Agent for preventing and / or treating acute renal insufficiency

Abstract

To provide a novel agent for preventing and / or treating acute renal insufficiency (AKI).SOLUTION: An agent for preventing and / or treating acute renal insufficiency comprises D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a preventive and / or therapeutic agent for acute kidney injury. [Background technology]

[0002] Acute kidney injury (AKI) is a broad clinical syndrome defined as a sudden decline in renal function (Non-Patent Document 1). It includes prerenal (shock, heart failure, dehydration, cirrhosis, etc.) and postrenal (lower urinary tract obstruction such as ureter, bladder, and urethra) causes that are not derived from the kidney. Even when the cause is derived from the kidney, there are cases where the pathology is specific to the kidney itself (glomerulonephritis, interstitial nephritis, renal infarction, etc.) or nonspecific pathology occurs as one of the organ symptoms of a systemic disease (infection, collagen disease, blood disease, etc.). When considering the treatment of AKI, it is essential to perform differential diagnosis, keeping in mind that it is the result of such a variety of pathologies.

[0003] From this perspective, new AKI treatment guidelines (KDIGO guidelines) were published by Kidney Disease: Improving Global Outcomes (KDIGO guidelines) in 2012. According to these guidelines, AKI is defined as follows (Non-Patent Document 2): If the SCr (serum creatinine) level rises by ≥ 0.3 mg / dL within 48 hours. or if the SCr value increases ≥ 1.5-fold above baseline levels known or expected within the previous 7 days. or a decrease in urinary output of <0.5 mL / kg / hour for 6 hours.

[0004] As a result, it became clear that AKI is a concept that encompasses acute renal dysfunction ranging from mild and reversible renal dysfunction (functional AKI) to severe and irreversible renal dysfunction (structural AKI), and that AKI is a broad clinical syndrome that encompasses not only organ-specific renal diseases such as nephritis, but also renal dysfunction caused by extrarenal lesions and systemic diseases. In addition, Chertow et al. reported that an increase in SCr >0.3 mg / dL correlates independently with mortality (Non-Patent Document 3). Therefore, early detection and treatment of AKI, especially intervention before functional AKI progresses to structural AKI, may improve survival and renal organ prognosis.

[0005] It has been reported that {4-[5-(3-chloro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid or a pharmacologically acceptable salt thereof is useful as a preventive and therapeutic agent for such AKI (Patent Document 1).

[0006] On the other hand, specific tetrapeptide amide derivatives are kappa opioid receptor agonist peptides, and are known to be useful as analgesics and antipruritus agents for dialysis patients (Patent Document 2, Non-Patent Document 4). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 6458016 [Patent Document 2] Patent No. 5244810 [Non-patent literature]

[0008] [Non-Patent Document 1] Journal of Dialysis 51(2):117~122,2018 [Non-Patent Document 2] KDIGO Clinical Practice Guideline for Acute Kidney Injury, Kidney Int Suppl 2012;2:1-138. [Non-Patent Document 3] Chertow GM, Burdick E, Honor M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-70. Summary of the Invention [Problem to be solved by the invention]

[0009] An objective of the present invention is to provide a new preventive and therapeutic agent for acute kidney injury (AKI). [Means for solving the problem]

[0010] Therefore, the present inventors have investigated the effects of various compounds on the symptoms of AKI using an AKI model, and have found that, among the tetrapeptide amides described in Patent Document 2, which are known as κ opioid receptor agonist peptides, D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof has an excellent effect in improving a decrease in urinary volume and / or an increase in serum creatinine level due to AKI, and is useful as a drug for the prevention and / or treatment of AKI, thereby completing the present invention.

[0011] That is, the present invention provides the following inventions [1] to

[12] . [1] A preventive and / or therapeutic agent for acute kidney injury, comprising D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof as an active ingredient. [2] A prophylactic and / or therapeutic agent for acute kidney injury according to [1], which improves the decrease in urine volume and / or the increase in serum creatinine level due to acute kidney injury. [3] The preventive and / or therapeutic agent for acute kidney injury according to [1] or [2], wherein the acute kidney injury is septic acute kidney injury. [4] Use of D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof for the manufacture of a prophylactic and / or therapeutic agent for acute kidney injury. [5] The use described in [4] to improve decreased urine volume and / or increased serum creatinine levels due to acute kidney injury. [6] The use according to [4] or [5], wherein the acute kidney injury is septic acute kidney injury. [7] D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof for use in the prevention and / or treatment of acute kidney injury. [8] The compound or salt thereof according to [7], which is used to improve a decrease in urine volume and / or an increase in serum creatinine level caused by acute kidney injury. [9] The compound or salt thereof according to [7] or [8], wherein the acute kidney injury is septic acute kidney injury.

[10] A method for preventing and / or treating acute kidney injury, comprising administering an effective amount of D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof.

[11] The method described in

[10] , which improves decreased urine volume and / or increased serum creatinine levels due to acute kidney injury.

[12] The method according to

[10] or

[11] , wherein the acute kidney injury is septic acute kidney injury. Effect of the Invention

[0012] Administration of D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof significantly improves the main symptoms of AKI, that is, decreased urinary volume and / or increased serum creatinine level due to AKI. [Brief description of the drawings]

[0013] [Figure 1] The effect of CR845 on improving renal function in a septic AKI model (LPS model). "Vehicle Control" is a group administered only with saline, "CR1.0 Control" is a group administered only with CR845 (1.0 mg / kg), "Vehicle LPS" is a group administered with saline before LPS administration, "CR0.3 LPS" is a group administered with CR845 (0.3 mg / kg) before LPS administration, and "CR1.0 LPS" is a group administered with CR845 (1.0 mg / kg) before LPS administration. [Diagram 2] The effect of CR845 on improving renal function in a septic AKI model (LPS model). "Normal control" refers to a group administered only saline, "LPS Vehicle" refers to a group administered saline before LPS administration, "CR0.3 LPS" refers to a group administered CR845 (0.3 mg / kg) before LPS administration, and "CR1.0 LPS" refers to a group administered CR845 (1.0 mg / kg) before LPS administration. [Diagram 3] The effect of CR845 on improving renal function in a septic AKI model (CLP model). "Vehicle Sham" refers to a group that underwent sham surgery and received only saline, "CR1.0 Sham" refers to a group that underwent sham surgery and received only CR845 (1.0 mg / kg), "Vehicle CLP" refers to a group that underwent cecal ligation and puncture and received saline, "CR0.3 CLP" refers to a group that underwent cecal ligation and puncture and received CR845 (0.3 mg / kg), and "CR1.0 CLP" refers to a group that underwent cecal ligation and puncture and received CR845 (1.0 mg / kg). [Figure 4] This shows the duration of the renal function improving effect of CR845 in a septic AKI model (LPS model). "Vehicle LPS" refers to the group that received saline before LPS administration, and "CR1.0 LPS (3d)" refers to the group that received CR845 (1.0 mg / kg) 3 days before LPS administration. In the figure, p<0.05 indicates a comparison with the vehicle LPS group. [Diagram 5]The improvement in survival rate is shown. "Control" indicates the group administered physiological saline, and "Treated" indicates the group administered CR845 (0.3 mg / kg). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The active ingredient of the AKI preventive and / or therapeutic agent of the present invention is D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH (hereinafter also referred to as compound (1)) or a salt thereof. As described above, compound (1) or a salt thereof is a compound described in Patent Document 2, and is a κ opioid receptor agonist peptide. It is known to be useful as an analgesic and as an antipruritic agent for dialysis patients, but its effect on AKI is completely unknown.

[0015] The salt of compound (1) may be any pharma- ceutically acceptable salt, and examples of such salts include acid addition salts with hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid, phosphoric acid, tartaric acid, etc., and basic salts with sodium, potassium, calcium, etc. Also, the salt may be in the form of a hydrate, etc.

[0016] As shown in the Examples below, compound (1) or a salt thereof has the effect of significantly improving the decrease in urine volume and the increase in serum creatinine caused by renal injury in an acute renal injury model animal, and improving these symptoms of acute renal injury. Furthermore, it has the effect of significantly increasing the survival rate after renal injury in a renal injury model animal. Therefore, compound (1) or a salt thereof is useful as a prophylactic and / or therapeutic agent for acute renal injury, and is particularly useful as a prophylactic and / or therapeutic agent for septic acute renal injury. Here, acute kidney injury (AKI) is a concept that encompasses acute renal dysfunction ranging from mild and reversible renal dysfunction (functional AKI) to severe and irreversible renal dysfunction (structural AKI), as described above, and is a broader clinical syndrome that encompasses not only organ-specific renal diseases such as nephritis, but also renal dysfunction caused by extrarenal lesions and systemic diseases. Specifically, AKI is a disease defined as follows based on the KDIGO guidelines: If the SCr (serum creatinine) level rises by ≥ 0.3 mg / dL within 48 hours. or if the SCr value increases ≥ 1.5-fold above baseline levels known or expected within the previous 7 days. or a decrease in urinary output of <0.5 mL / kg / hour for 6 hours.

[0017] According to the AKI treatment guidelines (Non-Patent Document 2), the diuretic furosemide should not be administered for the prevention and treatment of AKI, particularly septic acute kidney injury. Therefore, it was completely unexpected that compound (1) or a salt thereof is useful for AKI.

[0018] The prophylactic and / or therapeutic agent for AKI of the present invention may contain the compound (1) or a salt thereof, and is preferably formulated with a pharma- ceutically acceptable carrier to form a pharmaceutical composition in various dosage forms. The dosage form of such a pharmaceutical composition may be an injection, an oral agent (tablets, granules, powders, capsules, etc.), an ointment, a cream, a patch, a suppository, etc.

[0019] Examples of pharma- ceutically acceptable carriers used to form these pharmaceutical compositions include solvents, solubilizing agents, excipients, binders, lubricants, disintegrants, colorants, flavoring agents, preservatives, surfactants, and the like. More specific examples of the surfactant include water (purified water, distilled water, tap water, water for injection, etc.), ethanol, propylene glycol, polyethylene glycol, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, carboxymethylcellulose calcium salt, magnesium stearate, talc, acetylcellulose, white sugar, titanium oxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, nonionic surfactants, simple syrup, citric acid, glycerin, macrogol, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, sodium chloride, phenol, thimerosal, sodium hydrogen sulfite, carmellose, and hypromellose. Oral preparations can be produced by conventional methods using excipients, binders, lubricants, disintegrants, colorants, flavorings, etc. Preferred oral preparations are tablets, granules, powders, capsules, etc. When the drug is made into an injection, a solvent dissolving agent, particularly water for injection, is used. As the injection, an intravenous injection, a subcutaneous injection, or an intramuscular injection is preferable, and examples of the injection include a freeze-dried preparation and a powder filler. When the composition is made into an external preparation such as an ointment, cream, or external liquid preparation, for example, additives such as water (purified water, distilled water, ordinary water, etc.), thickeners, emulsifiers, neutralizers, preservatives, stabilizers, wetting agents, and oils and fats are used. Examples of additives include water, thickeners, emulsifiers, neutralizers, preservatives, stabilizers, wetting agents, and oils and fats. In addition, in the production of the skin wound healing agent of the present invention, one or more of commonly used additives for formulations may be used as necessary. Examples of such additives for formulations include water, thickeners, emulsifiers, neutralizers, preservatives, stabilizers, wetting agents, and oils and fats. In addition, in the production of the skin wound healing agent of the present invention, one or more of commonly used additives for formulations may be used as necessary. Examples of such additives for formulations include water, thickeners, emulsifiers, neutralizers, preservatives, stabilizers, wetting agents, and oils and fats.

[0020] The dosage of the pharmaceutical of the present invention varies depending on the active ingredient, the symptoms of the subject to be administered, the age, and the administration method, but the amount of the active ingredient can be, for example, 0.01 mg to 500 mg per day for an adult. This dosage can also be administered in 1 to 4 divided doses per day. In addition to administration at the time of AKI onset and after AKI onset, administration may be performed before AKI onset. In the case of before AKI onset, administration within 3 days is preferable. When administered to mice or rats, the active ingredient can be administered parenterally, for example, subcutaneously, intravenously, subcutaneously or intramuscularly, at a dose of 0.1 to 10 mg / kg body weight, preferably 0.1 to 3 mg / kg body weight, more preferably 0.1 to 1 mg / kg body weight, still more preferably 0.2 to 1 mg / kg body weight, and particularly preferably 0.3 to 1 mg / kg body weight per day in terms of compound (1) or a salt thereof. Furthermore, for oral administration, the compound (1) or a salt thereof can be administered at a dose of 10 to 1000 mg / kg body weight, preferably 10 to 300 mg / kg body weight, more preferably 10 to 100 mg / kg body weight, further preferably 20 to 100 mg / kg body weight, and particularly preferably 30 to 100 mg / kg body weight per administration. When administered to humans, the active ingredient can be administered parenterally, for example, subcutaneously, intravenously, subcutaneously or intramuscularly, in an amount of 0.0001 to 0.03 mg / kg body weight, preferably 0.0001 to 0.01 mg / kg body weight, more preferably 0.0003 to 0.01 mg / kg body weight, still more preferably 0.0003 to 0.003 mg / kg body weight, and particularly preferably 0.0003 to 0.001 mg / kg body weight, per administration to an adult per day. For oral administration, the compound (1) or a salt thereof can be administered at 0.01 to 3 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight, more preferably 0.03 to 1 mg / kg body weight, further preferably 0.03 to 0.3 mg / kg body weight, and particularly preferably 0.03 to 0.1 mg / kg body weight per administration. EXAMPLES

[0021] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0022] Male C57BL / 6J mice (CLEA Japan) aged 7 to 10 weeks were used in the experiment. In vivo imaging measurements were performed 6 hours after the model was created. Five hours after the septic AKI model was created, cannulas were inserted into the trachea and internal jugular vein under anesthesia. A small incision was made in the abdomen to expose the kidney, and a cover glass was attached. After 30 minutes, Lucifer Yellow (LY) was administered intravenously every 2 seconds up to 300 seconds, and the time until fluorescence was observed in the distal nephron was measured using a multiphoton laser microscope.

[0023] Example 1: Effect of CR845 on improving renal function in a septic AKI model (LPS model) (method) LPS (5mg / kg) was administered intraperitoneally to create a septic AKI model (LPS model). CR845 (0.3, 1.0mg / kg) was administered intravenously 1 hour before the LPS model was created. Separate mice were used to collect urine samples, and the mice were acclimated to metabolic cages 24 hours before urine collection. Urine was collected up to 24 hours after LPS administration.

[0024] (result) The CR845-treated group improved the decrease in tubular flow time induced by LPS administration. The percentage of LY that reached the distal nephron within 150 seconds increased to 64% at 0.3 mg / kg and 46% at 0.1 mg / kg, whereas it was 0% in the control group. The percentage of LY that reached the distal nephron after 300 seconds or more was 95% in the control group. The percentage was reduced to 21% and 22% at 0.3 mg / kg and 1.0 mg / kg, respectively (Figure 1). Administration of LPS reduced urinary volume, and administration of CR845 improved the decrease in urinary volume (Figure 2).

[0025] Example 2: Effect of CR845 on improving renal function in a septic AKI model (CLP model) (method) Sham surgery or cecal ligation and puncture were performed under anesthesia to create a septic AKI model (CLP model). CR845 (0.3, 1.0 mg / kg) was administered intravenously 1 hour before the CLP model was created.

[0026] (result) In the control group, 25% of LY reached the distal nephron within 150 seconds, and 71% reached the distal nephron after 300 seconds or more. On the other hand, CR845 (1 mg / kg) increased the proportion of LY that reached the distal nephron within 150 seconds (Figure 3).

[0027] Example 3: Duration of renal function improving effect of CR845 in septic AKI model (LPS model) (method) A septic AKI model (LPS model) was created by intraperitoneal administration of LPS (5 mg / kg). CR845 (1.0 mg / kg) was administered intravenously 3 days before the model creation.

[0028] (result) The group that received CR845 3 days before the creation of the LPS model showed a significant inhibitory effect on the decrease in renal tubule flow time observed in the control group (FIG. 4).

[0029] Example 4: Improved survival rate (method) After unilateral kidney removal, the remaining kidney was subjected to 30 min of ischemia and reperfusion. CR845 (0.3 mg / kg) or saline was administered intravenously on days 1, 3, and 5 after ischemia / reperfusion. LPS (15 mg / kg) was administered on day 6, and survival was monitored every 12 or 24 h thereafter.

[0030] (result) The median survival time in the control group was 54 hours. The median survival time in the CR845 group was over 144 hours. Treatment with CR845 improved survival rates (Figure 5).

Claims

1. A preventive and / or therapeutic drug for acute kidney injury, comprising D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a salt thereof as an active ingredient.

2. The preventive and / or therapeutic agent for acute kidney injury according to claim 1, which ameliorates a decrease in urine volume and / or an increase in serum creatinine level caused by acute kidney injury.

3. 3. The preventive and / or therapeutic agent for acute kidney injury according to claim 1 or 2, wherein the acute kidney injury is septic acute kidney injury.

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