Drug-induced renal dysfunction relieving agent

Abstract

To provide a drug-induced renal dysfunction relieving agent that enables inhibition or mitigation of renal dysfunction resulting from administration of a drug.SOLUTION: A drug-induced renal dysfunction relieving agent comprising, as an active ingredient, a dopamine D2-like receptor agonist. The dopamine D2-like receptor may be DRD2. The dopamine D2-like receptor agonist may be at least one selected from the group consisting of quinpirole, dopamine, ropinirole, and bromocriptine. The agent is preferably administered to a patient having drug-induced renal dysfunction caused by administration of a platinum-based anticancer agent, an antibacterial agent, an antiviral agent, a contrast medium, or an NSAIDs.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a drug for alleviating drug-induced nephropathy, which contains a dopamine D2-like receptor agonist. [Background technology]

[0002] Anticancer drugs, antibiotics, and NSAIDs can induce renal acute kidney injury by damaging renal tubular epithelial cells. Platinum drugs, such as cisplatin, are particularly well known to induce rapid renal dysfunction, and while steroids are sometimes used as a symptomatic treatment, no preventative or therapeutic drugs have been established to date. Particularly in cancer treatment, the onset of acute kidney injury leads to a poorer prognosis the higher the stage of damage, and the more likely patients are to have their medication reduced or discontinued, which reduces the rate of complete remission after six months.

[0003] To alleviate kidney damage caused by platinum-containing drugs, the basic clinical approach is to provide patients with large amounts of fluid to excrete unnecessary drugs in the urine. For example, a beverage composition for reducing nephrotoxicity has been proposed, which claims that adding a small amount of butyric acid as a component of replacement fluid can reduce nephrotoxicity (Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 7166475 Summary of the Invention [Problem to be solved by the invention]

[0005] However, providing large amounts of fluid places a significant burden on patients, and there is a need for drugs that not only promote urination but also alleviate kidney damage. The present invention provides a drug for alleviating drug-induced nephropathy, which is capable of suppressing or alleviating nephropathy caused by drug administration. [Means for solving the problem]

[0006] The present invention includes the following aspects. [1] A drug for the relief of drug-induced kidney damage that contains a dopamine D2 receptor agonist as its active ingredient. [2] The drug for alleviating drug-induced nephropathy according to [1], wherein the dopamine D2-like receptor is a dopamine D2 receptor. [3] The drug for alleviating drug-induced nephropathy according to [1], wherein the dopamine D2-like receptor agonist is one or more selected from the group consisting of quinpirole, dopamine, ropinirole, and bromocriptine. [4] A drug for alleviating drug-induced nephropathy according to any one of [1] to [3], which is administered to a patient whose drug-induced nephropathy has been induced by the administration of a platin-based platinum preparation, an antibacterial agent, an antiviral agent, a contrast agent, or an NSAID.

[0007] The drug for alleviating drug-induced nephropathy of the present invention may be used not only for the purpose of alleviating drug-induced nephropathy but also for the purpose of preventing drug-induced nephropathy. The drug for alleviating drug-induced nephropathy of the present invention may be used not only for the purpose of alleviating drug-induced nephropathy but also for the purpose of treating drug-induced nephropathy. An example of a therapeutic method related to the present invention is a therapeutic method in which an effective amount of the drug of the present invention for alleviating drug-induced nephropathy is administered to a patient suffering from drug-induced nephropathy. An invention of use related to the present invention includes the use of a dopamine D2-like receptor agonist for the manufacture of a drug for alleviating drug-induced nephropathy. Inventions related to the present invention include dopamine D2-like receptor agonists for use in treating or alleviating drug-induced nephropathy. [Effects of the Invention]

[0008] The drug for alleviating drug-induced nephropathy of the present invention can suppress or alleviate nephropathy caused by drug administration. [Brief explanation of the drawings]

[0009] [Figure 1A]Test results showing that quinpirole (a DRD2 agonist) alleviated kidney damage caused by cisplatin administration in mice. [Figure 1B] Test results showing that quinpirole (a DRD2 agonist) alleviated kidney damage caused by cisplatin administration in mice. [Figure 2A] Study results show that risperidone (a DRD2 blocker) does not alleviate kidney damage caused by cisplatin in mice. [Figure 2B] Test results showing that dopamine (DRD2 agonist) alleviated kidney damage caused by cisplatin administration in mice. [Figure 2C] Test results showing that SKF38393 (DRD1 agonist) does not alleviate cisplatin-induced kidney damage in mice. [Figure 3] Study results showing that quinpirole reduced kidney cell apoptosis in mice treated with cisplatin. [Figure 4] Test results showing that quinpirole reduced the expression of Kim1, a marker of kidney damage, in mice treated with cisplatin. [Figure 5] Study results showing that quinpirole reduced macrophage infiltration into kidney tissue in mice treated with cisplatin. [Figure 6] [Left panel] Test results showing that quinpirole changed the expression levels of inflammatory cytokines in mice 72 hours after cisplatin administration. [Right panel] Test results showing that quinpirole changed the expression levels of factors involved in renal cell fibrosis (TGF-β, fibronectin, type I collagen) in mice 72 hours after cisplatin administration. [Figure 7] Test results showing that quinpirole did not affect the expression of inflammatory cytokines in mice 24 hours after administration of cisplatin. [Figure 8] Results of a study demonstrating that renal tubular DRD2 is not involved in the attenuation of kidney damage by quinpirole in cisplatin-treated mice. [Figure 9] Results show that DRD2 in T cells is not involved in the attenuation of kidney damage by quinpirole in cisplatin-treated mice. [Figure 10] Test results showing that the involvement of DRD2, which is expressed outside of renal tubules and T cells, is important in reducing kidney damage caused by quinpirole in cisplatin-treated mice. [Figure 11] Test results showing that each of three dopamine D2-like receptor agonists (quinpirole, ropinirole, and bromocriptine) alleviated kidney damage caused by cisplatin administration in mice. DETAILED DESCRIPTION OF THE INVENTION

[0010] There are two known mechanisms by which drug-induced kidney damage occurs: a direct pathway in which the drug acts on kidney cells, resulting in the production of reactive oxygen species (ROS) within the cells and mitochondria, and an indirect pathway in which the drug accumulates in kidney cells, causing chronic inflammation and leading to immune cells such as macrophages attacking the kidney cells.

[0011] The present inventors discovered that administration of dopamine D2-like receptor agonists can alleviate drug-induced kidney injury (DKI), leading to the completion of the present invention. Although the details of the mechanism by which dopamine D2-like receptor agonists alleviate kidney injury are still unclear, experimental results described below suggest that alleviation of inflammation induced by immune cells is the main mechanism.

[0012] Dopamine D2-like receptors include D2 receptors, D3 receptors, and D4 receptors. On the other hand, dopamine D1-like receptors include D1 receptors and D5 receptors. These are generally known as a type of G protein-coupled receptor in the central nervous system, and bind to the neurotransmitter dopamine.

[0013] The dopamine D2-like receptor agonist includes one or more selected from the group consisting of quinpirole, dopamine, ropinirole, and bromocriptine.

[0014] Subjects to whom the drug of the present invention for alleviating drug-induced nephropathy is administered include patients who have or are at risk of developing drug-induced nephropathy. Examples of drugs that cause nephropathy include platin-based platinum agents, antibacterial agents, antiviral agents, contrast agents, and NSAIDs. Examples of platin-based platinum agents include cisplatin, oxaliplatin, and carboplatin. Antibacterial agents include, for example, gentamicin and vancomycin. Antiviral drugs include, for example, anti-HIV drugs, foscarnet, etc. Contrast agents include, for example, iodine contrast agents. Examples of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) include diclofenac sodium and loxoprofen sodium.

[0015] The mechanisms of injury in DKI include reduced renal blood flow, acute tubular necrosis caused by direct drug-induced damage to the renal tubules, acute interstitial nephritis due to an allergic reaction, and obstruction caused by drug precipitation in the urine. The above-mentioned drugs are known to induce DKI through acute tubular necrosis. In acute tubular necrosis, in addition to the direct effects of drugs on tubular cells, inflammatory responses by immune cells are also a major factor in tissue damage. As shown in Test Examples 7–9 below, dopamine D2-like receptor agonists are thought to target DRD2, which is expressed in cells other than tubular epithelial cells and T cells. Because inflammation is closely related to acute tubular necrosis, it is highly likely that dopamine D2-like receptor agonists target mast cells and macrophages. This also suggests the possibility that dopamine D2-like receptor agonists may also target DKI due to acute interstitial nephritis caused by allergic reactions. Drugs that cause acute interstitial nephritis include, for example, antibiotics, NSAIDs, diuretics, H2 receptor antagonists, drugs for treating gout and hyperuricemia, angiotensin-converting enzyme inhibitors, anticoagulants, antiepileptic drugs, and immunosuppressants. Examples of antibiotics include penicillins, cephalosporins, rifampicin, sulfonamides, and the like. Examples of NSAIDs include fenoprofen, indomethacin, ibuprofen, and the like. Diuretics include, for example, thiazides, furosemide, etc. Examples of H2 receptor antagonists include cimetidine. Examples of therapeutic agents for gout and hyperuricemia include allopurinol. Examples of angiotensin converting enzyme inhibitors include captopril. Anticoagulants include, for example, phenindione. Antiepileptic drugs include, for example, phenytoin. Immunosuppressants include, for example, azathioprine.

[0016] The drug for alleviating drug-induced nephropathy of the present invention may be a pharmaceutical composition containing, in addition to the active ingredient, other auxiliary ingredients contained in conventional common therapeutic drugs. For example, it can be formulated using additives such as fillers, lubricants, flavoring agents, coloring agents, coating agents, disintegrants, and glidants.

[0017] The drug for alleviating drug-induced nephropathy of the present invention can be administered by various routes, including enteral, intravenous, intramuscular, intraperitoneal, oral, or parenteral administration. The dosage form of the present invention may be appropriately selected depending on the mode of administration, and examples thereof include oral preparations such as tablets, granules, and capsules, as well as injections, transdermal preparations, and eye drops.

[0018] The drug for alleviating drug-induced nephropathy of the present invention can be administered at an effective dose determined appropriately depending on the state and stage of the patient's nephropathy, other concomitant diseases, and physical conditions such as age, sex, weight, etc. In one embodiment, for example, about 1 to 10,000 mg / day of a drug for alleviating drug-induced nephropathy containing a dopamine D2-like receptor agonist can be administered according to the patient's condition. [Example]

[0019] The present invention will be further described below with reference to examples, but the present invention should not be construed as being limited to these examples.

[0020] [Test Example 1] Ten-week-old male C57BL / 6 mice were intraperitoneally administered saline or 20 mg / kg cisplatin, and kidneys were harvested 3 days later. Quinpirole or risperidone was administered 10 mg / kg / day three times starting immediately after cisplatin administration. The harvested kidneys were fixed in 4% paraformaldehyde, paraffin-embedded, and stained with PAS to calculate renal injury scores. Although quinpirole administration did not improve the renal injury score, it significantly suppressed the appearance of hyaline bodies. Furthermore, cisplatin administration dramatically improved the prognosis. The results are shown in Figure 1A and Figure 1B.

[0021] [Test Example 2] Mice were treated in the same manner as in Test Example 1, and blood urea nitrogen and creatinine levels were measured. As a result, as shown in Figure 2A, the increase in blood urea nitrogen and creatinine levels caused by cisplatin administration was suppressed by administration of quinpirole, while risperidone showed no effect. *: p<0.05 vs. cisplatin-administered group Mice were treated in the same manner as in Test Example 1, except that quinpirole was replaced with dopamine, and blood urea nitrogen and creatinine levels were measured. Dopamine was administered three times at 10 mg / kg / day. As a result, as shown in Figure 2B, the increase in blood urea nitrogen and creatinine levels caused by cisplatin administration was suppressed by dopamine administration. *: p<0.05 Mice were treated as in Test Example 1, except that quinpirole was replaced with SKF38393, and blood urea nitrogen and creatinine levels were measured. SKF38393 was administered once daily for three days at the doses shown in the figure, starting immediately after cisplatin administration. As a result, as shown in Figure 2C, SKF38393 did not have an inhibitory effect on the increase in blood urea nitrogen and creatinine levels caused by cisplatin administration.

[0022] [Test Example 3] Mice were treated in the same manner as in Test Example 1, and their kidneys were removed. The removed kidneys were fixed in 4% paraformaldehyde, frozen sections were prepared, and fluorescent tissue staining was performed using anti-cleaved caspase-3 (CC3) antibody and FITC-labeled Lotus tetragolonobus lectin (LTL). As a result, as shown in Figure 3, it was revealed that apoptosis induced by cisplatin administration was significantly suppressed by administration of quinpirole. The graph shows the number of CC3-positive cells counted per field in each administration group. *: p<0.05, **: p<0.01, ***: p<0.005

[0023] [Test Example 4] Fluorescent tissue staining was performed on the frozen sections prepared in Test Example 3 using anti-Kim antibody and FITC-labeled LTL. As a result, as shown in Figure 4, it was revealed that the expression of Kim (Kidney Injury Molecule) induced by cisplatin administration was suppressed by quinpirole administration. Similar results were also obtained by qPCR and Western blotting using anti-Kim antibody. *: p<0.05, **: p<0.01

[0024] [Test Example 5] Fluorescent tissue staining was performed on the frozen sections prepared in Test Example 3 using anti-F4 / 80 antibody and FITC-labeled LTL. As a result, as shown in Figure 5, it was revealed that macrophage invasion induced by cisplatin administration was suppressed by quinpirole administration. Similar results were also obtained by qPCR. *: p<0.05, **: p<0.01

[0025] [Test Example 6] Mice were treated as in Test Example 1, and their kidneys were removed. qPCR revealed that quinpirole significantly suppressed or tended to suppress the expression of inflammatory cytokines, the expression of which was increased by cisplatin administration. Similar results were obtained for fibrosis-related genes induced by cisplatin administration. The results are shown in Figure 6.

[0026] [Test Example 7] Cisplatin and quinpirole were administered as in Test Example 1, and the kidneys were removed 24 hours later for qPCR. As a result, as shown in Figure 7, 24 hours after administration, it was revealed that the expression of Kim1 and Ngal induced by cisplatin administration tended to be suppressed, but was not significantly suppressed by quinpirole.

[0027] [Test Example 8] Ten-week-old male renal tubular epithelium-specific DRD2 knockout mice (Six2-EGFPcre;DRD2 flox / flox ) or control mice (DRD2 flox / flox ) were intraperitoneally administered 20 mg / kg cisplatin (C / V) or cisplatin and 10 mg / kg quinpirole (C / Q), and serum was collected 3 days later. As shown in Figure 8, quinpirole suppressed blood urea nitrogen and creatinine levels even in renal tubular epithelial-specific DRD2 knockout mice, indicating that quinpirole does not target DRD2 expressed in renal tubular epithelial cells. *: p<0.05, **: p<0.01, ***: p<0.005

[0028] [Test Example 9] 10-week-old male T cell-specific DRD2 knockout mice (Lck-cre;DRD2 flox / flox ; cKO) or control mice (DRD2 flox / flox ; ctrl) were intraperitoneally administered saline (V / V), 20 mg / kg cisplatin (C / V), or cisplatin and 10 mg / kg quinpirole (C / Q), and serum was collected 3 days later. As shown in Figure 9, quinpirole suppressed blood urea nitrogen and creatinine levels even in T cell-specific DRD2 knockout mice, indicating that quinpirole does not target DRD2 expressed in T cells.

[0029] [Test Example 10] 10-week-old ostamoxifen-induced systemic DRD2 knockout mice (Ubc-creERT2;DRD2 flox / flox ; cKO) or control mice (DRD2 flox / flox ; ctrl) were intraperitoneally administered saline (V / V), 20 mg / kg cisplatin (C / V), or cisplatin and 10 mg / kg quinpirole (C / Q), and serum was collected 3 days later. As shown in Figure 10, quinpirole did not suppress blood urea nitrogen or creatinine levels in systemic DRD2 knockout mice, indicating that quinpirole targets DRD2. Considering the results of Experiments 8 and 9, this suggests that DRD2 expressed in tissues other than renal tubules and T cells is necessary for quinpirole's action.

[0030] [Test Example 11] Mice were treated in the same manner as in Test Example 1, except that ropinirole and bromocriptine were also administered, and blood urea nitrogen and creatinine levels were measured. Ropinirole and bromocriptine were administered three times at 10 mg / kg / day. As a result, as shown in Figure 11, the increase in blood urea nitrogen and creatinine levels caused by cisplatin administration was suppressed by administration of ropinirole or bromocriptine, as was the case with quinpirole. *: p<0.05, ***: p<0.005 vs. cisplatin group

Claims

1. A drug for alleviating drug-induced nephropathy, containing a dopamine D2 receptor agonist as an active ingredient.

2. The drug for alleviating drug-induced nephropathy according to claim 1, wherein the dopamine D2-like receptor is a dopamine D2 receptor.

3. 2. The drug for alleviating drug-induced nephropathy according to claim 1, wherein the dopamine D2-like receptor agonist is one or more selected from the group consisting of quinpirole, dopamine, ropinirole, and bromocriptine.

4. The drug for alleviating drug-induced nephropathy according to any one of claims 1 to 3, which is administered to a patient in whom drug-induced nephropathy has been induced by the administration of a platin-based platinum preparation, an antibacterial agent, an antiviral agent, or an NSAID.

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