemetrexed, gemcitabine, and pentostatin; and antibiotics such as mitomycin C. Examples of molecular target drugs that cause acute kidney injury due to acute tubular necrosis or acute kidney injury include bevacizumab, imatinib, sorafenib, nivolumab, ipilimumab, sunitinib, and cetuximab. Examples of bisphosphonate preparations that cause acute kidney injury due to acute tubular necrosis or acute kidney injury include zoledronic acid and pamidronic acid. Acute kidney injury induced by anticancer agents or acute kidney injury caused by acute tubular necrosis induced by anticancer agents includes not only acute kidney injury caused by using these anticancer agents alone but also acute kidney injury caused by using a combination of two or more of these anticancer agents.

[0085] Another embodiment of the present invention relates to a method for predicting or determining whether the above-mentioned trisulfide compounds can be administered to a subject, the usage, or the dosage, which comprises: a measurement step of measuring the blood GDF-15 concentration of the subject; and a prediction or determination step of predicting or determining at least one of whether the above-mentioned trisulfide compounds can be administered to the subject, the usage, and the dosage based on the blood GDF-15 concentration.

[0086] The above prediction or determination step may include: a step of estimating the blood urea nitrogen concentration and / or the serum creatinine concentration of the subject based on the blood GDF-15 concentration; and a step of predicting or determining at least one of whether the above-mentioned trisulfide compounds can be administered to the subject, the usage, and the dosage based on the blood urea nitrogen concentration and / or the serum creatinine concentration.

[0087] Another embodiment of the present invention relates to a method for preparing a preventive or therapeutic agent for acute kidney injury induced by an anticancer agent containing the above-mentioned trisulfide compounds, which comprises: a measurement step of measuring the blood GDF-15 concentration of the subject; and a prediction or determination step of predicting or determining the content of the above-mentioned trisulfide compounds in the preventive or therapeutic agent based on the blood GDF-15 concentration.

[0088] The above method for preparing the preventive or therapeutic agent may further include the act of predicting or determining the content of the above-mentioned trisulfide compounds in the preventive or therapeutic agent for a subject to whom the preventive or therapeutic agent is administered. The above preventive or therapeutic agent is not limited to a single preparation and may be a combination of two or more preparations. When the above preventive or therapeutic agent is a single preparation, the subject can select a preparation containing an appropriate amount of the above-mentioned trisulfide compounds based on the measured value of GDF-15. When the above preventive or therapeutic agent is a combination of two or more preparations, the content of the above-mentioned trisulfide compounds in the preventive or therapeutic agent for the subject itself can be determined by changing the combination of the two or more preparations.

[0089] Another embodiment of the present invention relates to a method for determining in vitro an index for predicting and / or diagnosing the prognosis of acute kidney injury induced by an anticancer agent, which comprises a measurement step of measuring the concentration of GDF-15 as an index in a sample obtained from a subject. The method of this embodiment may further comprise: a step of estimating the blood urea nitrogen concentration and / or blood creatinine concentration of the subject based on the blood GDF-15 concentration; and a step of predicting or determining at least one of whether the trisulfide compound can be administered to the subject, the usage, and the dosage based on the blood urea nitrogen concentration and / or blood creatinine concentration.

[0090] Another embodiment of the present invention relates to a method for predicting or determining at least one of whether the trisulfide compound can be administered to a patient with acute kidney injury induced by an anticancer agent, the usage, and the dosage, which comprises a measurement step of measuring the blood GDF-15 concentration of the patient with acute kidney injury induced by the anticancer agent. The method of this embodiment may further comprise: a step of estimating the blood urea nitrogen concentration and / or blood creatinine concentration of the subject based on the blood GDF-15 concentration; and a step of predicting or determining at least one of whether the trisulfide compound can be administered to the subject, the usage, and the dosage based on the blood urea nitrogen concentration and / or blood creatinine concentration.

[0091] Another embodiment of the present invention relates to a method for providing the blood GDF-15 concentration of a patient with acute kidney injury induced by an anticancer agent in order to determine at least one of whether the trisulfide compound can be administered to the patient with acute kidney injury induced by the anticancer agent, the usage, and the dosage, which comprises a measurement step of measuring the blood GDF-15 concentration of the patient with acute kidney injury induced by the anticancer agent. The method of this embodiment may further comprise: a step of estimating the blood urea nitrogen concentration and / or blood creatinine concentration of the subject based on the blood GDF-15 concentration; and a step of predicting or determining at least one of whether the trisulfide compound can be administered to the subject, the usage, and the dosage based on the blood urea nitrogen concentration and / or blood creatinine concentration.

[0092] In this specification, the "subject" may be a patient diagnosed with cancer and scheduled to receive an anticancer agent, a patient already receiving an anticancer agent, or a patient who has developed acute kidney injury induced by an anticancer agent (particularly a patient who has developed acute kidney injury caused by acute tubular necrosis resulting from administration of an anticancer agent).

[0093] The blood GDF-15 concentration serving as a reference for predicting or determining at least one of whether the above-mentioned trisulfide compounds can be administered, the method of administration, and the dosage varies depending on symptoms, age, administration method, dosage form, etc. In the case of adults, it may be exemplified by 0.05 ng / mL to 100 ng / mL, more preferably 0.1 ng / mL to 10 ng / mL. When the blood GDF-15 concentration is within these ranges, it can be judged that it is better to administer the above-mentioned trisulfide compounds, and in this case, the methods of administration and / or dosages described in this specification can be applied.

[0094] Examples

[0095] The following experimental examples are given to illustrate the present invention in more detail, but the present invention is not limited thereto.

[0096] <Experimental Example 1: Evaluation of the inhibitory effect on cisplatin-induced cytotoxicity in renal tubular cells (in vitro)>

[0097] Cultured cells (HK-2) derived from human renal proximal tubules were seeded in a 96-well plate supplemented with medium at a concentration of 5×10 3 cells / well. After confirming that the seeded cells had adhered to the plate, the test compounds (GSSSG and Na2S4 respectively) were added in such a way that the final concentration reached 0 μM, 0.01 μM, 0.02 μM, 0.10 μM, 0.39 μM, 1.56 μM, 6.25 μM, 25 μM, or 100 μM, and left standing at 37 °C for 0.5 hours. The test compounds were added after being dissolved in PBS. The case where the final concentration of the test compound was 0 μM means that only PBS was added to the wells.

[0098] The supernatant was discarded from each well, and the cells were washed with PBS. Fresh medium was added to each well, and cisplatin was added in such a way that the final concentration reached 20 μM, and left standing at 37 °C for 24 hours. Then, the cell viability was evaluated using a cell counting kit-8 (Cell Counting Kit-8, Dojindo).

[0099] The composition of the medium used in Example 1 is shown below.

[0100] D-MEM / Ham’s F-12 (FUJIFILM Wako Pure Chemical Corporation) + penicillin-streptomycin-amphotericin B (FUJIFILM Wako Pure Chemical Corporation) + GlutaMAX (Thermo Fisher Scientific Inc.) + 10% FBS

[0101] Figure 1 The cell viability of each concentration of the test compound in Example 1 is shown. Figure 2The transmitted light image (upper part) of the test compound in Example 1 at a concentration of 0.1 μM, and the fluorescence images of live cells (middle part) and dead cells (lower part) are shown. Figure 1 , 2 In, "Cis-" means cisplatin was not added, and "Cis+" means cisplatin was added.

[0102] As Figure 1 shown, both GSSSG, an organic trisulfide, and Na2S4, an inorganic polysulfide, have a tendency to inhibit cell death in a concentration-dependent manner. However, GSSSG shows a significant inhibitory effect on cell death even at a low concentration of 0.1 μM, while Na2S4 shows a significant inhibitory effect on cell death only at a concentration of 100 μM. Therefore, it is suggested that the inhibitory effect of GSSSG on cell death may be about 1000 times stronger. In addition, as Figure 2 shown, it can be seen that the number of live cells in renal tubular cells administered with GSSSG is significantly higher even in the case of adding cisplatin.

Claims

1. A prophylactic or therapeutic agent for anticancer agent-induced acute kidney injury, which contains at least one selected from the group consisting of: glutathione trisulfide and its pharmaceutically acceptable salts; the compound represented by the following formula (1); the compound represented by the following formula (2); a cyclodextrin clathrate of at least one selected from the group consisting of pharmaceutically acceptable salts of the compound represented by the following formula (2), the compound represented by the following formula (1), and the compound represented by the following formula (2); and pantethine trisulfide and its pharmaceutically acceptable salts, In formula (1), R 1 and R 2 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5. In formula (2), R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.

2. The prophylactic or therapeutic agent according to claim 1, wherein, containing at least one selected from the group consisting of glutathione trisulfide and its pharmaceutically acceptable salts, the compound represented by the formula (1), the compound represented by the formula (2), and pantethine trisulfide and its pharmaceutically acceptable salts.

3. The prophylactic or therapeutic agent according to claim 1, wherein, The acute kidney injury induced by the anticancer agent is acute kidney injury caused by acute tubular necrosis induced by the anticancer agent.

4. The prophylactic or therapeutic agent according to claim 1, wherein, The anticancer agent is at least one selected from the group consisting of cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, methotrexate, pemetrexed, gemcitabine, pentostatin, and mitomycin C.

5. The prophylactic or therapeutic agent according to any one of claims 1 to 4, wherein, The anticancer agent is at least one selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.

6. A method for determining whether at least one selected from the group consisting of the following substances can be administered, the usage, or the dosage to a patient with acute kidney injury induced by an anticancer agent, said substances being: glutathione trisulfide and its pharmacologically acceptable salts; the compound represented by the following formula (1); the compound represented by the following formula (2); a cyclodextrin clathrate of at least one selected from the group consisting of the pharmacologically acceptable salts of the compound represented by the following formula (2), the compound represented by the following formula (1), and the compound represented by the following formula (2); and pantethine trisulfide and its pharmaceutically acceptable salts, The method includes: a measurement step of measuring the blood GDF-15 concentration of a patient with acute kidney injury induced by an anticancer agent; and a determination step of determining, based on the blood GDF-15 concentration, at least one of whether administration, usage, and dosage of at least one selected from the group consisting of: glutathione trisulfide and its pharmaceutically acceptable salts; the compound represented by the following formula (1); the compound represented by the following formula (2); a cyclodextrin clathrate of at least one selected from the group consisting of pharmaceutically acceptable salts of the compound represented by the following formula (2), the compound represented by the following formula (1), and the compound represented by the following formula (2); and pantethine trisulfide and its pharmaceutically acceptable salts are possible for the patient, In formula (1), R 1 and R 2 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer from 2 to 5. In formula (2), R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.

7. A method for preparing a prophylactic or therapeutic agent for acute kidney injury induced by an anticancer agent, the prophylactic or therapeutic agent containing at least one selected from the group consisting of: glutathione trisulfide and its pharmacologically acceptable salts; a compound represented by the following formula (1); a compound represented by the following formula (2); a cyclodextrin clathrate of at least one selected from the group consisting of a pharmacologically acceptable salt of a compound represented by the following formula (2), a compound represented by the following formula (1), and a compound represented by the following formula (2); and pantethine trisulfide and its pharmaceutically acceptable salts, The preparation method includes: a measurement step of measuring the blood GDF-15 concentration of the subject; and a determination step of determining, based on the blood GDF-15 concentration, the content of at least one selected from the group consisting of: glutathione trisulfide and its pharmaceutically acceptable salts; the compound represented by the following formula (1); the compound represented by the following formula (2); a cyclodextrin clathrate of at least one selected from the group consisting of pharmaceutically acceptable salts of the compound represented by the following formula (2), the compound represented by the following formula (1), and the compound represented by the following formula (2); and pantethine trisulfide and its pharmaceutically acceptable salts in the prophylactic or therapeutic agent, In formula (1), R 1 and R 2 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5. In formula (2), R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxyl group and -OR 5 , an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 , or -(CH2CH2O) n R 8 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.

8. A method for measuring an index for prognosis determination and / or diagnosis of acute kidney injury induced by an anticancer agent in vitro, which includes a measurement step of measuring the GDF-15 concentration as the index for a sample obtained from a subject.

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