Composition for oral administration to prevent nephropathy caused by cisplatin

Abstract

To establish a practical preventive method for effectively preventing nephropathy that may be induced by cisplatin administration; to mitigate deterioration in the quality of life (QOL) of subjects undergoing cisplatin administration and to improve survival prognosis reduced due to nephropathy; and to provide a nephropathy preventive agent for oral administration that is easy to take and highly safe.SOLUTION: An orally administrable composition for the prevention of nephropathy caused by cisplatin is provided, comprising 3-hydroxybutyric acid and / or a salt thereof as an active ingredient.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to a composition for oral administration for preventing nephropathy caused by cisplatin, which contains 3-hydroxybutyric acid and / or a salt thereof as an active ingredient. [Background technology]

[0002] Cisplatin is an anticancer drug classified as a platinum preparation that contains platinum in its structure. It has been shown to be effective against a wide range of cancers, including testicular cancer, bladder cancer, renal pelvis and ureter cancer, prostate cancer, ovarian cancer, lung cancer, gastric cancer, and malignant lymphoma. Therefore, although cisplatin is a classical anticancer drug, it has a wide anticancer spectrum and a strong anticancer effect, and is still one of the anticancer drugs frequently used as a central drug in many chemotherapy protocols.

[0003] However, as reported in Non-Patent Document 1, etc., renal damage such as acute renal failure has been observed in approximately 30% of patients administered cisplatin. Renal damage caused by cisplatin is mainly due to proximal tubule damage, and is related to the active uptake of cisplatin into the proximal tubule via organic cation transporter 2 (hereinafter sometimes abbreviated as "OCT2") present on the basement membrane side of the proximal tubule. Thus, administration of cisplatin places a heavy burden on the kidney, and may limit subsequent treatment, greatly affecting the possibility of continuing cancer treatment and the patient's QOL and life prognosis.

[0004] Since the treatment methods after the onset of renal damage are limited, prevention of cisplatin-induced nephrotoxicity is the most important. In the above-mentioned Non-Patent Document 1, it is usually recommended to perform sufficient (3L / day or more) replacement fluid mainly with physiological saline in order to prevent cisplatin-induced nephrotoxicity, and further, it is reported that, since it is sometimes difficult to perform replacement fluid of 3L / day or more when performing chemotherapy in an outpatient setting, a short hydration method in which 2,000 to 2,500 mL of replacement fluid is administered in about 4 hours is also recommended. It has also been reported that hypomagnesemia frequently occurs during administration of cisplatin due to enhanced excretion from the kidney and gastrointestinal toxicity, and that such hypomagnesemia may promote renal damage. Therefore, administration of magnesium to prevent renal damage is recommended. However, the current situation is that no fundamental preventive method for renal damage induced by administration of cisplatin has been established, and the establishment of such a preventive method is very important for improving the treatment outcome and treatment completion rate of cancer chemotherapy with cisplatin.

[0005] Non-Patent Document 2 reports that diphenhydramine, known as a histamine H1 receptor blocker, has been found to potentially provide a new method of prevention and treatment for cisplatin nephrotoxicity. In detail, it is reported that diphenhydramine inhibited cell necrosis and apoptosis induced by administration of cisplatin in the proximal tubules of the kidney, and that the concentration of cisplatin in the kidney tissue was significantly reduced. It has also been confirmed that diphenhydramine did not affect or inhibit the anticancer effect of cisplatin. It has also been reported in clinical studies that cancer patients who used diphenhydramine before cisplatin treatment had significantly less acute kidney injury than those who did not.

[0006] Non-Patent Document 3 reports that simultaneous administration of 3-hydroxybutyric acid and cisplatin improved renal tubule damage in mice with cisplatin-induced acute kidney injury. In detail, it is reported that cisplatin-induced acute kidney injury was improved by intraperitoneally injecting cisplatin at 20 mg / kg and subcutaneously administering 3-hydroxybutyric acid at 250 mg / kg to 8-week-old C57BL / 6 mice. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Yasuhiro Komatsu and Taisuke Ishii, "Kidney damage caused by anticancer drugs," Journal of the Japanese Society of Nephrology, 2016, 58(7), p.1064-1068 [Non-Patent Document 2] Hirofumi Hamano et al., “Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity”, Kidney International, 2021 Apr, 99(4):885-899:doi:10.1016 / j.kint.2020.10.041 [Non-Patent Document 3] Luo S et al., “β-Hydroxybutyrate against Cisplatin-Induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress”, International Immunopharmacology,05 Aug 2022, 111:109101 Summary of the Invention [Problem to be solved by the invention]

[0008] As mentioned above, cisplatin, a classical anticancer drug, is still frequently used as a therapeutic agent for various cancers, but its use may be restricted due to the side effect of kidney damage (Non-Patent Document 1, etc.). In Non-Patent Document 2, it is reported that diphenhydramine has the effect of suppressing kidney damage induced by the administration of cisplatin. However, diphenhydramine is contraindicated for open-angle glaucoma because its anticholinergic effect can increase intraocular pressure and worsen symptoms, and is also contraindicated for patients with prostatic hyperplasia because it can worsen symptoms by relaxing the smooth muscle of the bladder and tensioning the sphincter of the bladder. Side effects such as drowsiness, constipation, vomiting, dry mouth, decreased concentration, and decreased work efficiency have been reported. In addition, it is known that dependence and tolerance occur due to long-term use, and symptoms such as inability to sleep without diphenhydramine medication and gradual fading of the drug's efficacy appear, so it is not sufficient for practical use.

[0009] Non-Patent Document 3 reports that simultaneous administration of 3-hydroxybutyric acid and cisplatin improved acute kidney injury induced by cisplatin, but there is no report on the prevention of kidney injury. In addition, Non-Patent Document 3 reports that 3-hydroxybutyric acid is administered by subcutaneous injection, but oral administration is generally superior in terms of safety of administration, cost, continuous intake, etc. On the other hand, oral administration passes through the digestive tract, and there are cases in which the effect of the drug cannot be fully exerted due to degradation and absorption in the digestive tract, the first pass effect, etc.

[0010] Thus, at present, there is no orally administered prophylactic drug that has been put to clinical use to prevent nephropathy that can be induced by administration of cisplatin.

[0011] Therefore, the present invention aims to establish a practical method for preventing nephropathy induced by administration of cisplatin, to reduce the decline in QOL of subjects receiving cisplatin, and to improve the shortened prognosis of life due to nephropathy. In particular, the present invention aims to provide a preventive drug for oral administration that is easy to ingest and highly safe. [Means for solving the problem]

[0012] As a result of intensive research into solving the above-mentioned problems, the present inventors discovered that a composition for oral administration containing 3-hydroxybutyric acid and / or a salt thereof as an active ingredient is effective in preventing nephropathy that can be induced by administration of cisplatin, and thus completed the present invention.

[0013] In other words, the characteristic feature of the composition for oral administration for the prevention of cisplatin-induced nephropathy of the present invention for solving the above-mentioned problem is that it contains 3-hydroxybutyric acid and / or a salt thereof as an active ingredient.

[0014] According to the above characteristic configuration, the composition for oral administration containing 3-hydroxybutyric acid and / or a salt thereof as an active ingredient can prevent nephrotoxicity that may be induced by administration of cisplatin in a subject receiving administration of cisplatin. Prevention is the most important for nephrotoxicity of cisplatin, and by orally administering a composition containing 3-hydroxybutyric acid and / or a salt thereof as an active ingredient, the onset of nephrotoxicity that may be induced by administration of cisplatin can be easily and effectively prevented. This can reduce the decrease in QOL of a subject receiving administration of cisplatin and improve the decrease in life prognosis due to nephrotoxicity. In addition, since the onset of nephrotoxicity, which is a dose-limiting factor in cisplatin treatment, can be prevented, the continuation and dosage of cisplatin treatment can be increased, the treatment completion rate can be improved, and the cancer treatment effect can be improved. In addition, it is highly safe for the human body and does not have any adverse effect on the effect of cisplatin, such as inhibiting the anticancer effect of cisplatin. Furthermore, by orally administering 3-hydroxybutyric acid, it is possible to administer it safely, at low cost, and simply, which is advantageous for continuous intake.

[0015] Furthermore, a further characteristic feature of the composition for oral administration for preventing nephropathy caused by cisplatin according to the present invention is that the salt is one or more salts selected from the group consisting of sodium salts, potassium salts, magnesium salts and calcium salts of 3-hydroxybutyric acid.

[0016] According to the above-mentioned characteristic configuration, 3-hydroxybutyric acid can be administered in the form of sodium salt, potassium salt, magnesium salt, or calcium salt, which is easy to prepare and has no adverse effects on the body. Furthermore, by administering it in the form of a salt, it is expected that the ease of administration and the ease of handling during formulation can be improved.

[0017] Furthermore, a further characteristic feature of the composition for oral administration for preventing cisplatin-induced nephropathy according to the present invention is that it contains a mixed salt of sodium salt, potassium salt, magnesium salt, and calcium salt of 3-hydroxybutyric acid as the active ingredient.

[0018] According to the above characteristic configuration, it is possible to administer a combination of multiple types of salts of 3-hydroxybutyric acid. When 3-hydroxybutyric acid is administered in the form of only one specific salt, there are cases where excessive intake of the specific salt may have an undesirable effect on the body. On the other hand, according to the above characteristic configuration, it is possible to avoid undesirable effects on the body caused by excessive intake of the specific salt.

[0019] A further characteristic feature of the composition for oral administration for preventing nephropathy caused by cisplatin according to the present invention is that it is administered before administration of cisplatin.

[0020] According to the above characteristic configuration, by administering 3-hydroxybutyric acid and / or a salt thereof before administration of cisplatin, nephropathy that may be induced by administration of cisplatin can be effectively prevented. [Brief description of the drawings]

[0021] [Figure 1]FIG. 1 shows an outline of the drug administration schedule in an evaluation system in which the preventive effect of 3-hydroxybutyric acid on nephropathy that can be induced by administration of cisplatin in Example 1 was confirmed. [Diagram 2] FIG. 1 is a graph showing the results of confirming the preventive effect of 3-hydroxybutyric acid against nephropathy that can be induced by administration of cisplatin in Example 1, where Panel A shows the relative mRNA level of interleukin-1β, Panel B shows the relative mRNA level of collagen 1a1, and Panel C shows the relative mRNA level of fibronectin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Hereinafter, an embodiment of the composition for oral administration for preventing nephropathy caused by cisplatin according to the present invention will be described in detail. However, the present invention is not limited to the embodiment, and various modifications are possible within the scope of the present invention, and the present invention is not limited to the following description.

[0023] The composition for oral administration for preventing cisplatin-induced nephropathy according to this embodiment contains 3-hydroxybutyric acid and / or a salt thereof as an active ingredient.

[0024] The composition according to the present embodiment is a composition for oral administration for preventing nephropathy caused by cisplatin, and here, nephropathy caused by cisplatin refers to all nephropathy that may be induced by the nephrotoxicity of cisplatin. Nephropathy is an important side effect that is a dose-limiting factor in cisplatin treatment. In detail, nephropathy induced by administration of cisplatin is thought to occur when cisplatin is actively taken up into cells via OCT2 present on the basement membrane side of the proximal tubule after being filtered from the glomerulus, and accumulates in the proximal tubule, damaging the proximal tubule cells. Nephropathy induced by administration of cisplatin is mainly damage to the proximal tubule, and generally necrosis or apoptosis of the proximal tubule cells is observed, which leads to acute renal failure. In some cases, patients may develop Fanconi syndrome (a condition in which reabsorption of solutes such as amino acids, glucose, bicarbonate, and inorganic phosphate in the proximal tubule is impaired, resulting in acid-base imbalance and electrolyte abnormalities such as aminoaciduria, renal glycosuria, proximal tubular acidosis, hypophosphatemia, and hypouricemia). In addition, long-term administration of cisplatin can cause chronic tubulointerstitial fibrosis and irreversible chronic tubulopathy, which can progress to chronic renal failure.

[0025] Prevention means to prevent or suppress the onset of nephropathy that may be induced by the administration of cisplatin in advance, and therefore includes completely suppressing the onset of nephropathy, and even if nephropathy does occur, reducing the severity and delaying the time until onset, compared to the administration of cisplatin alone.

[0026] 3-Hydroxybutyric acid (hereinafter sometimes abbreviated as "3HB"), also known as β-hydroxybutyric acid, is a compound represented by the following formula (I).

[0027] [ka]

[0028] The salt of 3HB is not limited to the form of the salt, and may be crystalline or amorphous. Examples of salts include salts with metals such as alkali metals such as sodium, potassium, and lithium, and alkaline earth metals such as magnesium and calcium, salts with organic bases such as ammonium salts, salts with inorganic acids such as hydrochloric acid and phosphoric acid, and salts with organic acids such as acetic acid, citric acid, and succinic acid, but are not limited thereto. The salt of 3HB may be used in combination with 3HB in the free acid form that is not a salt form, or in combination with two or more salts, and preferably, the sodium salt, potassium salt, magnesium salt, and calcium salt of 3HB can be used in combination. By combining multiple types of salts, it is possible to avoid excessive intake of a specific salt.

[0029] In particular, when 3HB is administered orally, in the free acid form, it has a strong sour taste and is difficult to take. Furthermore, taking a large amount of 3HB in the free acid form may have an unfavorable effect on the body due to a decrease in blood pH, and may put a strain on renal function due to the regulation of acidity. On the other hand, in the salt form, although it is easy to take, salt is taken at the same time. In particular, excessive intake of a specific salt may put a strain on renal function due to its excretion, and may have an unfavorable effect on the body, especially renal tissue. Therefore, it is preferable to appropriately adjust the form of 3HB depending on the administration form and the administration subject. Specifically, the proportion of 3HB in the salt form in the total 3HB can be any proportion from 0 to 100%, for example, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 95, 99%. In addition, the ratio of 3HB in a specific salt form to the total salt forms of 3HB can be any ratio between 0 and 100%, for example, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 95, 99%. Preferably, 3HB in an acid form and a salt form are used in combination. This allows the blood pH and salt concentration to be adjusted, and effectively protects against renal dysfunction.

[0030] 3HB, which is included as an active ingredient in the present invention, is a substance biosynthesized from fatty acids in human liver cells, but there is no particular limit to the method of obtaining it. 3HB may be produced by a conventionally known method, or a commercially available product may be used. For example, 3HB can be obtained by carrying out a fermentation process in which 3HB-producing Halomonas bacteria are added, and the Halomonas bacteria are separated and removed from the resulting fermentation liquid and purified. The fermentation process can be carried out as a process in which 3HB-producing Halomonas bacteria are added directly to a raw material liquid containing a carbohydrate nutrient source such as fruit juice, and aerobic fermentation and microaerobic fermentation are carried out in sequence (see JP 2013-081403 A, etc.). As a result, carbohydrates are converted into 3HB, which is produced in the fermentation liquid. The produced 3HB is used as pure 3HB after undergoing membrane separation, separation and purification in the usual manner. In addition, a salt of 3HB can also be produced by a conventionally known method, for example, by a salt formation process, a desalting process, a salt exchange process, etc. that have been commonly used in the past.

[0031] The composition according to the present embodiment may contain other ingredients in combination with the above-mentioned active ingredient. The other ingredients may contain, for example, pharma- ceutically or food-acceptable ingredients. Specifically, the composition may contain a base, a stabilizer, an excipient, a coating agent, an emulsifier, a flavoring agent, a dissolving agent, a binder, a solvent, a dispersant, a preservative, a colorant, a lubricant, a wetting agent, a suspending agent, a disintegrating agent, a buffer, a viscosity adjuster, a pH regulator, an antioxidant, and the like. These ingredients may be contained alone or in combination of two or more kinds, and may be appropriately selected according to the dosage form of the composition.

[0032] The composition according to the present embodiment can be a composition for oral administration such as a pharmaceutical composition, a food and drink composition such as a functional food composition, or a feed composition for animals such as livestock or pets. The composition according to the present embodiment can be formulated based on a conventionally known method. The dosage form may be any of a solid preparation, a semi-solid preparation, and a liquid preparation, as long as it can be formulated for oral administration, and can be a conventionally known dosage form without any particular limitation. For example, tablets, capsules, liquid preparations for internal use, syrups (including dry syrups), powders, granules, pills, chewable tablets, buccal tablets, sublingual tablets, lozenges, etc. can be mentioned, and can be appropriately set according to the usage of the composition. It can also be a formulation for sustained release.

[0033] The proportion of the active ingredient 3-hydroxybutyric acid and / or its salt contained in the composition according to this embodiment can be appropriately set, and can be appropriately selected and changed depending on various conditions such as the dosage form and usage of the composition according to this embodiment. For example, when the composition according to this embodiment is formulated as a solid preparation or semi-solid preparation, the proportion can be about 0.1 to 99% by weight, preferably 5 to 80% by weight, more preferably 10 to 50% by weight or 10 to 30% by weight. When the composition according to this embodiment is formulated as a liquid preparation, the proportion can be about 0.05 to 30% by weight, preferably 0.5 to 30% by weight, more preferably 1 to 10% by weight.

[0034] The composition according to the present embodiment can be administered to a mammalian animal that is a target of treatment with cisplatin. Therefore, any mammalian animal can be administered as long as it has a possibility of developing renal damage caused by administration of cisplatin. Diseases that are the target of treatment with cisplatin include cancer, etc., and the cancer may be a solid cancer such as carcinoma or sarcoma, or a blood cancer. In addition to cancers that are applicable to cisplatin, cancers that are the target of treatment by combination with other anticancer drugs are also included. Examples of solid cancers include lung cancer, breast cancer, gastric cancer, esophageal cancer, colon cancer, head and neck cancer, bladder cancer, renal pelvis and ureter cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, liposarcoma, and angiosarcoma, and examples of blood cancers include, but are not limited to, leukemia, malignant lymphoma, and myeloma.

[0035] The mammal is preferably a human, but may be a non-human mammal, including, but not limited to, dogs, cats, monkeys, cows, horses, pigs, sheep, goats, mice, rats, rabbits, and the like used as livestock, pets, or laboratory animals.

[0036] The composition according to the present embodiment is administered orally. Cisplatin is generally administered repeatedly, with one course of administration followed by a break, so that continuous intake of 3HB is required to prevent renal damage that may be induced by administration of cisplatin. For this reason, oral administration is preferred, as it is highly safe, low-cost, and a simple administration method. Here, oral administration of 3HB has been confirmed to have lower bioavailability compared to subcutaneous administration by calculation of the area under the blood concentration curve (AUC) in experiments in mice (see, for example, Naoki Horii et al., “Effect of Exogenous Acute β-hydroxybutyrate Administration on Different Modalities of Exercise Performance in Healthy Rats”, Med Sci Sports Exerc. 2023 Jul 1;55(7):1184-1194.doi:10.1249 / MSS.0000000000003151). However, the following examples have confirmed that the composition of this embodiment can effectively prevent kidney damage that can be induced by administration of cisplatin.

[0037] The administration interval and number of administrations of the composition according to this embodiment can be appropriately selected and changed depending on various conditions such as the state of the disease, the condition of the subject such as age, weight, and sex, the dosage form of the composition, and the content of the active ingredient. For example, the number of administrations can be set to once to several times a day (e.g., 2 to 5 times), once every two days, once every three days, once a week, once every two weeks, once a month, etc. In addition, the administration period can be set to one day, two days, three days, one week, two weeks, three weeks, one month, two months, three months, half a year, one year, or more.

[0038] The composition according to the present embodiment may be administered before, during, or after the administration of cisplatin, but is preferably administered before the administration of cisplatin from the viewpoint of effectively preventing nephropathy that may be induced by the administration of cisplatin. For example, the composition may be administered 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or more before the administration of cisplatin, and may be continuously administered during and / or after the administration of cisplatin.

[0039] The compositions of this embodiment may also be administered after administration of cisplatin, for example 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks or more after administration of cisplatin, and may also be administered continuously from the time of and / or before administration of cisplatin.

[0040] The composition of this embodiment can be administered in the same manner when cisplatin is administered multiple times, and can be administered before, during, or after each administration of cisplatin, or can be designed to be administered before, during, or after alternate or predetermined administrations of cisplatin.

[0041] Cisplatin can be administered according to the recommended dosage and administration method depending on the type and stage of the cancer to be treated. Usually, cisplatin is administered after a certain drug-free period. For example, 10 to 100 mg / m once a day 2 (body surface area), it is administered for one day or for 2 to 5 consecutive days, followed by a drug-free period of at least 1 to 3 weeks. This constitutes one course, and can be repeated once or more, or three or more times. The composition according to this embodiment can be administered during such a drug-free period. In addition, the composition according to this embodiment can be administered in conjunction with the administration interval of cisplatin, or at intervals shorter or longer than the administration interval of cisplatin.

[0042] The dosage of the composition according to the present embodiment can be appropriately selected and changed depending on various conditions such as the state of the disease, the condition of the subject such as age, body weight, and sex, and the dosage form and method of use of the composition according to the present embodiment. For example, the dosage of 3HB and / or its salt per kg of body weight per day can be appropriately set within the range of 0.005 g / kg body weight to 1 g / kg body weight, with 0.005 to 2 g as a guide, and the composition of the invention can be administered so that the dosage is, for example, 0.01 g / kg body weight to 0.5 g / kg body weight, or 0.015 g / kg body weight to 0.3 g / kg body weight, preferably 0.02 g / kg body weight to 0.1 g / kg body weight, more preferably 0.03 g / kg body weight to 0.08 g / kg body weight, and particularly preferably 0.04 g / kg body weight to 0.06 g / kg body weight. Here, the dosage per day can be administered at once or in multiple divided doses. There is no particular limitation on the timing of administration, and the composition may be administered, for example, before or after a meal, between meals, or before going to bed.

[0043] The ability of the composition according to the present embodiment to prevent renal damage that may be induced by administration of cisplatin can be evaluated by expression analysis of renal damage biomarkers (interleukin-1β, collagen 1a1, fibrinogen), blood tests (measurement of blood urea nitrogen and serum creatinine), etc. Furthermore, it can be evaluated by the degree of fibrosis in renal tissue. EXAMPLES

[0044] The present invention will be described in more detail below based on examples. However, these examples are described in order to more specifically illustrate the present invention, and the present invention is not limited to these examples.

[0045] (Example 1) Confirmation of the preventive effect of 3HB on renal damage that can be induced by administration of cisplatin

[0046] [Experimental materials]

[0047] 3HB: Obtained from Osaka Gas Chemicals Co., Ltd.

[0048] Cisplatin: Cisplatin was purchased from Fujifilm Wako Pure Chemical Industries, Ltd.

[0049] mouse: Eight-week-old female CD1 mice were used, and were divided into three groups of six mice each: the "cisplatin group" administered cisplatin alone, the "cisplatin + 3HB group" administered 3HB before cisplatin administration, and the "control group." The average weight of the mice in each group at the start of the experiment was 33.7 g.

[0050] [Evaluation method]

[0051] (Administration of drugs) Mice in each group were kept in an environment with appropriately controlled temperature, humidity, and light-dark cycles, and were given a standard diet and free access to water. Water intake was 4 to 5 mL / day on average. The drug administration schedule is shown in Figure 1.

[0052] Cisplatin group: Mice were intraperitoneally administered cisplatin at a dose of 8 mg / kg three times, once a week. The first cisplatin administration was counted as day 0, and cisplatin was administered on days 0, 7, and 14. Analysis was performed on day 21, one week after the third cisplatin administration.

[0053] Cisplatin + 3HB group: Cisplatin administration on days 0, 7, and 14, and analysis on day 21 were performed in the same manner as in the cisplatin administration group described above, but from 3 days before the first cisplatin administration (day -3), the mice were continuously given a 1.55 wt% 3HB aqueous solution (NaOH and KOH were added at 2.05 g / L each to adjust the pH) orally in drinking water ad libitum.

[0054] Control group: The mice were kept in the same environment as the cisplatin-administered group and the cisplatin+3HB-administered group, without receiving any drugs.

[0055] (analysis) On day 21, blood was collected from the abdominal vena cava of each group of mice under anesthesia, kidney tissue was excised, and the tissue weight was measured.

[0056] As biomarkers of renal injury, gene expression levels of interleukin-1β, collagen 1a1, and fibronectin were examined.

[0057] RNA was isolated from the collected kidney tissue using TRIzol RNA Isolation Reagents (Thermo Fisher Scientific) to prepare total RNA. Next, the RNA was dissolved in RNase-free water and mixed with 5x First-Strand buffer, 10 mM dNTP mix, random primer (TOYOBO), and RevaTra Ace RT to carry out reverse transcription. After incubation at 30°C for 10 minutes, the mixture was incubated at 42°C for 60 minutes, and then heat-treated at 95°C for 10 minutes to stop the reaction. The cDNA obtained by reverse transcription was diluted with dH2O and subjected to gene expression analysis by qPCR. The THUNDERBIRD TM SYBR (registered trademark) qPCR Mix (TOYOBO) was used. A primer set containing both sense and antisense strands was used at a final concentration of 5 μM. The obtained cDNA was added as a template to the reaction solution, set in a StepOne real-time PCR system (Applied biosystems), and heat denatured at 95°C for 2 minutes, followed by 40 cycles of reaction at 90°C for 15 seconds and 60°C for 1 minute, and the calculated Ct value was used for analysis. Correction of gene expression analysis was performed using the expression level of the L19 gene.

[0058] The sequence information of the primers used for gene expression analysis is summarized in Table 1.

[0059] [Table 1]

[0060] (result) The results are shown in Figure 2. Panel A of Figure 2 shows the relative mRNA levels of interleukin-1β in each group, Panel B shows the relative mRNA levels of collagen 1a1, and Panel C shows the relative mRNA levels of fibronectin. It was confirmed that the expression levels of these biomarkers of kidney damage were reduced in the cisplatin + 3HB administration group compared to the cisplatin administration group. From these results, it was confirmed that administration of 3HB can prevent kidney damage that can be induced by administration of cisplatin. [Industrial Applicability]

[0061] The composition of the present invention can be used in the fields of medicine, functional foods, livestock, and the like to prevent nephropathy caused by cisplatin, which is frequently used as an anticancer drug, and can be used in particular as a drug for oral administration to prevent nephropathy caused by cisplatin, and further as a drug for improving the treatment completion rate of cisplatin.

Claims

1. A composition for oral administration for preventing nephropathy caused by cisplatin, comprising: A composition comprising, as an active ingredient, 3-hydroxybutyric acid and / or a salt thereof.

2. The composition of claim 1, wherein the salt is one or more salts selected from sodium, potassium, magnesium and calcium salts of 3-hydroxybutyric acid.

3. The composition according to claim 2, comprising as the active ingredient a mixed salt of sodium, potassium, magnesium and calcium salts of 3-hydroxybutyric acid.

4. 10. The composition of claim 1 administered prior to administration of cisplatin.

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