Treatment and prevention of nephrotoxin-induced kidney injury

Abstract

This invention provides novel treatments and preventative measures for renal conditions or diseases induced by exposure to nephrotoxin. [Solution] In subjects exposed to nephrotoxins that may induce renal conditions or diseases, cyclic peptide compounds or pharmaceutically acceptable salts thereof are provided herein for use in the prevention and / or treatment of such renal conditions or diseases.

Description

Background Art

[0001] Many approved active ingredients are known to be nephrotoxic and may induce renal conditions such as acute kidney injury or acute renal failure. As a result, even if the therapeutic value of such active ingredients is highly anticipated, such types of active ingredients are often dosage-limited, and there is a need to carefully monitor for signs of nephrotoxicity when administering drugs to patients. In particular, patients with renal dysfunction or a history of renal dysfunction should refrain from these medications. Nephrotoxicity is caused by exposing the kidneys to endogenous toxins resulting from cytotoxic or destructive phenomena that cause, among other functions, the transport and excretion of metabolites and the regulation of water balance, and may also occur as a result of conditions such as rhabdomyolysis.

[0002] U.S. Patent No. 6,583,265 discloses Compound I. JPEG2026102838000001.jpg75123Compound I

[0003] This compound is mentioned in Example 27 of U.S. Patent No. 6,583,265, and includes hundreds of named compounds having modifications at various positions around the ring. However, data on biological tests and specific uses for this compound or related analogs are not described.

[0004] Compound I is also disclosed in International Publication No. 2019 / 0169572 for use in the treatment or prevention of acute or chronic inflammatory diseases such as acute kidney injury, ischemia-reperfusion injury, or chronic or acute pancreatitis. International Publication No. 2019 / 0169572 does not disclose the use of Compound I in the prevention or treatment of renal conditions or diseases in subjects exposed to nephrotoxin. In this case, nephrotoxin is a nephrotoxic drug or endogenous endotoxin. International Publication No. 2019 / 0169572 describes a model study of acute kidney injury in mice based on the use of LP (lipopolysaccharide). LP is not a nephrotoxic drug but is a bacterial endotoxin, and exposure to it can cause sepsis-induced kidney injury.

[0005] Accordingly, the object of this disclosure and the present invention is to provide novel treatments and defenses for renal conditions or diseases related to or induced by exposure to nephrotoxin, and to provide protection of the kidneys from nephrotoxic side effects in subjects treated with nephrotoxic active pharmaceutical ingredients, particularly aminoglycoside antibiotics or chemotherapeutic agents. It is also the object of the present invention to provide treatments and defenses for renal conditions or diseases related to endogenous nephrotoxin, resulting from conditions such as rhabdomyolysis, or renal conditions or diseases induced by exposure to endogenous nephrotoxin.

[0006] Further objectives of the present invention will be made clear based on the following description of the invention, examples, and claims. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 6,583,265 [Patent Document 2] International Publication No. 2019 / 0169572 [Overview of the project] [Problems that the invention aims to solve]

[0008] In a first aspect, the Disclosure relates to Compound I for use in treating or preventing a renal condition or disease in a subject exposed to nephrotoxin, which can induce a renal condition or disease. JPEG2026102838000002.jpg89145 Compound I Or, with respect to a pharmaceutically acceptable salt thereof, in this case, nephrotoxin is a nephrotoxic active pharmaceutical ingredient or endogenous nephrotoxin. In a further embodiment, the use of compound I or a pharmaceutically acceptable salt thereof is provided in the manufacture of a drug for the prevention or treatment of a renal condition or disease in a subject exposed to nephrotoxin, i.e., a nephrotoxic active pharmaceutical ingredient, or in a subject exposed to endogenous nephrotoxin capable of inducing such renal condition or disease. In a further embodiment, the disclosure provides a method for preventing a renal condition or disease induced by exposure to a nephrotoxic active pharmaceutical ingredient or endogenous nephrotoxin in a subject. This method comprises administering compound I or a pharmaceutically acceptable salt thereof to the subject. In a further embodiment, nephrotoxin is an aminoglycoside. [Brief explanation of the drawing]

[0009] [Figure 1A] This graph shows the average body weight of male Wistar rats recorded over a 10-day period for gentamicin-induced acute kidney injury, as described in Example 1. The control group (not treated with gentamicin) is represented as a circular dot, the solvent group as a square, and the compound I group as a triangle. The solvent group rats and the compound I group were treated with either the solvent or compound I (3 mg / kg) once daily via intraperitoneal administration. Both the solvent group and the compound I group received intraperitoneal administration of gentamicin once daily for acute kidney injury modeling.

[0010] [Figure 1B]The data for Example 1 shows the delta body weight, which is the change in mean body weight from baseline (day 1) to the endpoint (day 10) in male Wistar rats with gentamicin-induced acute kidney injury. The X-axis, from left to right, represents the control group (treatment without gentamicin), the solvent group (solvent once daily and gentamicin once daily), and the compound I group (compound I in solvent once daily (dosage: 3 mg / kg) and gentamicin once daily, starting from day 1).

[0011] [Figure 2] The table shows the serum blood urea nitrogen (BUN) levels, which were the study endpoint. From left to right, the X-axis represents the control group (no treatment), the solvent group (solvent once daily and gentamicin once daily), and the compound I group (compound I in solvent once daily (dosage: 3 mg / kg) and gentamicin once daily, starting from day 1).

[0012] [Figure 3] The graph shows the serum creatinine levels of the study endpoint. Represented from left to right on the X-axis are the control group (no treatment), the solvent group (solvent once daily and gentamicin once daily), and the compound I group (compound I in solvent once daily (dosage: 3 mg / kg) and gentamicin once daily, starting from day 1).

[0013] [Figure 4A]The overall acute kidney injury pathology scoring for kidney tissue samples (left and right kidney tissue) obtained at the endpoint of the gentamicin-induced acute kidney injury model study described in Example 2 is shown. The figures on the X-axis, from left to right, represent the overall acute kidney injury score for each test group. Groups G1 (Group 1, control, no treatment with gentamicin or compound I), G2 (Group 2, once daily doses of solvent and gentamicin), G3 (Group 3), G4 (Group 4), and G5 (Group 5) received intraperitoneal administration of compound I at doses of 0.5 mg / mg, 3 mg / mg, and 9 mg / mg, respectively, once daily, and gentamicin once daily. Based on one-way ANOVA and Dunnett's multiple comparison test, ** indicates P<0.01, and *** indicates P<0.001 relative to G2.

[0014] [Figure 4B] For the specific renal tissue pathologies evaluated, the scoring for acute kidney injury in renal tissue samples (left and right kidneys) obtained at the endpoint of the gentamicin-induced acute kidney injury study, as described in Example 2, is shown. The scores for each of the groups G1 to G5 shown in Figure 4A are presented. Represented on the X-axis from left to right are the following acute kidney injury pathologies: the number of necrotic and apoptotic cells, tubular dilation, loss of tubular brush margins, cast formation, and neutrophil infiltration, and represent the scoring for the study groups G1 to G5. Based on bidirectional ANOVA and Bonferroni's multiple comparison test, * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001 for G2.

[0015] [Figure 5]Shows the serum creatinine levels of the test endpoints. Represented on the X-axis from left to right are G1 (Group 1, control, no treatment with gentamicin or Compound I), G2 (Group 2, once-daily doses of vehicle and gentamicin respectively), G3 (Group 3, once-daily dose of 0.5 mg / kg of Compound I and once-daily administration of gentamicin), G4 (Group 4, once-daily dose of 3 mg / kg of Compound I and once-daily dose of gentamicin), and G5 (Group 5, once-daily dose of 9 mg / kg of Compound I and once-daily dose of gentamicin). Based on one-way ANOVA and Dunnett's multiple comparison test, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001 compared to G2.

[0016] [Figure 6] Shows the serum urea nitrogen (BUN) levels of the test endpoints. Represented on the axes from left to right are the serum BUN levels measured for test groups G1 - G5 as described in Figure 5. Based on one-way ANOVA and Dunnett's multiple comparison test, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001 compared to G2.

[0017] [Figure 7] Shows the test endpoint levels of the acute kidney injury biomarker Kim-1 (Kidney Injury Molecule-1) in plasma. The measured values obtained for test groups G1 - G5 as described in Figure 5 are shown on the axes from left to right. Based on one-way ANOVA and Dunnett's multiple comparison test, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001 compared to G2.

[0018] [Figure 8]Shows the measured values of the test endpoints obtained for the acute kidney injury biomarker NGAL (neutrophil gelatinase-associated lipocalin) in plasma. The measured values obtained for test groups G1 to G5 as described in Figure 5 are shown on the left to right axes. Based on one-way ANOVA and Dunnett's multiple comparison test, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001 compared to G2.

Mode for Carrying Out the Invention

[0019] In a first aspect, the present disclosure relates to Compound I for use in treating or preventing a renal condition or disease in a subject exposed to a nephrotoxin capable of inducing the renal condition or disease JPEG2026102838000003.jpg89145Compound I or a pharmaceutically acceptable salt thereof, where the nephrotoxin is a nephrotoxic prodrug or an endogenous nephrotoxin.

[0020] Compound I is a derivative of cyclosporin A substituted at the 3-position by an N,N-dimethylaminoethoxy residue (known as sarcosine, also known as N-methylglycine), and its synthesis and preparation are described, for example, in International Publication No. 2019 / 0169572. Compound I as described above is [(R)-2’(2-dimethylaminoethoxy)-ar] 3It may be referred to by one of its chemical names, such as cyclosporine A. Compound I, as described in this disclosure and in the context of the present invention, should be understood herein to refer to any pharmaceutically acceptable salt thereof, as well as its enantiomers, diastereomers, or racemates and their polymorphs, hydrates, or complexes. In alternative and optional embodiments, Compound I may be provided as a mixture of (R) and () stereoisomers at the 3-sarcosine position. The use of optically pure stereoisomers of Compound I, and combinations of its stereoisomers, are also mentioned. The term “optically pure,” interchangeable with “stereochemically pure,” refers to a compound having a level of stereochemical purity recognized by those skilled in the art, based on conventional methods for determining stereoselectivity and stereochemical purity. In further optional embodiments, Compound I or a pharmaceutically acceptable salt thereof may be provided as isotopes. For example, one or more of its atoms 13 It can be replaced with isotopes such as 1C, or with deuterium.

[0021] Nephrotoxin is a compound or substance that may interfere with or impair the function of one or two kidneys and their associated tissues. In one embodiment of the present disclosure, the nephrotoxin that may induce a renal condition or disease is a nephrotoxic active pharmaceutical ingredient.

[0022] As used herein, the term “nephrotoxic API” refers to an active pharmaceutical ingredient or compound or mixture of compounds that is pharmacologically or diagnostically active, and is useful for medical or therapeutic purposes in the prevention, diagnosis, stabilization, treatment or management of symptoms, disorders or diseases, and which may interfere with, impair or reduce renal function. A nephrotoxic API may be provided or administered to a subject as a drug or pharmaceutical dosage form comprising the nephrotoxic API or mixture of nephrotoxic substances and one or more non-pharmacological active excipients or non-pharmacological active carriers. In particular, a nephrotoxic API may be a dose-restricted substance if its administration for its indicated therapeutic or diagnostic purpose is limited in terms of a threshold dose given in single doses and / or cumulative doses due to its potential for nephrotoxic side effects. Nephrotoxic active pharmaceutical ingredients (APIs) may also be further defined as APIs in which nephrotoxicity is listed as a side effect or adverse effect according to their prescribing information, and / or their prescribed use for the therapeutic / diagnostic uses intended herein shall include a note regarding the dose concentration (e.g., its serum concentration) of the API in the subject to which the nephrotoxic API is administered, and / or a note regarding monitoring the renal function of the transplant recipient for signs and markers related to nephrotoxicity.

[0023] As understood herein, the terms “exposure to nephrotoxin” and similar terms may refer to the exposure of a subject to nephrotoxin during the course of treatment for a condition, symptom, or disease. In this case, the subject is administered one or more doses of nephrotoxin, such as one nephrotoxic active pharmaceutical ingredient or a combination thereof, as defined in the various embodiments herein, for therapeutic or diagnostic purposes. As used herein, the terms “exposure to nephrotoxin” also include any unintentional exposure of a subject to nephrotoxin. Examples include, but are not limited to, accidental exposure resulting from a needle stick injury, or situational / unforeseen circumstances such as physical trauma or prolonged physical stress that could cause the release and / or accumulation of endogenous nephrotoxin.

[0024] In one embodiment, the nephrotoxic active pharmaceutical ingredient is selected from the group consisting of antibacterial agents, cancer chemotherapy agents, antihypertensive drugs including ACE inhibitors and angiotensin receptor antagonists, macrocyclic lactone immunosuppressants, HIV protease inhibitors, peptic ulcer drugs, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, laxatives, and contrast agents.

[0025] As understood herein, the terms “API” and its genus, family, or species may refer to the API itself, and any pharmaceutically acceptable salts thereof, hydrates thereof, derivatives thereof, or prodrugs thereof. For example, the term “gentamicin” may also include gentamicin sulfate, which is its common commercial form. Similarly, the term “aminoglycoside,” which is interchangeable with the term “aminoglycoside antibiotic,” may refer to any compound that exists, for example, within its common definition or classification in the art.

[0026] In a particular embodiment, the nephrotoxic active pharmaceutical ingredient is a chemotherapeutic agent. The chemotherapeutic agent is preferably a cytotoxic or anti-cancer agent used to treat cancers within a target, for example, to target and kill tumor cells. In a specific embodiment, the chemotherapeutic agent is selected from the group consisting of platinum (e.g., carboplatin, cisplatin, oxaliplatin, or nedaplatin), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin), bleomycin, mitomycin, actinomycin, cyclophosphamide, capecitabine, cytarabine, gemcitabine, ifosfamide, interleukin-2, streptozocin, gemtuzumab ozogamicin, melphalan, methotrexate, pemetrexed, pricamycin, and trimethrexate.

[0027] Preferably, the chemotherapeutic agent is cisplatin. Cisplatin, a platinum complex, is used to treat a variety of cancers, including ovarian cancer, lung cancer, head cancer, cervical cancer, testicular cancer, and bladder cancer. However, high doses are limited because cisplatin can induce nephrotoxicity and dose-dependent nephrotoxicity. Cisplatin is absorbed by renal tubular cells, particularly proximal tubular cells in the endocortex and extramedullary region. These cells and sites undergo injury and necrotic cell loss, leading to acute kidney injury and impaired renal function. Nephrotoxicity becomes more severe with repeated treatments using cisplatin, and methods to reduce cisplatin nephrotoxicity include the use of intravenous fluid replacement via infusion over 6-8 hours. In specific embodiments of this disclosure, compound I is used to treat and / or prevent cisplatin-induced acute kidney injury.

[0028] In one embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject undergoing cancer treatment. This cancer treatment may include the administration of a chemotherapeutic agent to the subject. In one embodiment, the subject may be administered a dose of compound I before receiving a dose of the chemotherapeutic agent (e.g., a certain dose of cisplatin). Compound I may be administered throughout the course of the chemotherapeutic treatment. Alternatively, it may be administered to a subject undergoing cancer treatment with a chemotherapeutic agent who has developed a renal condition or disease after exposure to the chemotherapeutic agent or as a result thereof. The chemotherapeutic agent may be cisplatin.

[0029] In another embodiment of this disclosure, the nephrotoxic drug substance is an antimicrobial agent. Preferably, the antimicrobial agent is an antibiotic that is effective against bacteria (e.g., Gram-negative bacteria and / or Gram-positive bacteria).

[0030] In one embodiment, the antibacterial agent may be selected from the group consisting of aminoglycosides, β-lactams, polypeptide antibiotics, glycopeptide antibiotics, peptide-mimetic antibiotics, outer membrane protein-targeting antibiotics, and antifungal agents (e.g., amphotericin B), as well as combinations thereof.

[0031] In one specific embodiment, compound I or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of renal conditions or diseases induced by exposure to a nephrotoxic drug substance, in which case the drug substance is an aminoglycoside antibiotic. Aminoglycoside antibiotics are used particularly for clinical management and treatment of infections (especially Gram-negative bacterial infections). Aminoglycosides have been found to contribute to the injury and necrosis of renal tubular cells. Compound I may be used to protect renal function in subjects receiving treatment with an aminoglycoside antibiotic. In one embodiment, the aminoglycoside antibiotic is selected from the group consisting of gentamicin, tobramycin, amikacin, netylmycin, apramycin, streptomycin, kanamycin, neomycin, and shisomecin.

[0032] In a preferred embodiment, the aminoglycoside antibiotic is gentamicin. Gentamicin is administered by injection (intramuscular or intravenous) for the treatment of serious infections caused by Staphylococcus species, Citrobacter species, Enterobacter species, Escherichia coli, Klubsiella-Enterobacter-Serratia species, Proteus species, and Pseudomonas aeruginosa. While effective as an antibiotic, its use requires careful monitoring and control by a physician. This is due to the potential for adverse nephrotic effects and nephrotoxicity, characterized by elevated renal function markers such as blood urea nitrogen (BUN), serum creatinine, or oliguria. The administration of gentamicin requires careful monitoring, adjustment, and close supervision, especially in patients with impaired renal function, to ensure that the therapeutically appropriate but not excessive drug levels are maintained.

[0033] As demonstrated in model studies based on gentamicin-induced renal conditions, i.e., acute kidney injury, the inventors have found that compound I provides significant protection against renal function decline. In a particular embodiment of this disclosure, compound I or a pharmaceutically acceptable salt thereof is used for the treatment and / or prevention of gentamicin-induced acute kidney injury. Compound I may be used for the treatment of a subject suffering from an infection that requires treatment with gentamicin. The subject is administered gentamicin. In one embodiment, a dose of compound I is administered to the subject before a dose of gentamicin is administered. In another embodiment, compound I is administered to the subject after the onset of renal function decline, for example, after exposure to gentamicin.

[0034] In further embodiments, the antibacterial agent is a β-lactam. Examples of β-lactam antibiotics include, but are not limited to, cephalosporins, and penicillins including ureidopenicillin (e.g., piperacillin), aminopenicillin, and carboxypenicillin, and carbapenems. Combination therapy with β-lactamase inhibitors such as tazobactam, sulbactam, and clavulanic acid is also included in the scope of this disclosure.

[0035] In another embodiment, the antimicrobial agent is a polypeptide antibiotic, a glycopeptide antibiotic, or a peptide-mimicking antibiotic. Examples of polypeptide antibiotics that may consist of non-ribosomal polypeptides include bacitracin and polymyxins such as polymyxins A, B, C, D, and E (colistin). Examples of glycopeptide peptides include vancomycin and teicoplanin. The antimicrobial agent may be based on naturally occurring peptides or glycopeptides, or alternatively, it may be a synthetic or semi-synthetic compound, such as a peptide-mimicking compound, using amino acid modifications. An example of a peptide-mimicking antibiotic is murepabadin, an outer membrane protein-targeting antibiotic used to treat severe infections associated with Pseudomonas aeruginosa.

[0036] In one embodiment, the antibacterial agent is murepavadin. In one embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject suffering from an infection (e.g., a Pseudomonas aeruginosa infection). The infection is treated by the administration of murepavadin. In one embodiment, a dose of compound I may be administered to the subject before the administration of a dose of murepavadin. Compound I may also be administered throughout the treatment process prescribed using murepavadin.

[0037] In another embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject suffering from an infection (e.g., a bacterial and / or fungal infection). The infection is treated by administering an antimicrobial agent to the subject. In one embodiment, the subject may be administered a dose of compound I before receiving a dose of the antimicrobial agent (e.g., a dose of gentamicin). Compound I may also be administered throughout the course of treatment with the antimicrobial agent, or to a subject who has developed a renal condition or disease following or as a result of exposure to the antimicrobial agent and is receiving treatment with the antimicrobial agent. In this embodiment, the antimicrobial agent is preferably an aminoglycoside antibiotic such as gentamicin.

[0038] In alternative embodiments, the antimicrobial agent is an antifungal agent that is effective against fungal species such as, but not limited to, Aspergillus, Candida, and Cryptococcus, and is used to treat subjects suffering from fungal infections. Examples of antifungal agents include 5-fluorocytosine, amphotericin B, fluconazole, and caspofungin.

[0039] In yet another embodiment, the nephrotoxic active pharmaceutical ingredient is a blood pressure control agent or drug such as an ACE (angiotensin-converting enzyme) inhibitor or an angiotensin receptor antagonist. Compound I or a pharmaceutically acceptable salt thereof may be administered to a subject suffering from hypertension or a condition requiring a reduction in blood pressure, the condition being treated by the administration of the blood pressure control agent or drug to the subject. Examples of ACE inhibitors include, but are not limited to, captopril, ramipril, benazepril, enalapril, fosinopril, lisinopril, and quinapril. Examples of angiotensin receptor antagonists include, but are not limited to, candesartan, valsartan, telmisartan, irbesartan, olmesartan, telmisartan, eprosartan, and losartan.

[0040] In another embodiment, the nephrotoxic active ingredient is a macrocyclic lactone immunosuppressant. These compounds, also known as macrolide immunosuppressants, may be used to prevent or treat conditions or diseases such as organ transplant rejection in organ transplant patients. In one embodiment, the macrocyclic lactone immunosuppressant is an mTor inhibitor such as tacrolimus or sirolimus (rapamycin).

[0041] In another embodiment, the nephrotoxic active pharmaceutical ingredient is an HIV protease inhibitor. Compound I or a pharmaceutically acceptable salt thereof may be administered to a subject diagnosed with or suffering from HIV or an associated condition. The HIV or associated condition is treated by administering an HIV protease inhibitor to the subject. Examples of HIV protease inhibitors include, but are not limited to, indinavir and ritonavir.

[0042] In one embodiment, the nephrotoxic active pharmaceutical ingredient is a peptic ulcer drug or agent. Compound I or a pharmaceutically acceptable salt thereof may be administered to a subject diagnosed with or suffering from an ulcer, such as a gastric ulcer. The ulcer is treated by administering the peptic ulcer drug or agent to the subject. Examples of peptic ulcer drugs include, but are not limited to, cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

[0043] In one embodiment, the nephrotoxic active ingredient is a nonsteroidal anti-inflammatory drug (NAID). Compound I or a pharmaceutically acceptable salt thereof may be administered to a subject suffering from pain, fever, and / or inflammation. The pain, fever, and / or inflammation are treated by administering a nonsteroidal anti-inflammatory drug (NAID) to the subject. Alternatively, Compound I may also be administered to a subject who has taken a large dose of NAID at once. Examples of NAIDs include, but are not limited to, ibuprofen, ketoprofen, diclofenac, and aspirin.

[0044] In one embodiment, the nephrotoxic active ingredient is a laxative. Compound I or a pharmaceutically acceptable salt thereof may be administered to a subject suffering from constipation. The constipation is treated by administering a laxative to the subject. Alternatively, Compound I may also be administered to a subject who has taken a large amount of laxative at once. An example of a laxative in the view of this disclosure is sodium phosphate.

[0045] In yet another embodiment, the nephrotoxic active pharmaceutical ingredient is a contrast agent. The contrast agent is a substance used as a diagnostic tool for visualizing internal organs or tissues. The contrast agent may be administered intravenously. In one specific embodiment, the contrast agent is an iodinated contrast agent, such as diatrizoate, iotalamate, iohexol, iodixanol, or iopamidol, but is not limited to these. Compound I or a pharmaceutically acceptable salt thereof may be used for the prevention or treatment of contrast agent-induced acute kidney injury or nephropathy. Alternatively, this may be administered to a subject under diagnosis, a diagnosed subject, or a subject requiring diagnosis, using a contrast agent such as an iodinated contrast agent.

[0046] In one embodiment, a subject treated with or administered with compound I or a pharmaceutically acceptable salt thereof may be administered a nephrotoxic drug as a therapeutic agent or for in vivo diagnostic purposes. In other embodiments, the subject may be administered two or more nephrotoxic active pharmaceutical ingredients (APIs). For example, a subject treated with or administered with compound I may be administered two or more APIs in conjunction, for example, as concomitant therapy, or alternatively, as separate treatments for different conditions, different manifestations, or symptoms associated with a condition or disease. In one embodiment, a subject administered with compound I may undergo a treatment process with a specific combination of nephrotoxic APIs and optionally a second additional API (e.g., piperacillin / tazobactam), in which case the second additional API is also a nephrotoxic API. In one embodiment, treatment with one nephrotoxic drug may cause or enhance the nephrotoxic risk from another (nephrotoxic) API. In other embodiments, the subject may be administered two or more APIs during the period in which compound I is administered.

[0047] In another embodiment of this disclosure, the nephrotoxin that may induce a renal condition or disease is endogenous nephrotoxin. As defined herein, endogenous nephrotoxin is a molecule or substance (e.g., a protein) that is endogenously produced by the subject. It is not administered externally, in contrast to the nephrotoxic drug agents described above, which may be considered exogenous toxins. Endogenous nephrotoxin may be present in the subject or the subject's blood or serum at non-nephrotoxic concentrations or amounts under standard physiological and homeostatic conditions. However, at elevated levels that are above so-called threshold or baseline concentrations, this concentration is nephrotoxic and may degrade or destroy nephrotoxic components and / or trigger cellular or inflammatory response events that lead to the development of nephrotoxicity and renal tissue damage.

[0048] In one embodiment, the endogenous nephrotoxin is myoglobin, and optionally any destruction, degradation, or release product related to myoglobin. Myoglobin is an oxygen and iron-binding protein found in muscle tissue. High levels of myoglobin and its related components can be directly toxic to renal tubular cells. They can also cause renal vasoconstriction and tubular cast formation, among other pathological conditions.

[0049] Rhabdomyolysis is a condition characterized by injury or destruction of skeletal muscle tissue, whose contents are released into the circulation. The release of high levels of myoglobin is also associated with the related condition myoglobinuria. Other conditions in which endogenous cellular components can be nephrotoxic include, but are not limited to, hemolysis (the lysis of red blood cells, in which the contents of damaged red blood cells (e.g., heme iron) are released into the circulation), as well as conditions such as oncolysis or myeloma. Tumors in cancer patients can lyse (e.g., during chemotherapy), releasing tumor cell contents into the circulation and into the kidneys.

[0050] In particular, subjects may be susceptible to rhabdomyolysis, or are at risk of developing rhabdomyolysis and related conditions, and are at risk of exposure to endogenous nephrotoxins such as myoglobin due to a number of factors, especially physical activity or trauma. In one embodiment, compound I or a pharmaceutically acceptable salt thereof is used to prevent and / or treat renal conditions or diseases induced by exposure to endogenous nephrotoxins (e.g., rhabdomyolysis-induced acute kidney injury or myoglobinuria-induced acute kidney injury) and is administered to subjects who have experienced or suffered from any one or a combination of other activities or events that may cause physical trauma, crush trauma, extreme physical exercise or activity, exposure to extreme temperatures or electric currents, and damage to muscle tissue and destruction of muscle fibers and / or blood cells.

[0051] In further relevant embodiments, compound I or a pharmaceutically acceptable salt thereof may be administered to a subject before exposure to or before engaging in activities associated with or at risk of developing rhabdomyolysis (e.g., extreme physical activity or exercise). Extreme or physical activity or exercise may be, for example, strenuous exercise that causes or results in skeletal muscle injury and optionally severe dehydration.

[0052] Subjects at risk of developing rhabdomyolysis include those exposed to toxins or active pharmaceutical ingredients, such as statins, that cause or may cause muscle damage. Optionally, compound I or a pharmaceutically acceptable salt thereof may also be used to prevent or treat rhabdomyolysis and related conditions or diseases in subjects with hereditary myopathy.

[0053] In another embodiment, compound I or a pharmaceutically acceptable salt thereof is provided for use in the prevention and / or treatment of rhabdomyolytic hemolysis, myoglobinuria, or optionally oncolysis or myeloma-induced acute kidney injury or myeloma-induced acute renal failure.

[0054] In relevant embodiments, subjects to whom compound I or a pharmaceutically acceptable salt thereof may be administered may have elevated serum and / or urinary myoglobin levels, i.e., elevated concentrations of myoglobin in serum and / or urine. Alternatively or in addition, the subjects may also have elevated serum levels indicating the presence of muscle injury, i.e., elevated serum concentrations of any one of creatine phosphokinase, lactate dehydrogenase, calcium, potassium, and phosphate, or a combination thereof. In further relevant embodiments, subjects to whom compound I or a pharmaceutically acceptable salt thereof is provided may have serum creatine phosphokinase levels at least 5 times higher than baseline.

[0055] Where defined herein, the term “baseline” as used in relation to serum creatine phosphokinase levels refers to a medically applicable or expected serum creatine phosphokinase level or range, or a nephrotoxicity level or concentration of endogenous nephrotoxin, such as myoglobin, for an individual who has not yet been exposed to nephrotoxin at that time. This includes variations that may result from one or a combination of criteria, such as, but not limited to, age group, sex, and the presence of complications. The baseline value or baseline range of serum creatine phosphokinase, or any other marker, may be determined by the knowledge of a person skilled in the art or by common methods of the art.

[0056] As used herein, the terms “treating” or “treatment,” which may be used interchangeably with the term “therapy,” refer to therapeutic interventions that can achieve the cure, improvement, relief, control, control of progression, or prevention of progression of a disease or condition or symptoms associated with such disease or condition.

[0057] As understood herein, the term "prevention," which may be used interchangeably with the term "protection," refers to the use of a compound or composition for the purpose of preventing the onset of a disease, condition or symptom, or for significantly reducing the likelihood of the onset of a disease, condition or symptom, and also for the purpose of preventing further recurrence of, for example, the disease, condition or associated symptom. The prevention of progression of a disease, condition or associated symptom after the initial improvement of the disease, condition or symptom, or after the initial removal of the cause of the disease, condition or symptom, is also included within the scope of this term.

[0058] It can also be understood that any one or a combination of the treatments or defenses described herein involves the administration of a pharmacologically effective amount of Compound I to the subject in need. A pharmacologically effective amount refers to the quantity, dose, concentration, or intensity of the compound or compound equivalent that is useful for, produces, or contributes to, a desired therapeutically appropriate pharmacological effect and / or a prophylactically appropriate pharmacological effect.

[0059] In one embodiment, the nephrotoxic drug substance is administered repeatedly to the subject. In other words, the drug substance is administered two or more times, i.e., at least twice. The nephrotoxic drug substance may be administered at regular intervals over a predetermined period, for example, over the course of a clinically determined treatment period. In some embodiments, the nephrotoxic drug substance may be administered at least once a day for a period of at least 3 days, or at least 7 days. Or it may be administered at least once a day for 7 to 10 days. In an alternative embodiment, the nephrotoxic drug substance may be administered once, for example, for diagnostic purposes.

[0060] Compound I or a pharmaceutically acceptable salt thereof may be used for the prevention and / or treatment of renal conditions or diseases in subjects induced by nephrotoxic drug substances or endogenous nephrotoxins. In preferred embodiments, the renal condition or disease is nephrotoxin-induced acute kidney injury or renal failure. In one embodiment, the induced acute kidney injury is prerenal acute kidney injury and is associated, for example, with reduced blood flow to the kidney. For example, ACE inhibitors and angiotensin receptor blockers can impair renal perfusion. NAIDs can also reduce glomerular filtration rate. In further embodiments, the induced acute kidney injury is endogenous and involves damage to cells or tissues of the kidney, including glomeruli, tubules (acute tubular injury or necrosis), interstitium and / or vascular structures. Acute tubular injury or necrosis may result, for example, from the accumulation or localization of cytotoxic drug substances in tubular cells.

[0061] As understood herein, the term “subject” may be used interchangeably with the term “patient.” In one preferred embodiment, the subject is a human subject. In any embodiment, the subject may be other animals, such as other mammals. In any embodiment, the present invention may also apply to, for example, livestock or other veterinary subjects, particularly mammals such as cats, dogs, primates, horses, cattle, and pigs.

[0062] In one embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject with a pre-existing condition or disease that increases the risk of the subject developing renal condition or disease upon exposure to nephrotoxin as defined herein. For example, the subject may have a pre-existing condition or comorbidity, such as pre-existing dysfunction or impairment, in an organ such as the lungs (e.g., chronic obstructive pulmonary obstruction), liver (e.g., chronic liver disease), or heart (e.g., coronary artery disease, or heart failure), and / or the subject may have recently undergone major surgery related to such organ. In a further embodiment, the subject is elderly and / or has diabetes.

[0063] In further embodiments, subjects may also have pre-existing renal conditions such as chronic kidney disease, polycystic kidney disease, kidney stones, or nephritis. Optionally, subjects may have a history of renal impairment and / or require dialysis.

[0064] In a further embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject with impaired renal function. Impaired renal function may be characterized by any one or a combination thereof of a blood urea nitrogen (BUN) level at least 1.5 to 3 times higher than baseline, and / or a serum creatinine level at least 1.5 to 3 times higher than approximately baseline, and / or oliguria. In one embodiment, the subject has impaired renal function characterized by serum creatinine and BUN levels at least 2 times higher than baseline.

[0065] Where defined herein, the term “baseline” used in relation to serum levels (i.e., serum creatinine concentration) and / or blood urea nitrogen (BUN) levels (i.e., blood urea nitrogen concentration) may refer to baseline values ​​of these renal function markers determined for a subject before the initiation of exposure to a nephrotoxic drug (e.g., before a treatment regimen including administration of a nephrotoxic drug). In situations where a subject did not have serum creatinine or BUN levels measured before exposure to nephrotoxin and before the onset of renal impairment, the term “baseline” may refer to medically applicable or expected serum creatine and / or blood urea nitrogen values, or ranges thereof, for an individual that has not yet been exposed to nephrotoxin at that time. This factorizes variations that may result from criteria such as, for example, age group, sex, and the presence of complications. These baseline values ​​or ranges thereof may be within the scope of knowledge of those skilled in the art and / or determined within the scope of common methods in the art.

[0066] Compound I or a pharmaceutically acceptable salt thereof may, in one embodiment, be administered to the subject before exposure to the nephrotoxic drug. Administration of compound I before exposure means, as understood herein, the administration of the first dose of compound I before the administration of the first dose of the nephrotoxic drug.

[0067] Furthermore, in some embodiments, a dose of compound I or a pharmaceutically acceptable salt thereof may be administered before any dose of the nephrotoxic drug substance (API) is administered, for example, two or more times during the prescribed course of treatment, if the API is administered repeatedly. Thus, the total dose of compound I may be administered during the period between consecutive doses of the nephrotoxic drug substance. Optionally, two or more doses of compound I may be administered during the period between consecutive doses of the nephrotoxic drug substance.

[0068] In one embodiment, the Disclosure provides Compound I or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a renal condition or disease (e.g., acute kidney injury) induced by a nephrotoxic drug as defined herein. In this case, Compound I or a pharmaceutically acceptable salt thereof is administered repeatedly to the subject during a first period which is initiated before a second period and overlaps therewith, and the subject is repeatedly exposed to or administered the nephrotoxic drug. As used herein, “repeated” means at least two (i.e., two or more) doses or exposures. The period may be understood as a medically determined course or duration of treatment, for example, therapeutically relevant with respect to the pharmacological effect intended with respect to the prevention, stabilization, treatment or management of a condition, disorder or disease.

[0069] As used herein, the terms “dose” or “administered dose” themselves refer to a single dose or unit dose of Compound I or a pharmaceutically acceptable salt thereof, or the active pharmaceutical ingredient, unless a time, time interval, or time amount is explicitly indicated or follows. For example, “daily dose” or “daily dosage” refers to the total amount of Compound I or the active pharmaceutical ingredient administered over a 24-hour period. A single dose may be administered once per day, but this may be a total amount based on the sum of multiple unit doses administered during the day (for example, if two or more unit doses are administered at two or more time intervals during the day). The interval between doses may be, for example, two doses administered approximately 12 hours apart, or three doses administered approximately 8 hours apart. As used herein, the dose of Compound I also refers to a unit dose of Compound I or a pharmaceutically acceptable salt thereof. However, this may apply to a drug, composition, or dosage form containing such unit dose of compound I or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, a dose of compound I or a pharmaceutically acceptable salt thereof is administered to the subject within 24 hours prior to the administration of a dose of the nephrotoxic drug substance. In a further embodiment, a dose of compound I is administered to the subject within a range of approximately 6 hours or less, and optionally within a range of approximately 2 hours or less, prior to the administration of the nephrotoxic drug substance.

[0071] In specific embodiments, compound I or a pharmaceutically acceptable salt thereof is administered to the subject within a range of 24 hours or less, or within a range of about 6 hours or less, prior to the administration of a dose of an aminoglycoside (e.g., gentamicin) to the subject.

[0072] In another embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject after the onset of renal impairment. The onset of renal impairment may be characterized by elevated serum creatinine levels and / or blood urea nitrogen (BUN) levels and / or oliguria levels, among other physiological markers. In one embodiment, the onset of renal impairment may be characterized by blood urea nitrogen levels at least 1.5 to 3 times higher than baseline and / or serum creatinine levels at least 1.5 to 3 times higher than baseline and / or oliguria. In one embodiment, the subject has renal impairment characterized by serum creatinine and BUN levels at least 2 times higher than baseline.

[0073] In one embodiment, the onset of renal dysfunction may be due to exposure to a nephrotoxic drug. For example, a subject may suddenly develop renal impairment or dysfunction during treatment with a nephrotoxic drug, resulting from the accumulation of the nephrotoxic drug (e.g., blood concentration or localization to specific renal cells or tissues), i.e., exposure to a cumulative dose of the nephrotoxic drug. Comorbidities with diseases or conditions that develop or worsen during treatment with a nephrotoxic drug may contribute to the development of renal dysfunction leading to acute kidney injury. In other embodiments, the onset of renal dysfunction may be due to exposure to endogenous nephrotoxin, as described, for example, under any one of the embodiments described above and any of the conditions leading to the accumulation of endogenous nephrotoxin.

[0074] In one embodiment, a dose of compound I or a pharmaceutically acceptable salt thereof, or a drug or pharmaceutical composition containing a dose of compound I or a pharmaceutically acceptable salt thereof, is administered to a subject approximately 1 to 24 hours, optionally approximately 1 to 6 hours, after the onset of renal impairment characterized by, for example, a blood urea nitrogen level at least 1.5 to 3 times higher than baseline, and / or a serum creatinine level at least 1.5 to 3 times higher than baseline, and / or oliguria level. In another embodiment, compound I is administered to a subject approximately 1 to 24 hours, optionally approximately 1 to 6 hours, after the onset of renal impairment characterized by renal impairment characterized by blood urea nitrogen levels and serum creatinine levels at least 2 times higher than baseline.

[0075] In another embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to a subject, preferably in a dose of about 0.001 to 5 mg / kg, or in a dose of about 0.001 to 10 mg / kg to a human subject. Optionally, compound I may be administered to a subject, preferably in a dose of about 0.1 to 5 mg / kg, or in a dose of about 0.1 to 10 mg / kg to a human subject. The dose refers to a single dose. A single dose may be administered two or more times during the course of treatment. Where described herein with respect to any pharmaceutically acceptable salt of compound I, the dose refers to an equivalent of compound I. A single dose of compound I may further be provided in a pharmaceutically acceptable dosage form and administered to the subject by administering a composition or agent containing a dose of compound I.

[0076] As used herein, the term “about” or its equivalent, relating to attributes or values ​​such as dosage, includes the exact attribute or exact value, any attribute or value that is typically considered to be within the range of standard or acceptable variation relevant to the art, and the method for measuring or determining such attribute or value. This term allows for any variation that, in common practice, enables the product being evaluated to be considered biologically equivalent in mammals to the described strength or dose of the claimed product.

[0077] In a further embodiment, the Disclosure provides Compound I or a pharmaceutically acceptable salt thereof for use in preventing and / or reducing serum urea nitrogen levels and / or serum creatinine levels that are at least 1.5 to 3 times higher than baseline in subjects exposed to nephrotoxins, such as nephrotoxic drug agents or endogenous nephrotoxins, as defined in any one of the embodiments or combinations of embodiments described above.

[0078] In further embodiments, compound I or a pharmaceutically acceptable salt thereof is used in subjects exposed to nephrotoxin to prevent or reduce blood urea nitrogen levels and serum creatinine levels that are at least 2 times higher than baseline, in which case nephrotoxin is a nephrotoxic active pharmaceutical ingredient (e.g., gentamicin, or any one or a combination thereof of the substances described herein). In even further embodiments, compound I or a pharmaceutically acceptable salt thereof is used in subjects exposed to nephrotoxin to prevent and / or reduce blood urea nitrogen levels and serum creatinine levels that are at least 1.5 to 3 times higher than baseline, in which case nephrotoxin is an aminoglycoside antibiotic, preferably gentamicin.

[0079] In another embodiment, compound I or a pharmaceutically acceptable salt thereof is used to reduce blood urea nitrogen levels and / or serum creatinine levels in subjects exposed to nephrotoxic drug substances (e.g., gentamicin) or endogenous nephrotoxin, optionally in which case the blood urea nitrogen levels and / or serum creatinine levels are reduced after administration of a dose, for example, an initial dose of compound I. The reduction in BUN and serum creatinine may be determined before and after administration of a dose of compound I (e.g., an initial dose) by comparing measured BUN and serum creatinine values ​​using methods established in the art.

[0080] The use of Compound I or a pharmaceutically acceptable salt thereof, and methods of treatment or prevention as described in any one of the embodiments herein, are provided in terms of this disclosure for the manufacture or preparation of a prescribed agent or drug that is compatible with such use or method of treatment or prevention.

[0081] A pharmaceutically acceptable salt of compound I is one that retains its biological properties, is non-toxic, and is suitable for pharmaceutical use. The salts of the present invention can be produced by adding an acid to compound I. Examples of acid addition salts obtained include acetic acid, 2,2-dichloroacetic acid, citric acid, lactic acid, mandelic acid, glycolic acid, adipic acid, alginic acid, aryl sulfonic acid (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, and 4-acetamide benzoic acid. Camphor acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (for example, D-gluc). Conic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), (±)-DL-mandelic acid, metaphosphate, methane Examples include those formed from sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid. In particular, examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid; and organic acids such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, and arylsulfonic acid.

[0082] Compound I or a pharmaceutically acceptable salt thereof may be administered to a subject enterally or parenterally. In one embodiment, Compound I, or a composition or agent containing Compound I, is administered parenterally, for example, by intravenous injection, subcutaneous or intramuscular injection, or intravenous or subcutaneous infusion. In an alternative embodiment, Compound I, or a composition or agent containing Compound I, is administered enterally, for example, by oral administration.

[0083] The present invention may also relate to a drug or pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof in any one or a combination thereof from the embodiments described herein, and one or more pharmaceutically acceptable excipients. The drug or pharmaceutical composition comprising compound I may be formulated into a dosage form suitable or adapted for injection or intravenous infusion by any of the above-described administration methods. Alternatively, for oral administration, the drug or pharmaceutical composition comprising compound I may be provided in a dosage form suitable or adapted for oral administration, such as, but not limited to, tablets, capsules, gelatinous capsules, or films. The drug or pharmaceutical composition may be used according to any of the treatment or prevention methods or uses described herein.

[0084] In one embodiment, compound I is formulated in a dosage form suitable for or compatible with injection or intravenous infusion, but the formulation may be provided in the form of a clear solution, or as a lyophilized or freeze-dried powder, from which the clear solution may be re-prepared (i.e., formulated for re-preparation) in a suitable solvent or solution. In one embodiment, the re-prepared solvent may contain a solubilizer and / or surfactant. In a specific embodiment, the re-prepared solution contains a polysorbate, for example, polysorbate 80 or Tween 80. Further optionally, the solvent has a pH of 3.5 to 4.5, or 4.2 to 4.5. In another embodiment, the drug or pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof may further contain a polysorbate. In one embodiment, the composition is a clear aqueous solution having a pH of 3.5 to 4.5. In another embodiment, the solution has a pH of 4.2 to 4.5. In yet another embodiment, the composition comprising compound I or a salt thereof further comprises polysorbate and optionally one or more further excipients. For example, in this case the excipients are an acid (e.g., an organic acid) and / or one or more buffers. The polysorbate (e.g., polyoxyethylene sorbitan monoester) is, in one embodiment, polysorbate 80 or Tween 80 (polyoxyethylene sorbitan monooleate). In one embodiment, the composition comprises or consists of an effective amount of compound I or an effective amount of its salt, polysorbate, acetic acid, and an acetate salt (e.g., sodium acetate).

[0085] In another embodiment, compound I is formulated with a suitable acid. For example, compound I may be formulated from an acid selected from succinic acid, L-malic acid, or phosphoric acid. In a further embodiment, the composition comprising compound I may further comprise a solubilizer and / or a surfactant such as polyethylene glycol, such as PEG-400, or a polysorbate, such as Tween 80. In one specific embodiment, the composition comprising compound I may further comprise an acid such as succinic acid, L-malic acid, phosphoric acid, or acetic acid, and a surfactant and / or a solubilizer such as polyethylene glycol, such as PEG-400, or a polysorbate, such as Tween 80. In one embodiment, the composition may be suitable or adapted for bolus injection and may be provided in the form of a clear aqueous solution having a pH between 5.4 and 5.6.

[0086] Compositions suitable for injection or intravenous infusion are generally in the form of a solution, meaning that the formulation components, including the active ingredient, must be completely dissolved or solubilized. The formation or presence of a micelle phase of any one of the components or the active ingredient, or the formation or presence of any kind of phase separation, is undesirable in terms of administration, or optionally when the composition is stored as a solution during storage. In one embodiment, the composition comprising compound I or a salt thereof according to this disclosure, as described herein, is in the form of a clear solution. Preferably, the solution composition is in the form of a clear solution that is stable for at least 1 hour or at least 15 hours, for example, at room temperature (or under refrigeration, such as 0°C). The stability of the solution may be determined, for example, by visual inspection (e.g., phase separation or other visible changes), or optionally based on turbidity detector measurement.

[0087] Optionally, a pharmaceutical composition containing the drug or compound I or a pharmaceutically acceptable salt thereof may further contain an active pharmaceutical ingredient, such as a nephrotoxic active pharmaceutical ingredient. That is, compound I may be co-formulated as a dosage form with a nephrotoxic active pharmaceutical ingredient, such as a single composition or as defined herein. Optionally, compound I may be provided in a pharmaceutical composition further containing gentamicin.

[0088] In further embodiments, the present invention also relates to a kit comprising a composition comprising compound I or a pharmaceutically acceptable salt thereof, a composition comprising a nephrotoxic active pharmaceutical ingredient as described in any one embodiment herein, and optionally a kit comprising instructions for the administration of compound I or a salt thereof as described in any one of the methods or uses herein. Optionally, the kit may also comprise a composition comprising compound I or a pharmaceutically acceptable salt thereof, and a nephrotoxic active pharmaceutical ingredient as described in any one embodiment herein, such as gentamicin.

[0089] The following list of numbered items are embodiments included in this disclosure:

[0090] 1. The use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention and / or treatment of a nephrotoxin that can induce a renal condition or disease in a subject exposed to such nephrotoxin, JPEG2026102838000004.jpg89145 Compound I This nephrotoxin is a nephrotoxic active ingredient or endogenous nephrotoxin, and is used.

[0091] 2. Nephrotoxic active pharmaceutical ingredients are selected from the group consisting of antibacterial agents, cancer chemotherapy agents, antihypertensive drugs including ACE inhibitors and angiotensin receptor antagonists, macrocyclic lactone immunosuppressants, HIV protease inhibitors, peptic ulcer drugs, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, laxatives, and contrast agents, as described in item 1.

[0092] 3. The chemotherapy agent is selected from the group consisting of platinum (e.g., carboplatin, cisplatin, oxaliplatin, or nedaplatin), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin), bleomycin, mitomycin, actinomycin, cyclophosphamide, cytarabine, capecitabine, gemcitabine, ifosfamide, interleukin-2, streptozocin, gemtuzumab ozogamicin, melphalan, methotrexate, pemetrexed, pricamycin, and trimethrexate, for use as described in item 2.

[0093] 4. Use as described in item 3, where the subject is undergoing cancer treatment, and said cancer treatment includes the administration of chemotherapy drugs to the subject.

[0094] 5. Antimicrobial agents are selected from the group consisting of aminoglycosides (e.g., gentamicin, tobramycin, amikacin, netylmycin, apramycin, streptomycin, kanamycin, neomycin, shisomycin), β-lactams (e.g., tazobactam, or piperacillin / tazobactam), polypeptide antibiotics (e.g., polymyxins (colistin) such as polymyxin A, B, C, D, E), glycopeptide antibiotics (e.g., vancomycin), outer membrane protein-targeting antibiotics (e.g., murepavadin), antifungal agents (e.g., amphotericin B), and combinations thereof, as described in item 2.

[0095] 6. Use of the antibiotic gentamicin as described in item 5.

[0096] 7. Use of the antibiotic murepabadin as described in item 5.

[0097] 8. Use as described in any one of items 5-7, where the subject has an infectious disease and the infectious disease is treated by administering an antibiotic to the subject.

[0098] 9. Use as described in item 2, where the blood pressure drug is an ACE inhibitor, optionally selected from the group consisting of captopril, benazepril, enalapril, fosinopril, and ramipril, or an angiotensin receptor antagonist, optionally selected from the group consisting of candesartan, valsartan, irbesartan, olmesartan, telmisartan, eprosartan, and losartan.

[0099] 10. Use as described in item 2, wherein the HIV protease inhibitor is selected from the group consisting of indinavir and ritonavir.

[0100] 11. Use as described in item 2, wherein the peptic ulcer drug is selected from the group consisting of cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

[0101] 12. Use as described in item 2, wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, and aspirin.

[0102] 13. Use as described in item 2, when the laxative is selected from sodium phosphate.

[0103] 14. Use as described in item 2, where the nephrotoxic active pharmaceutical ingredient is a contrast agent, and optionally an iodized contrast agent (e.g., iotalamate, or iodixanol, or iohexanol).

[0104] 15. Endogenous nephrotoxin is myoglobin, use as described in item 1.

[0105] 16. Use as described in item 15, in which the subject has serum creatine phosphokinase levels at least 5 times higher than baseline.

[0106] 17. Use as described in either item 15 or 16, where the subject has experienced or is suffering from physical trauma or crush trauma, exposure to electric current, extreme physical exercise or activity, and extreme temperatures.

[0107] 18. The use described in any one of items 1 to 17, in which the drug is administered to the subject before exposure to or before engaging in activities associated with rhabdomyolysis or activities that pose a risk of developing rhabdomyolysis (e.g., extreme physical activity).

[0108] 19. Use of any one of items 1 to 18, in which a nephrotoxic active pharmaceutical ingredient is repeatedly administered to the subject.

[0109] 20. The use described in item 19, wherein the nephrotoxic active pharmaceutical ingredient is administered at least twice over a period of at least 3 days or 7 days, and optionally at least once a day.

[0110] 21. Use as described in any one of items 1 to 20, where the renal condition or disease is nephrotoxin-induced acute kidney injury or renal failure, the renal condition or disease is aminoglycoside-induced acute kidney injury such as gentamicin-induced acute kidney injury, or the renal condition or disease is cisplatin-induced acute kidney injury.

[0111] 22. Use as described in any one of items 1 to 21, where the renal condition or disease is selected from rhabdomyolysis, hemolysis, myoglobinuria, or optionally from oncolysis or myeloma-induced acute kidney injury.

[0112] 23. Use as described in any one of items 1 to 22, where the subject has a pre-existing condition or disease that increases the risk of the subject developing renal condition or disease upon exposure to nephrotoxin.

[0113] 24. Use as described in item 23, where the subject has a pre-existing renal condition or disease, and optionally, the pre-existing renal condition is chronic kidney disease, and optionally, the subject has a history of renal dysfunction or requires dialysis.

[0114] 25. Use as described in item 23 or 24, where the subject has impaired renal function, and optionally, the subject has a serum urea nitrogen level at least 1.5 to 3 times higher than baseline, and / or a serum creatinine level at least 1.5 to 3 times higher than baseline, and / or oliguria.

[0115] 26. Use as described in any one of items 1 to 25, in which the drug is administered to the subject before the subject's exposure to the nephrotoxic active pharmaceutical ingredient.

[0116] 27. Use as described in any one of items 1 to 26, in which a certain dose of the drug is administered to the subject within a period of 24 hours or less before a dose of the nephrotoxic drug substance is administered to the subject.

[0117] 28. Use as described in item 27, where the drug dose is administered to the subject within a timeframe of approximately 6 hours or less, or optionally within a timeframe of approximately 2 hours or less, prior to the administration of the nephrotoxic drug substance to the subject.

[0118] 29. Uses described in any one of items 1 to 28, in which the drug is administered to a subject after the onset of renal impairment, characterized by one or a combination of the following: a serum urea nitrogen level at least 1.5 to 3 times higher than baseline, a serum creatinine level at least 1.5 to 3 times higher than baseline, and oliguria.

[0119] 30. The drug is administered to the patient 1 to 24 hours after the onset of renal dysfunction, or optionally 1 to 6 hours, as described in item 29.

[0120] 31. Use as described in any one of items 1 to 30, in which the drug is administered repeatedly to the subject during the first period, which overlaps with the second period, and the subject is repeatedly exposed to the nephrotoxic active pharmaceutical ingredient.

[0121] 32. Use of the drug as described in any one of items 1 to 31, where the drug is administered to the subject at a dose of approximately 0.001 to 10 mg / kg, or optionally at a dose of approximately 0.1 to 10 mg / kg.

[0122] 33. Use described in any one of items 1 to 32, where the subject is a human subject.

[0123] 34. The use described in any one of items 1 to 33, wherein the drug is formulated for administration by intravenous infusion or injection, preferably parenteral injection, intramuscular injection, or intravenous infusion or parenteral infusion.

[0124] 35. Use of compound I as defined in item 1 or a pharmaceutically acceptable salt thereof in the manufacture of agents for the prevention and / or reduction of blood urea nitrogen levels and / or serum creatinine levels that are at least 1.5 to 3 times higher than baseline in subjects exposed to nephrotoxin.

[0125] 36. The use of nephrotoxin as defined in any one of items 1-3, 5-7, or 9-15, and optionally, the subject exposed to the nephrotoxin has a renal condition or disease induced by exposure to the nephrotoxin, for example, a renal condition or disease as defined in either item 21 or 22, as described in item 35.

[0126] 37. Uses described in item 35 or 36, where the subject is defined in any one of items 1, 4, 8, 16-17, 23-25, or 33.

[0127] 38. The use of the drug as defined in any one of items 18-22 or 26-32, as described in any one of items 35-37.

[0128] 39. The use described in any one of items 35 to 38, wherein the drug is formulated for administration by injection or infusion, preferably by intravenous injection or intravenous infusion.

[0129] 40. Compound I or a pharmaceutically acceptable salt thereof for use in subjects exposed to nephrotoxin, which can induce renal condition or disease, in the prevention and / or treatment of renal condition or disease. JPEG2026102838000005.jpg89145Compound I A compound or pharmaceutically acceptable salt thereof in which this nephrotoxin is a nephrotoxic active ingredient or endogenous nephrotoxin.

[0130] 41. Nephrotoxic active pharmaceutical ingredients are compounds for use as described in item 40, selected from the group consisting of antibacterial agents, cancer chemotherapy agents, antihypertensive drugs including ACE inhibitors and angiotensin receptor antagonists, macrocyclic lactone immunosuppressants, HIV protease inhibitors, peptic ulcer agents, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, laxatives, and contrast agents.

[0131] 42. The chemotherapeutic agent is a compound for use as described in item 41, selected from the group consisting of platinum (e.g., carboplatin, cisplatin, oxaliplatin, or nedaplatin), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin), bleomycin, mitomycin, actinomycin, cyclophosphamide, capecitabine, cytarabine, gemcitabine, ifosfamide, interleukin-2, streptozocin, gemtuzumab ozogamicin, melphalan, methotrexate, pemetrexed, pricamycin, and trimethrexate.

[0132] 43. Compounds for use as described in item 42, in which the subject is undergoing cancer treatment, and said cancer treatment includes the administration of chemotherapy drugs to the subject.

[0133] 44. Antimicrobial agents are compounds for use as described in item 41, selected from the group consisting of aminoglycosides (e.g., gentamicin, tobramycin, amikacin, netylmycin, apramycin, streptomycin, kanamycin, neomycin, shisomecin), β-lactams (e.g., tazobactam, or piperacillin / tazobactam), polypeptide antibiotics (e.g., polymyxins (colistin) such as polymyxin A, B, C, D, E), glycopeptide antibiotics (e.g., vancomycin), outer membrane protein-targeting antibiotics (e.g., murepavadin), antifungal agents (e.g., amphotericin B), and combinations thereof.

[0134] 45. The antibacterial agent is an aminoglycoside antibiotic, preferably gentamicin, the compound for use as described in item 44.

[0135] 46. ​​The antimicrobial agent is murepabadin, a compound for use as described in item 44.

[0136] 47. A compound for use as described in any one of items 44-46, wherein the subject has an infectious disease, and the infectious disease is treated by administering an antimicrobial agent to the subject.

[0137] 48. A compound for use as described in item 41, wherein the blood pressure drug is an ACE inhibitor, optionally selected from the group consisting of captopril, benazepril, enalapril, fosinopril, and ramipril, or an angiotensin receptor antagonist, optionally selected from the group consisting of candesartan, valsartan, irbesartan, olmesartan, telmisartan, eprosartan, and losartan.

[0138] 49. A compound for use as described in item 41, wherein the HIV protease inhibitor is selected from the group consisting of indinavir and ritonavir.

[0139] 50. A compound for use as described in item 41, wherein the peptic ulcer agent is selected from the group consisting of cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

[0140] 51. A compound for use as described in item 41, wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, and aspirin.

[0141] 52. A laxative compound selected from sodium phosphate for use as described in item 41.

[0142] 53. Compounds for use as described in item 41, wherein the nephrotoxic active ingredient is a contrast agent, optionally an iodized contrast agent (e.g., iotalamate, or iodixanol, or iohexanol).

[0143] 54. Endogenous nephrotoxin is myoglobin, a compound for use as described in item 40.

[0144] 55. The compound for use described in item 54, wherein the subject has serum creatine phosphokinase levels at least 5 times higher than baseline.

[0145] 56. Compounds for use as described in either item 54 or 55, in which the subject has experienced or is suffering from physical trauma or crush trauma, exposure to electric current, extreme physical exercise or activity, and extreme temperature.

[0146] 57. A compound for use as described in any one of items 40-56, administered to a subject before exposure to or before engaging in activities associated with rhabdomyolysis or activities that pose a risk of developing rhabdomyolysis (e.g., extreme physical activity).

[0147] 58. A compound for use described in any one of items 40-57, in which a nephrotoxic active pharmaceutical ingredient is administered repeatedly to the subject.

[0148] 59. The compound for use as described in item 58, wherein the nephrotoxic active pharmaceutical ingredient is administered at least twice, optionally at least once daily, over a period of at least 3 or 7 days.

[0149] 60. Compounds for use as described in any one of items 40-59, for which the renal condition or disease is nephrotoxin-induced acute kidney injury or renal failure.

[0150] 61. Compounds for use as described in any one of items 40 to 60, wherein the renal condition or disease is selected from rhabdomyolysis, hemolysis, myoglobinuria, or optionally from oncolysis or myeloma-induced acute kidney injury.

[0151] 62. A compound for use according to either item 60 or 61, wherein the renal condition or disease is aminoglycoside-induced acute kidney injury, preferably gentamicin-induced acute kidney injury.

[0152] 63. Compounds for use as described in any one of items 40-60, for which the renal condition or disease is cisplatin-induced acute kidney injury.

[0153] 64. A compound for use as described in any one of items 40 to 63, in which the subject has a pre-existing condition or disease that increases the risk of the subject developing renal condition or disease upon exposure to nephrotoxin.

[0154] 65. Compounds for use as described in item 64, in which the subject has a pre-existing renal condition or disease, optionally, the pre-existing renal condition is chronic kidney disease, and optionally, the subject has a history of renal dysfunction or requires dialysis.

[0155] 66. The subject has impaired renal function, and optionally, the subject has one or a combination of the following: a serum urea nitrogen level at least 1.5 to 3 times higher than baseline, a serum creatinine level at least 1.5 to 3 times higher than baseline, or oliguria, and the compound for use as described in item 64 or 65.

[0156] 67. A compound for use as described in any one of items 40 to 66, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject prior to the subject's exposure to a nephrotoxic active pharmaceutical ingredient.

[0157] 68. A dose of Compound I or a pharmaceutically acceptable salt thereof is administered to the subject within 24 hours prior to the administration of a dose of the nephrotoxic active pharmaceutical ingredient to the subject, as described in any one of items 40 to 67.

[0158] 69. The compound for use as described in item 68, wherein a dose of compound I or a pharmaceutically acceptable salt thereof is administered to the subject within a period of approximately 6 hours or less, and optionally within a period of approximately 2 hours or less, prior to the administration of the nephrotoxic active pharmaceutical ingredient to the subject.

[0159] 70. A compound for use as described in any one of items 40-69, which is administered to a subject after the onset of renal impairment, characterized by a serum urea nitrogen level at least 1.5-3 times higher than baseline, a serum creatinine level at least 1.5-3 times higher than baseline, and oliguria, or a combination thereof.

[0160] 71. Compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject 1 to 24 hours, optionally 1 to 6 hours, after the onset of renal impairment as defined in item 70, for use as described in item 70.

[0161] 72. A compound for use as described in any one of items 40 to 71, wherein the compound is administered repeatedly to the subject during the first period, which is initiated before the second period and overlaps therewith, and the subject is repeatedly exposed to the nephrotoxic active pharmaceutical ingredient.

[0162] 73. A compound for use as described in any one of items 40 to 72, in which the compound is administered to the subject at a dose of approximately 0.001 to 10 mg / kg, or optionally at a dose of approximately 0.1 to 10 mg / kg.

[0163] 74. Compounds for use as described in any one of items 40-73, for which the subject is human.

[0164] 75. A compound for use as described in any one of items 40 to 74, which is formulated for administration by intravenous infusion or injection, preferably parenteral injection, intramuscular injection, or intravenous infusion or parenteral infusion.

[0165] 76. Compound I as defined in item 40 or a pharmaceutically acceptable salt thereof for use in the prevention and / or reduction of blood urea nitrogen levels and / or serum creatinine levels that are at least 1.5 to 3 times higher than baseline in subjects exposed to nephrotoxin.

[0166] 77. Nephrotoxin is as defined in any one of items 40-42, 44-46, or 48-54, and optionally, a compound for use as described in item 76, wherein the subject exposed to the nephrotoxin has a renal condition or disease induced by exposure to the nephrotoxin, for example, a renal condition or disease as defined in any one of items 60-63.

[0167] 78. Compounds for use as described in item 76 or 77, the subject being defined in any one of items 43, 47, 55-56, 64-66, or 74.

[0168] 79. A compound for use as described in any one of items 76-78, wherein the compound or a pharmaceutically acceptable salt thereof is administered as defined in any one of items 57-59 or 67-73.

[0169] 80. A compound for use as described in any one of items 76-79, which is administered by injection or infusion, preferably by intravenous injection or infusion.

[0170] 81. A method for preventing and / or treating a renal condition or disease in a subject exposed to a nephrotoxin capable of inducing such renal condition or disease, wherein the nephrotoxin is a nephrotoxic active pharmaceutical ingredient or endogenous nephrotoxin, and the method comprises administering compound I or a pharmaceutically acceptable salt thereof to the subject. JPEG2026102838000006.jpg89145Compound I

[0171] 82. The nephrotoxic active pharmaceutical ingredient is selected from the group consisting of antibacterial agents, cancer chemotherapy agents, antihypertensive drugs including ACE inhibitors and angiotensin receptor antagonists, macrocyclic lactone immunosuppressants, HIV protease inhibitors, peptic ulcer drugs, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, laxatives, and contrast agents, as described in item 81.

[0172] 83. The method according to item 82, wherein the chemotherapeutic agent is selected from the group consisting of platinum (e.g., carboplatin, cisplatin, oxaliplatin, or nedaplatin), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin), bleomycin, mitomycin, actinomycin, cyclophosphamide, capecitabine, cytarabine, gemcitabine, ifosfamide, interleukin-2, streptozocin, gemtuzumab ozogamicin, melphalan, methotrexate, pemetrexed, pricamycin, and trimethrexate.

[0173] 84. The method described in item 83, wherein the subject is undergoing cancer treatment, and said cancer treatment includes the administration of chemotherapy drugs to the subject.

[0174] 85. The antibacterial agent is selected from the group consisting of aminoglycosides (e.g., gentamicin, tobramycin, amikacin, netylmycin, apramycin, streptomycin, kanamycin, neomycin, shisomycin), β-lactams (e.g., tazobactam, or piperacillin / tazobactam), polypeptide antibiotics (e.g., polymyxins (colistin) such as polymyxin A, B, C, D, E), glycopeptide antibiotics (e.g., vancomycin), outer membrane protein-targeting antibiotics (e.g., murepavadin), antifungal agents (e.g., amphotericin B), and combinations thereof, as described in item 82.

[0175] 86. The antibacterial agent is an aminoglycoside antibiotic, preferably gentamicin, as described in item 85.

[0176] 87. The method described in item 85, wherein the antibacterial agent is murepabadin.

[0177] 88. The method described in any one of items 85-87, wherein the subject has an infectious disease, and the infectious disease is treated by administering an antimicrobial agent to the subject.

[0178] 89. The method according to item 82, wherein the blood pressure drug is an ACE inhibitor, which is optionally selected from the group consisting of captopril, benazepril, enalapril, fosinopril, and ramipril, or an angiotensin receptor antagonist, which is optionally selected from the group consisting of candesartan, valsartan, irbesartan, olmesartan, telmisartan, eprosartan, and losartan.

[0179] 90. The method according to item 82, wherein the HIV protease inhibitor is selected from the group consisting of indinavir and ritonavir.

[0180] 91. The method according to item 82, wherein the peptic ulcer drug is selected from the group consisting of cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

[0181] 92. The method according to item 82, wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, and aspirin.

[0182] 93. The method according to item 82, wherein the laxative is selected from sodium phosphate.

[0183] 94. The method according to item 82, wherein the nephrotoxic active ingredient is a contrast agent, and optionally an iodized contrast agent (e.g., iotalamate, or iodixanol, or iohexanol).

[0184] 95. Endogenous nephrotoxin is myoglobin, as described in item 81.

[0185] 96. The method according to item 95, wherein the subject has a serum creatine phosphokinase level at least 5 times higher than baseline.

[0186] 97. The method described in either item 95 or 96, wherein the subject has experienced or is subjected to physical trauma or crush trauma, exposure to electric current, extreme physical exercise or activity, and extreme temperature.

[0187] 98. The method according to any one of items 81-97, wherein compound I or a pharmaceutically acceptable salt thereof is administered to a subject before exposure to or before engaging in activities associated with rhabdomyolysis or activities that pose a risk of developing rhabdomyolysis (e.g., extreme physical activity).

[0188] 99. The method described in any one of items 81 to 98, wherein a nephrotoxic active pharmaceutical ingredient is repeatedly administered to the subject.

[0189] 100. The method according to item 99, wherein the nephrotoxic active pharmaceutical ingredient is administered at least twice, optionally at least once daily, over a period of at least 3 or 7 days.

[0190] 101. The method described in any one of items 81-100, wherein the renal condition or disease is nephrotoxin-induced acute kidney injury or renal failure.

[0191] 102. The method according to any one of items 81 to 101, wherein the renal condition or disease is selected from rhabdomyolysis, hemolysis, myoglobinuria, or optionally from oncolysis or myeloma-induced acute kidney injury.

[0192] 103. The method according to any one of the items 101 or 102, wherein the renal condition or disease is aminoglycoside-induced acute kidney injury, preferably gentamicin-induced acute kidney injury.

[0193] 104. The method described in any one of items 101-102, wherein the renal condition or disease is cisplatin-induced acute kidney injury.

[0194] 105. The method according to any one of items 81 to 104, wherein the subject has a pre-existing condition or disease that increases the risk of the subject developing renal condition or disease upon exposure to nephrotoxin.

[0195] 106. The method according to item 105, wherein the subject has a pre-existing renal condition or disease, optionally, the pre-existing renal condition is chronic kidney disease, and optionally, the subject has a history of renal dysfunction or requires dialysis.

[0196] 107. The method according to item 105 or 106, wherein the subjects have impaired renal function, and optionally, the subjects have one or a combination of the following: a serum urea nitrogen level at least 1.5 to 3 times higher than baseline, a serum creatinine level at least 1.5 to 3 times higher than baseline, or oliguria.

[0197] 108. The method according to any one of items 81 to 107, wherein compound I or a pharmaceutically acceptable salt thereof is administered to the subject before the subject's exposure to a nephrotoxic drug substance.

[0198] 109. A dose of compound I or a pharmaceutically acceptable salt thereof is administered to the subject within 24 hours prior to the administration of a certain dose of a nephrotoxic active pharmaceutical ingredient, by any one of items 81-108.

[0199] 110. The method according to item 109, wherein a dose of compound I or a pharmaceutically acceptable salt thereof is administered to the subject within a period of approximately 6 hours or less, and optionally within a period of approximately 2 hours or less, prior to the administration of a nephrotoxic active pharmaceutical ingredient to the subject.

[0200] 111. The method according to any one of items 81 to 110, wherein compound I or a pharmaceutically acceptable salt thereof is administered to a subject after the onset of renal impairment, characterized by at least 1.5 to 3 times higher serum urea nitrogen levels than baseline, at least 1.5 to 3 times higher serum creatinine levels than baseline, and oliguria, or a combination thereof.

[0201] 112. The method according to item 111, wherein a dose of compound I or a pharmaceutically acceptable salt thereof is administered to a subject 1 to 24 hours, optionally 1 to 6 hours, after the onset of renal impairment as defined in item 111.

[0202] 113. The method according to any one of items 81 to 112, wherein compound I or a pharmaceutically acceptable salt thereof is repeatedly administered to the subject during the first period, which is initiated before the second period and overlaps therewith, and the subject is repeatedly exposed to the nephrotoxic drug substance.

[0203] 114. The method according to any one of items 81 to 113, wherein compound I or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.001 to 10 mg / kg, or optionally at a dose of about 0.1 to 10 mg / kg.

[0204] 115. A method described in any one of items 81-114, wherein the subject is a human subject.

[0205] 116. The method according to any one of items 81 to 115, wherein compound I or a pharmaceutically acceptable salt thereof is administered by drip infusion or injection, preferably by parenteral injection, intramuscular injection, or intravenous injection, or by intravenous drip infusion or parenteral drip infusion.

[0206] 117. A method for preventing and / or reducing a blood urea nitrogen level and / or a serum creatinine level that is at least 1.5 to 3 times higher than baseline in a subject exposed to nephrotoxin (e.g., nephrotoxic active pharmaceutical ingredient or endogenous nephrotoxin), wherein the method comprises administering to the subject compound I as defined in item 81 or a pharmaceutically acceptable salt thereof.

[0207] 118. The method of item 117, wherein the nephrotoxin is as defined in any one of items 81-83, 85-87, or 89-95.

[0208] 119. The method of item 117 or 118, wherein the subject is as defined in any one of items 84, 88, 96-97, 105-107, or 115.

[0209] 120. The method according to any one of items 117-119, wherein the compound or a pharmaceutically acceptable salt thereof is administered as defined in any one of items 98-100, 108-114, or 116.

[0210] 121. The method according to any one of items 117 to 120, wherein a subject exposed to nephrotoxin has a renal condition or disease induced by exposure to nephrotoxin, for example, a renal condition or disease as defined in any one of items 101 to 104.

[0211] 122. The method described in any one of items 117 to 121, wherein the compound or a pharmaceutically acceptable salt thereof is administered by injection or infusion, preferably by intravenous injection or infusion.

[0212] 123. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, and one or more further excipients, wherein the composition optionally further comprises a polysorbate (e.g., polysorbate 80 or Tween 80).

[0213] 124. The pharmaceutical composition according to item 123, wherein the composition is a clear aqueous solution having a pH of 3.5 to 4.5, or a pH of 4.2 to 4.5.

[0214] 125. A pharmaceutical composition according to item 123 or 124, wherein the composition further comprises acetic acid and / or an acetate.

[0215] 126. A process for preparing the pharmaceutical compositions described in items 123 to 125, comprising the step of combining a lyophilized powder of compound I or a salt thereof with a re-prepared solvent comprising polysorbate (e.g., polysorbate 80).

[0216] 127. A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof (e.g., succinate, L-malate, or phosphate), and one or more further excipients, wherein the composition optionally further comprises polysorbate (e.g., polysorbate 80 or Tween 80) or polyethylene glycol (e.g., PEG400).

[0217] 128. The pharmaceutical composition according to item 127, wherein the composition is a clear aqueous solution having a pH of 5.4 to 5.6, and optionally the composition is suitable for bolus injection or administered as bolus injection.

[0218] 129. Pharmaceutical compositions according to items 123 to 128 for use in accordance with any use or method of treatment and / or defense as defined in any one of items 1 to 122.

[0219] The following examples are helpful in illustrating the present invention, but should not be understood as limiting the scope of the invention. [Examples]

[0220] Example 1 - A model of gentamicin-induced acute kidney injury in rats In a model study using male Wistar rats (180-220g) randomly grouped based on body weight, the efficacy of compound I against gentamicin-induced acute kidney injury was tested. As part of the study, three groups were formed: a control group, a solvent group, and a compound I group (see Table 1). Except for the control group, gentamicin (100 mg / kg) was administered intraperitoneally once daily for 10 consecutive days from day 1 to day 10. Day 1 of the gentamicin injection was designated as day 1 of the study.

[0221] [Table 1]

[0222] From day 1 to day 10 of the study, compound I, either in a solvent or formulated in a solvent, was administered intraperitoneally (ip) (11 times in total). At the start of the experiment (day 1), compound I (3 mg / kg) was administered by intraperitoneal injection 6 hours and 1 hour before gentamicin injection. Subsequently, from day 2 to day 10, compound I (3 mg / kg) was administered once daily 1 hour before gentamicin injection. The rats' body weight was recorded daily. On day 10, the animals were euthanized, and blood samples were collected via cardiac puncture. Serum was collected and stored at -80°C for renal function analysis of blood urea nitrogen (BUN) and creatinine.

[0223] result Body weight - Acute kidney injury has a rapid effect on growth / weight gain in Wistar rats. As shown in Figure 1A, for the solvent group (rats administered only the solvent before gentamicin), the rate of weight gain over the 10-day study period was observed to be slow. In contrast, for the group treated with compound I before gentamicin administration, the rate of weight gain was more rapid. As shown in Figure 1B, it was also observed that the overall weight change from baseline measurement on day 1 was higher in rats treated with compound I compared to rats treated with the solvent alone.

[0224] Serum urea nitrogen (BUN) / creatinine endpoint measurement (see Figures 2 and 3) - Rats administered with the solvent and gentamicin alone had elevated levels of BUN and creatinine, which are associated with acute kidney injury, as predicted based on high doses of gentamicin. In contrast, serum BUN and creatinine levels in rats treated with compound I and administered with gentamicin were lower than those determined for the solvent group, despite receiving the same high doses of gentamicin. Unexpectedly, serum levels were found to be at or similar levels to those measured in the control group that did not receive gentamicin. This demonstrates that compound I is effective in treating or preventing the increase of these renal function markers during gentamicin exposure. This data shows the protective effect of compound I against gentamicin toxicity.

[0225] Example 2 - A gentamicin-induced acute kidney injury model in rats - Pathological study To further evaluate the efficacy and effects of compound I on gentamicin-induced acute kidney injury and to examine the dose-response, further studies were conducted in rats, essentially similar to the general test protocol described in Example 1. Histopathology and additional biomarkers were evaluated.

[0226] As part of the study, five groups were formed: a control group (Group 1), a solvent group (Group 2), animals administered compound I at a dose of 0.5 mg / kg (Group 3), animals administered compound I at a dose of 3 mg / kg (Group 4), and animals administered compound I at a dose of 9 mg / kg (Group 5) (see Table 2). Except for control group 1, gentamicin (100 mg / kg) was administered by intraperitoneal injection once daily for 10 consecutive days from day 1 to day 10.

[0227] [Table 2]

[0228] From day 1 to day 10 of the study, compound I, either in a solvent or formulated in a solvent, was administered intraperitoneally (ip) (11 times in total). At the start of the experiment (day 1), compound I was administered at a specific dose by intraperitoneal injection to animals in groups 3, 4, and 5, 6 hours and 1 hour prior to gentamicin injection. Subsequently, from day 2 to day 10, compound I was administered once daily at a specific dose to specific investigation groups approximately 1 hour prior to gentamicin injection. On day 10, the rats were euthanized. Blood samples were collected, and kidney tissue (both left and right kidneys) was also taken from the rats for H&E staining (hematoxylin and eosin staining). To assess the degree of tissue damage caused by gentamicin-induced acute kidney injury, kidney sections were histopathologically evaluated using standard methods and scoring criteria in the art. These kidney sections were evaluated and scored for renal tubular necrosis, renal tubular dilation, loss of tubular brush margins, renal tubular cast formation, and interstitial inflammatory cell (neutrophil) infiltration. Scoring was performed for left and right kidney tissue on a scale of 0 to 4 (0 = 0%, i.e. not observed; 1 ≤ 5%; 2 = 5-25%; 3 = 25-50%; 4 ≥ 50%, i.e., extensive and severe injury or extensively visible injury). The scores were collected and the combined total score was provided.

[0229] Renal function analysis was performed based on serum blood urea nitrogen (BUN) and creatinine levels. Plasma assays for the biomarkers NGAL (neutrophil gelatinase-related lipocalin) and Kim-1 (renal injury molecule-1) were also determined. These biomarker proteins are typically upregulated in acute kidney injury and are useful as early indicators of acute kidney injury caused, for example, by nephrotoxin exposure.

[0230] result Histopathological evaluation—particularly in the gentamicin-induced acute kidney injury model rats (3 mg / kg and 9 mg / kg groups)—was observed to have a statistically significant effect in generally reducing the severity of gentamicin-induced or induced physical injury in rat renal tissue compared to the model group (G2) administered only with a solvent containing gentamicin (see Figure 4A). Figure 4B shows the analyzed pathology, which also demonstrates a significant reduction in the severity of injury pathologies particularly affected by gentamicin under model conditions, such as renal tubular dilation and neutrophil infiltration, in the groups administered with compound I.

[0231] Serum creatinine / blood urea nitrogen (BUN) endpoint measurement (see Figures 5 and 6, respectively) - Rats administered with the solvent and gentamicin alone (Group 2) had high levels of BUN and creatinine, which are associated with acute kidney injury, as predicted based on high doses of gentamicin. In contrast, serum BUN and creatinine levels in rats treated with compound I and gentamicin were both low, despite actually receiving the same high dose levels of gentamicin.

[0232] Measurement of KIM-1 / NGAL biomarker endpoints in plasma (see Figures 7 and 8, respectively) – these biomarkers may be more specific and useful as early indicators of acute kidney injury. Rats administered only the solvent and gentamicin (Group 2) were determined to have high levels of both of these biomarkers. Compared to the Model G2 group, a statistically similar decrease in these biomarker levels was observed in the rat study groups administered compound I (particularly study groups G4 and G5).

[0233] Example 3 - Rhabdomyolysis-induced acute kidney injury model in rats The efficacy of compound I for protection against rhabdomyolysis-induced acute kidney injury was tested in a model study using male D rats. Acute kidney injury was induced in rats by bilateral intramuscular injection of 50% glycerin (10 mL per kg of body weight, with two injection sites per limb). Glycerin induces physiological conditions closely associated with rhabdomyolysis, such as myoglobinuria, tubular necrosis, and renal vasoconstriction.

[0234] As part of the study, three groups were formed: placebo, solvent, and compound I. Except for the placebo group, which did not receive glycerin injections, animals received two intraperitoneal doses of either compound I or the solvent, 6 hours and 1 hour before administering glycerin injections (see Table 3).

[0235] [Table 3]

[0236] After 48 hours, the animals were euthanized, and the right and left kidneys were fixed in 10% formalin. Each kidney was cut in half longitudinally, both halves were positioned in a cassette, and treated with paraffin. The sections were cut and stained with hemotoxylin and eosin (H&E). The kidney sections were examined, and histopathological analysis and scoring were performed for tubular injury, endothelial injury, glomerular injury, and tubulointerstitial injury based on a scoring system of the art (e.g., Khalid U. et al, Journal of Hitology & Hitopathology, Volume 3, Article 1, 2016). Tubuloepistemic necrosis scoring was based on the total number of tubules in the outer zone (OOM) outside the medulla. Tubulointerstitial injury was scored as the total percentage of the total tissue observed in the section. Scores for each parameter were also added to provide a total histopathological score.

[0237] result Glycerin injection was observed to induce mild to moderate necrosis of tubular epithelial cells in the outer zone (OOM) outside the medulla. Protein cast formation and tubulointerstitial necrosis were mild. No endothelial or glomerular damage was observed. These findings correspond to transient ischemia modeled by the study. The sham group, which served as a control, did not receive glycerin injection. The mean tubular injury score after glycerin injection showed a statistically significant increase in both the solvent group and compound I group compared to the sham group that did not receive glycerin injection (0.00±0.00 in group 1, compared to 1.40±0.15 and 1.10±0.07 in groups 2 and 3, respectively, with p<0.01). The mean tubulointerstitial injury score was also statistically significantly higher in both the solvent group and compound I group compared to the placebo group (0.00±0.00 for group 1, compared to 2.00±0.00 and 1.15±0.08 for groups 2 and 3, respectively, with p<0.01). As a result, the mean total histopathology score was also statistically significantly higher in both the solvent group and compound I group compared to the placebo group that did not receive glycerin (0.00±0.00 for group 1, compared to 3.20±0.14 and 2.15±0.08 for groups 2 and 3, respectively, with p<0.01).

[0238] Table 4 summarizes the histopathological scoring results for the test groups: sham (Group 1), solvent (Group 2), and compound I (Group 3). All data are expressed as mean ± EM. All treatment groups were compared to the sham group (Group 1) or the solvent group (Group 2) using Student's t-test. A p-value of less than 0.05 is considered to indicate a statistically significant difference.

[0239] [Table 4]

[0240] Injection of compound I before the onset of glycerin-induced acute kidney injury and ischemia resulted in statistically significant improvements compared to the solvent group in the mean tubulointerstitial score (2.00±0.00 in group 2 vs. 1.15±0.08 in group 3, p<0.01 for both) and the mean total histopathological score (3.20±0.14 in group 2 vs. 2.15±0.08 in group 3, p<0.01 for both). These results indicate a beneficial effect of administering compound I to prevent or reduce acute kidney injury caused or induced by rhabdomyolysis (e.g., tubular epithelial cell necrosis, tubulointerstitial necrosis).

[0241] Example 4 - A mouse model of cisplatin-induced acute kidney injury. The efficacy of compound I against cisplatin-induced acute kidney injury (AKI) was tested in a mouse model. On day 1 of the 4-day (72-hour) study, 5 mg / kg of cisplatin was administered intraperitoneally to all groups defined in Table 5 below, except for the control group (group 1). One hour before cisplatin administration, 0.9% saline was administered intravenously to the model group (group 2). Compound I was administered to groups 3 and 4, and cyclosporine A (CA) was administered to group 5. On days 2 and 3 of the experiment, the respective treatments were administered to the test groups at 24 and 48 hours from the start of the model (t=0 with cisplatin injection).

[0242] [Table 5]

[0243] Physiological assays and histophysiological analyses of kidney tissue, similar to those described in the above examples, were performed in the test group animals at baseline and at predetermined intervals / at the end of the study (72 hours after cisplatin injection). Compound I is expected to be effective in treating and / or protecting against cisplatin-induced acute kidney injury.

[0244] Example 5 - Formulation of Compound I The injectable formulation of compound I was prepared according to the following protocol.

[0245] (1) Freeze-dried powder (100 mg of compound I per vial) JPEG2026102838000012.jpg27136

[0246] Acetic acid and sterile water for injection were weighed to prepare a 1% acetic acid solution. Compound I was added and the solution was stirred until clear. The pH of this composition was approximately 4.0 to 4.3. After sterilization by filtration, packing, lyophilization, and sealing, a lyophilized powder containing compound I was obtained.

[0247] (2) Solvent for re-preparation (5 g per vial) JPEG2026102838000013.jpg34133

[0248] Water for injection, anhydrous sodium acetate, acetic acid, and Tween 80 were mixed and stirred until all components were dissolved (tired). After sterilization by filtration, packing, and sealing, a solvent for re-preparation (pH 3.7-4.4) was obtained.

[0249] To prepare a composition for intravenous injection, the lyophilized powder was dissolved in a re-preparation solvent to obtain a clear solution. This solution could then be further diluted with physiological saline (e.g., 0.9% physiological saline) or glucose water (e.g., 5% glucose water) to the desired concentration of compound I for intravenous administration. These formulations of compound I were observed to be clear, meaning they were stable solutions in which compound I remained completely dissolved without being in micelle solution form or any phase-separated form (at least 18 hours before use).

[0250] Example 6 - Formulation of Compound I for Bolus Injection A formulation of compound I suitable for bolus injection was prepared according to the following protocol. JPEG2026102838000014.jpg40136

[0251] 0.295 g of succinic acid was dissolved in water to obtain a 50 mL solution. 100 mg of Tween 80 was added to 5 mL of the succinic acid solution to prepare a solution. 3 mL of this succinic acid / Tween 80 aqueous solution was added to 150 mg of compound I in a 10 mL vial, and the mixture was sonicated until compound I was dissolved. 1 M NaOH aqueous solution was added to adjust the pH to 5.4-5.6. The mixture was further sonicated to form a solution, which was then filtered using a 0.22 μm filter to obtain a clear filtrate suitable for bolus injection.

[0252] Example 7 - Formulation of Compound I for bolus injection A formulation of compound I suitable for bolus injection was prepared according to the following protocol. JPEG2026102838000015.jpg40136

[0253] 0.295 g of succinic acid and 5.0 g of PEG400 were added to water to obtain a 50 mL solution. 3 mL of this solution was added to 150 mg of compound I in a 10 mL vial. The resulting mixture was sonicated to obtain a solution. 1 M NaOH aqueous solution was added to adjust the pH to 5.4-5.6, and the mixture was sonicated again. The resulting solution was filtered through a 0.22 μm filter to obtain a clear filtrate suitable for bolus injection.

Claims

1. The use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention and / or treatment of a nephrotoxin-exposed subject that may induce a renal condition or disease, Compound I The use of the nephrotoxin is provided if it is a nephrotoxic active ingredient or endogenous nephrotoxin.

2. The use according to claim 1, wherein the nephrotoxic active pharmaceutical ingredient is selected from the group consisting of antibacterial agents, cancer chemotherapy agents, ACE inhibitors and antihypertensive drugs including angiotensin receptor antagonists, macrocyclic lactone immunosuppressants, HIV protease inhibitors, peptic ulcer agents, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, laxatives and contrast agents.

3. The use according to claim 2, wherein the chemotherapeutic agent is selected from the group consisting of platinum (e.g., carboplatin, cisplatin, oxaliplatin, or nedaplatin), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin), bleomycin, mitomycin, actinomycin, cyclophosphamide, cytarabine, capecitabine, gemcitabine, ifosfamide, interleukin-2, streptozocin, gemtuzumab ozogamicin, melphalan, methotrexate, pemetrexed, pricamycin, and trimethrexate.

4. The use according to claim 3, wherein the subject is undergoing cancer treatment, and the cancer treatment includes the administration of the chemotherapy drug to the subject.

5. The use according to claim 2, wherein the antibacterial agent is selected from the group consisting of aminoglycosides (e.g., gentamicin, tobramycin, amikacin, netylmycin, apramycin, streptomycin, kanamycin, neomycin, shisomycin), β-lactams (e.g., tazobactam, or piperacillin / tazobactam), polypeptide antibiotics (e.g., polymyxins (colistins) such as polymyxin A, B, C, D, E), glycopeptide antibiotics (e.g., vancomycin), outer membrane protein-targeting antibiotics (e.g., murepavadin), antifungal agents (e.g., amphotericin B), and combinations thereof.

6. The use according to claim 5, wherein the antibacterial agent is gentamicin.

7. The use according to claim 5, wherein the antibacterial agent is murepabadin.

8. The use according to any one of claims 5 to 7, wherein the subject is suffering from an infectious disease, and the infectious disease is treated by administering the antibacterial agent to the subject.

9. The use according to claim 2, wherein the blood pressure drug is an ACE inhibitor, optionally selected from the group consisting of captopril, benazepril, enalapril, fosinopril, and ramipril, or an angiotensin receptor antagonist, optionally selected from the group consisting of candesartan, valsartan, irbesartan, olmesartan, telmisartan, eprosartan, and losartan.

10. The use according to claim 2, wherein the HIV protease inhibitor is selected from the group consisting of indinavir and ritonavir.

11. The use according to claim 2, wherein the peptic ulcer agent is selected from the group consisting of cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.

12. The use according to claim 2, wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, and aspirin.

13. The use according to claim 2, wherein the laxative is selected from sodium phosphate.

14. The use according to claim 2, wherein the nephrotoxic active pharmaceutical ingredient is a contrast agent, and optionally an iodized contrast agent (e.g., iotalamate, or iodixanol, or iohexanol).

15. The use according to claim 1, wherein the endogenous nephrotoxin is myoglobin.

16. The use according to claim 15, wherein the subject has a serum creatine phosphokinase level at least five times higher than baseline.

17. The use according to any one of claims 15 or 16, wherein the subject has experienced or is subjected to physical trauma or crush trauma, exposure to electric current, extreme physical exercise or activity, and extreme temperature.

18. The use according to any one of claims 1 to 17, wherein the drug is administered to the subject before exposure to or before engaging in activities related to rhabdomyolysis or activities that pose a risk of developing rhabdomyolysis (e.g., extreme physical activity).

19. The use according to any one of claims 1 to 18, wherein the nephrotoxic active pharmaceutical ingredient is repeatedly administered to the subject.

20. The use according to claim 19, wherein the nephrotoxic active ingredient is administered at least twice, optionally at least once a day, over a period of at least three days or seven days.

21. The use according to any one of claims 1 to 20, wherein the renal condition or disease is nephrotoxin-induced acute kidney injury or renal failure.

22. The use according to any one of claims 1 to 21, wherein the renal condition or disease is selected from rhabdomyolysis, hemolysis, myoglobinuria, or optionally from oncolysis or myeloma-induced acute kidney injury.

23. The use according to any one of claims 1 to 22, wherein the subject has a pre-existing condition or disease that increases the risk of the subject developing a renal condition or disease upon exposure to the nephrotoxin.

24. The use according to claim 23, wherein the subject has a pre-existing renal condition or disease, optionally the pre-existing renal condition is chronic kidney disease, optionally the subject has a history of renal dysfunction, or requires dialysis.

25. The use according to claim 23 or 24, wherein the subject has impaired renal function, and optionally the subject has a serum urea nitrogen level at least 1.5 to 3 times higher than baseline, and / or a serum creatinine level at least 1.5 to 3 times higher than baseline, and / or oliguria.

26. The use according to any one of claims 1 to 25, wherein the drug is administered to the subject before exposure to the subject of the nephrotoxic active pharmaceutical ingredient.

27. The use according to any one of claims 1 to 26, wherein the dose of the drug is administered to the subject within a period of 24 hours or less before the dose of the nephrotoxic active pharmaceutical ingredient is administered to the subject.

28. The use according to claim 27, wherein, prior to the administration of the nephrotoxic active pharmaceutical ingredient to the subject, the dose of the drug is administered to the subject within a period of approximately 6 hours or less, and optionally within a period of approximately 2 hours or less.

29. The use according to any one of claims 1 to 28, wherein the agent is administered to the subject after the onset of renal impairment, characterized by one or a combination thereof, of a serum urea nitrogen level at least 1.5 to 3 times higher than baseline, a serum creatinine level at least 1.5 to 3 times higher than baseline, and oliguria.

30. The use according to claim 29, wherein the dose of the drug is administered to the subject 1 to 24 hours after the onset of renal dysfunction, and optionally 1 to 6 hours after the onset of renal dysfunction.

31. The use according to any one of claims 1 to 30, wherein the drug is administered repeatedly to the subject during a first period that is initiated before a second period and overlaps therewith, and the subject is repeatedly exposed to the nephrotoxic active pharmaceutical ingredient.

32. The use according to any one of claims 1 to 31, wherein the drug is administered to the subject at a dose of approximately 0.001 to 10 mg / kg, or optionally at a dose of approximately 0.1 to 10 mg / kg.

33. The use according to any one of claims 1 to 32, wherein the subject is a human subject.

34. The use according to any one of claims 1 to 33, wherein the drug is formulated for administration by intravenous drip or injection, preferably parenteral injection, intramuscular injection, or intravenous drip or parenteral drip.

35. The use of compound I as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of an agent for the prevention and / or reduction of blood urea nitrogen levels and / or serum creatinine levels that are at least 1.5 to 3 times higher than baseline in subjects exposed to nephrotoxin.

36. The use according to claim 35, wherein the nephrotoxin is defined in any one of claims 1 to 3, 5 to 7, or 9 to 15.

37. The use according to claim 35 or 36, wherein the subject is defined in any one of claims 1, 4, 8, 16-17, 23-25, or 33.

38. The use according to any one of claims 35 to 37, wherein the drug is administered as defined in any one of claims 18 to 20 or 26 to 32.

39. The use according to any one of claims 35 to 38, wherein the drug is formulated for administration by injection or intravenous drip, preferably by intravenous injection or intravenous drip.

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