Prevention and / or treatment of contrast-induced acute kidney injury

Abstract

This invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury. [Solution] In one embodiment, a method is provided for preventing, mitigating and / or treating contrast-induced acute kidney injury, comprising administering a fatty acid oxidation inhibitor to a patient in need thereof. The method also provides for the use of trimetazidine or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of contrast-induced acute kidney injury. The method also provides for administering one or more of the following: trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof. This invention provides a method for preventing and / or treating nephropathy.

Description

[Technical Field]

[0001] This invention relates to a method for preventing contrast-induced acute kidney injury by administering fatty acid oxidation inhibitors to patients who require them. [Background technology]

[0002] Contrast-induced acute kidney injury (CI-AKI) (also known as contrast-induced nephropathy) is a sudden decline in renal function that may be associated with the use of contrast agents. Contrast agents are substances used in medical imaging to enhance the contrast of structures or fluids within the body. Renal impairment can be associated with a rapid decline in renal function over 48-72 hours and potentially with chronic kidney disease over one year, increased mortality, and infarction / reinfarction. This can lead to an increased rate of major adverse cardiovascular events (MACE). Symptoms may be similar to those of kidney disease and include more severe fatigue, loss of appetite, swelling of the feet and ankles, swelling around the eyes, or dry and itchy skin. In some cases, this can lead to serious kidney problems as well as potential heart and vascular problems.

[0003] Numerous treatments for renal impairment have been investigated, including the use of statins, bicarbonates, N-acetylcysteine, ascorbic acid, theophylline and aminophylline, vasodilators, forced diuretics, and renal replacement therapy. Trimetazidine (1-(2,3,4-trimethoxybenzyl)piperazine) has been used for angina and has been marketed in over 90 countries outside the United States for more than 35 years. However, trimetazidine has never been approved in the United States for any indication. It was developed by Les Laboratoires Servier (France) and was first approved in France in 1978. Trademarks: Vastarel® and Vastarel MR Under the registered trademark, three drug forms are available in Europe: 20 mg tablets, 20 mg / ml oral solution, and 35 mg controlled-release tablets (MR). It is also available in over 90 countries as generic or brand-name generics under various names. Trimetazidine is described as the first cytoprotective anti-ischemic agent that improves myocardial glucose utilization by inhibiting fatty acid metabolism. Trimetazidine has been tested for the prevention of contrast-induced nephropathy, for example, in patients with high serum creatinine levels undergoing coronary angiography / angiopathy. For example, four studies... A researcher-initiated Phase 2 clinical trial tested trimetazidine for the prevention of CI-AKI. The results of the study were published in a peer-reviewed paper, and it was found that trimetazidine increases the risk of contrast-induced nephropathy (CIN). It has been shown to be more effective than isotonic saline in reducing contrast. See Onbasili AO, et al., HEART, 2007. 93:698-702, RahmanMM, et al., MYMENSINGH MED J, 2012. 21(2):292-299, Shehata M, Am. J Cardiol, 2014. 114:389-394, and Liu W, et al., Am. J. Med Sci, 2015. 350:398-402. However, contrast-induced acute kidney injury (CI-AKI) is serious. This remains an unmet medical need, and improvements in methods for preventing contrast-induced acute kidney injury are still required. [Overview of the Initiative]

[0004] One embodiment provides a method for preventing, reducing the incidence of, and / or treating contrast-induced acute kidney injury, comprising administering a fatty acid oxidation inhibitor to a patient in need. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. For example, contrast-induced acute kidney injury in a patient undergoing a cardiac procedure requiring the administration of a contrast agent for imaging. The present invention provides a method for preventing contrast-induced acute kidney injury. In one embodiment, the present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering more than 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, the present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering more than 35 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, the present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need. In one embodiment, the present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need. In one embodiment, the preparation involves administering one or more of the following to a patient in need: trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, lanolazine, or any pharmaceutically acceptable salt thereof. This invention provides methods for preventing, mitigating, and / or treating contrast agent-induced acute kidney injury.

[0005] In one embodiment, the patient is administered a fatty acid oxidation inhibitor before undergoing cardiac treatment. In one embodiment, the patient is administered trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, before undergoing cardiac treatment. In one embodiment, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof before undergoing cardiac treatment. For example, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 24, 48, or 72 hours before undergoing cardiac treatment. In other examples, the patient who requires it is administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing cardiac treatment. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered four times daily.

[0006] In one embodiment, the patient is administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, before undergoing cardiac treatment. For example, the patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for example, for more than 24, 48, or 72 hours before undergoing cardiac treatment. In other examples, the patient who requires it is administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for at least 96 hours before undergoing cardiac treatment. In one embodiment, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, may be administered once, two, three, or four times a day. In one embodiment, trimetazidi The pharmaceutically acceptable salt thereof may be administered together with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or at least one of the pharmaceutically acceptable salts thereof.

[0007] In one embodiment, a patient may be administered a fatty acid oxidation inhibitor for, for example, 30, 45, 60, 75, or 90 days or more after a cardiac procedure. In one embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for, for example, 30, 45, 60, 75, or 90 days or more after a cardiac procedure. For example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 60 days or more after a cardiac procedure. In another example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 90 days. In one embodiment, a patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above for, for example, 30, 45, 60, 75, or 90 days or more after a cardiac procedure, such as computed tomography (CT). For example, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, twice daily for more than 60 days after cardiac treatment. In other cases, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, twice daily for a total of 90 days.

[0008] In one embodiment, a patient may be administered a fatty acid oxidation inhibitor three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In another embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In yet another embodiment, a patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment.

[0009] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury involves administering a fatty acid oxidation inhibitor to the patient via non-enteral administration within 6 hours prior to administering the contrast agent to the patient. This includes, in one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury involves administering a fatty acid oxidation inhibitor to the patient before administering the contrast agent to the patient (5, 4, 3). , including non-enteral administration within 2 or 1 hour. In one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury involves administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient non-enterally within 6 hours prior to administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient non-enterally within 5, 4, 3, 2, or 1 hours prior to administering a contrast agent to the patient. A method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering to the patient, by enteral administration, one or more of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, within six hours prior to administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering to the patient, one or more of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof This includes administering it non-enterally within 5, 4, 3, 2, or 1 hour before administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury comprises administering to a patient, by non-enteral administration, within 6 hours prior to administering a contrast agent, trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof. In one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury comprises administering to a patient, by combining trimetazidine or a pharmaceutically acceptable salt thereof with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, to the patient. This includes administering the drug non-enterally within 5, 4, 3, 2, or 1 hour prior to the action. Non-enteral administration is intravenous administration.

[0010] In one embodiment, a method for preventing contrast-induced acute kidney injury comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition contains more than about 65 μg / ml of C max A method is provided for providing an in vivo plasma profile having the following characteristics.

[0011] In one embodiment, a method for preventing contrast-induced acute kidney injury is provided, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an in vivo plasma profile having an AUC greater than approximately 500 μg·hr / ml.

[0012] One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of a fatty acid oxidation inhibitor to a patient in need before, during, and after a procedure involving the use of a device, such as a guidewire and intra-coronary pressure wire, cardiac catheter, atherectomy device, intra-coronary stent, thrombus aspiration catheter, embolic protection device, replacement heart valve and / or vascular closure device. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need before, during, and after a procedure involving the use of a device, such as a guidewire and intra-coronary pressure wire, cardiac catheter, atherectomy device, intra-coronary stent, thrombus aspiration catheter, embolic protection device, replacement heart valve and / or vascular closure device. One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need before, during, and after a procedure involving the use of a device, such as a guidewire and intracoronary pressure wire, cardiac catheter, atherectomy device, intracoronary stent, thrombus aspiration catheter, embolic protection device, replacement cardiac valve, and / or vascular occlusion device.

[0013] In one embodiment, a method for preventing, reducing, and / or treating contrast agent-induced acute kidney injury is provided by administering to a patient in need thereof an effective amount of an inhibitor of fatty acid oxidation, in combination with or before and after administration of a contrast agent, an anticoagulant, and an antiplatelet agent. In one embodiment, a method for preventing, reducing, and / or treating contrast agent-induced acute kidney injury is provided by administering to a patient in need thereof an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof, in combination with or before and after administration of a contrast agent, an anticoagulant, and an antiplatelet agent. In one embodiment, a method for preventing, reducing, and / or treating contrast agent-induced acute kidney injury is provided by administering to a patient in need thereof an effective amount of etomoxir, oxyphenisatin, perhexiline, meldonium, or ranolazine, or a pharmaceutically acceptable salt of any of the foregoing, in combination with or before and after administration of a contrast agent, an anticoagulant, and an antiplatelet agent. In certain embodiments, for example, the following items are provided. (Item 1) A method of treating contrast agent-induced acute kidney injury, comprising administering to a patient undergoing a procedure that requires a contrast agent an amount of trimetazidine or a pharmaceutically acceptable salt thereof that is greater than 20 mg. (Item 2) The method according to item 1, wherein the patient is administered 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof in 24 hours. (Item 3) The method according to item 1, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof 48 hours before undergoing the procedure. (Item 4) The method according to item 1, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered three times a day. of the method. (Item 5) The method according to item 1, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered as an immediate-release dosage form of 20 mg. (Item 6) The method according to item 1, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times a day for more than 48 hours prior to the administration of a contrast agent. (Item 7) The method according to item 1, wherein the patient has renal impairment and is administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after treatment. (Item 8) The method according to item 1, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for a total of 90 days after treatment. (Item 9) The method according to item 1, wherein the patient has renal impairment and is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to receiving a cardiac procedure, and is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for at least 60 days after the procedure. (Item 10) The method according to item 1, wherein administration of trimetazidine or a pharmaceutically acceptable salt thereof reduces the incidence of major adverse kidney or cardiac events. (Item 11) A method for reducing contrast-induced acute kidney injury in a patient undergoing a procedure requiring a contrast agent, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof, wherein the composition contains more than approximately 65 μg / ml of C max A method for providing an in vivo plasma profile including the following. (Item 12) The method according to item 11, wherein the patient is administered 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof over 24 hours. (Item 13) The method according to item 11, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof 48 hours prior to receiving the procedure. (Item 14) The method according to item 11, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered three times daily. (Item 15) The method according to item 11, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered as a 20 mg immediate-release dosage form. (Item 16) The method according to item 11, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times a day for more than 48 hours prior to the administration of a contrast agent. (Item 17) The method according to item 11, wherein a patient requiring treatment is administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after treatment. (Item 18) The method according to item 11, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for a total of 90 days after treatment. (Item 19) The method according to item 11, wherein a patient requiring treatment is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to receiving cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof three times daily for at least 60 days after receiving treatment. (Item 20) The method according to item 11, wherein administration of rimetazidine or a pharmaceutically acceptable salt thereof reduces the incidence of major adverse kidney or cardiac events. (Item 21) A method for mitigating contrast-induced acute kidney injury in a patient undergoing a contrast-enhanced procedure, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient, wherein the composition provides an in vivo plasma profile containing an AUC greater than approximately 500 μg·hr / ml. (Item 22) The method according to item 21, wherein the patient is administered 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof over 24 hours. (Item 23) The method according to item 21, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof 48 hours prior to receiving the procedure. (Item 24) The method according to item 21, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered three times daily. (Item 25) The method according to item 21, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered as a 20 mg immediate-release dosage form. (Item 26) The method according to item 21, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times a day for more than 48 hours prior to the administration of a contrast agent. (Item 27) The method according to item 21, wherein a patient requiring treatment is administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after treatment. (Item 28) The method according to item 21, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for a total of 90 days after treatment. (Item 29) The method according to item 21, wherein the patient has renal impairment and is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to receiving a cardiac procedure, and is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for at least 60 days after the procedure. (Item 30) The method according to item 21, wherein administration of trimetazidine or a pharmaceutically acceptable salt thereof reduces the incidence of major adverse kidney or cardiac events. [Modes for carrying out the invention]

[0014] Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury are described, including administering fatty acid oxidation inhibitors to patients who require them. Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury are described, including administering trimetazidine or a pharmaceutically acceptable salt thereof to patients who require it. Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury are described, including administering etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above to patients who require it. Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury are described, including administering one or more of trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above to patients who require it. This document describes a method for reducing the incidence of contrast-induced acute kidney injury. It describes administering trimetazidine or a pharmaceutically acceptable salt thereof to patients requiring it, along with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any of the aforementioned pharmaceutically acceptable salts. This section describes methods for reducing the incidence of contrast-induced acute kidney injury, including administration in combination with the above.

[0015] The present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. One embodiment provides a method for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). One embodiment provides a method for preventing contrast-induced acute kidney injury by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. One embodiment provides a method for mitigating contrast-induced acute kidney injury. Several embodiments provide methods for reducing major adverse kidney and cardiac events (MARCE) in subjects undergoing coronary angiography. The present invention provides a method for reducing the incidence of major adverse kidney and cardiac events in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, the present invention provides a method for reducing and / or preventing contrast-induced acute kidney injury in subjects undergoing coronary angiography by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, the present invention provides a method for reducing and / or preventing contrast-induced acute kidney injury in subjects undergoing coronary angiography for acute coronary syndrome (ACS) by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. To provide a method for reducing and / or preventing nephropathy.

[0016] In some embodiments, a method is provided to reduce and / or prevent contrast-induced acute kidney injury in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient. In other embodiments, a method is provided to reduce and / or prevent contrast-induced acute kidney injury in subjects undergoing coronary angiography for acute coronary syndrome (ACS) other than ST-elevation myocardial infarction by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient. The present invention provides a method for / or prevention of contrast agent induction in subjects undergoing coronary angiography for acute coronary syndrome (ACS) other than ST-elevation myocardial infarction with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. The present invention provides a method for reducing and / or preventing acute kidney injury. In some embodiments, the present invention provides a method for reducing and / or preventing acute coronary syndrome (ACS) excluding ST-elevation myocardial infarction with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient undergoing coronary angiography. The present invention provides a method for reducing and / or preventing major adverse kidney and cardiac events in subjects undergoing coronary angiography for ACS. This provides a method to reduce the risk of CI-AKI and related MARCE.

[0017] In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering more than 40 mg of trimetazidine or a pharmaceutically acceptable salt thereof. For example, the method may include administering more than 40 mg of trimetazidine to a patient in doses once or more daily. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof three times a day. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof three times a day. In some embodiments, patients administered trimetazidine according to the disclosed method may have estimated glomerular filtration rates (eGFR) of <45 mL / min and >15 mL / min as determined by the Modification of Diet in Renal Disease (MDRD) formula. Patients administered trimetazidine according to the disclosed method may have eGFR <60 mL / min and >15 mL / min as determined by the MDRD formula.

[0018] Many pharmaceuticals are administered at fixed intervals as a fixed dose to achieve a therapeutic effect. The duration of action is reflected by the plasma half-life. Because efficacy often depends on sufficient exposure, management may require frequent maintenance doses. Advantageously, a method for preventing contrast-induced acute kidney injury is disclosed herein by administering trimetazidine or a pharmaceutically acceptable salt thereof. For example, in one embodiment, about 20 mg to about 200 mg of trimetazidine or a pharmaceutically acceptable salt thereof. The present invention provides a method for treating contrast-induced acute kidney injury, comprising administering a pharmaceutical composition containing a pharmaceutically acceptable salt of to a patient in need thereof.

[0019] In one embodiment, the patient is administered a fatty acid oxidation inhibitor before undergoing cardiac treatment. In another embodiment, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof before undergoing cardiac treatment. For example, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 24, 48, or 72 hours before undergoing cardiac treatment. In another embodiment, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing contrast treatment. In some embodiments, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 48 hours before undergoing contrast treatment.

[0020] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once daily. It may be administered twice daily. In one embodiment, trimetazidin or a pharmaceutically acceptable substance thereof The salt may be administered three times a day. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered four times a day. In one embodiment, the fatty acid oxidation inhibitor is 1 It may be administered once, twice, three times, or four times a day.

[0021] In one embodiment, a patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, before undergoing cardiac treatment. For example, a patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for example, for more than 24, 48, or 72 hours before undergoing cardiac treatment. In other examples, a patient who requires it may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for at least 96 hours before undergoing cardiac treatment. In one embodiment, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, may be administered once, two, three, or four times a day. In one embodiment, trimetad Zin or a pharmaceutically acceptable salt thereof is etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one of the pharmaceutically acceptable salts thereof. It may be administered in combination with one or more of the following. In one embodiment, the patient may administer trimetazidine or a pharmaceutically acceptable salt thereof in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof. It may be administered before cardiac procedures. For example, a patient may receive trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof before a cardiac procedure. It may be administered for more than 24, 48, or 72 hours before, for example. In other examples, trimetazidine or a pharmaceutically acceptable salt thereof may be combined with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the aforementioned pharmaceutically acceptable salts. Patients requiring it are given it at least 96 hours before undergoing cardiac treatment. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once, twice, three or four times daily in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof.

[0022] In one embodiment, a patient may be administered a fatty acid oxidation inhibitor for, for example, 30, 45, 60, 75, or 90 days after contrast-enhanced treatment. In one embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for, for example, 30, 45, 60, 75, or 90 days after cardiac treatment. For example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 60 days after cardiac treatment. In another example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 90 days. In one embodiment, a patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, for, for example, 30, 45, 60, 75, or 90 days after contrast-enhanced treatment. For example, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, twice daily for more than 60 days after cardiac treatment. In another example, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, twice daily for a total of 90 days. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be used in combination with one or more etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, in contrast-enhanced treatment. It may be administered for more than 30, 45, 60, 75, or 90 days after receiving the initial treatment.

[0023] In one embodiment, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In one embodiment, the patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof is administered in combination with one or more of etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof. It is possible.

[0024] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury involves administering a fatty acid oxidation inhibitor to a patient in need within 6 hours prior to administration of the contrast agent. This includes, in one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury includes administering a fatty acid oxidation inhibitor to a patient in need within 5, 4, 3, 2, or 1 hour prior to administration of a contrast agent. A method for preventing, mitigating, and / or treating harm includes administering a fatty acid oxidation inhibitor non-enterally to patients in need within 6 hours prior to administration of a contrast agent. In one embodiment, A method for preventing, mitigating, and / or treating contrast-induced acute kidney injury is to administer a fatty acid oxidation inhibitor non-enterally to patients who require it within 5, 4, 3, 2, or 1 hour prior to contrast agent administration. This includes, in one embodiment, such non-enteral administration is intravenous administration.

[0025] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury involves administering a contrast agent to a patient in need, either alone with trimetazidine or a pharmaceutically acceptable salt thereof, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof. This includes administering the drug within 6 hours prior to administration. In one embodiment, contrast agent-induced acute kidney injury is pre-treated. Methods for prevention, mitigation, and / or treatment include using trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof. To patients who require it, administer it within 5, 4, 3, 2, or 1 hour before administration of the contrast agent. In one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury includes administering one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine or any pharmaceutically acceptable salt thereof to a patient in need within 6 hours prior to administration of a contrast agent. A method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, to a patient in need within 5, 4, 3, 2, or 1 hour prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, This includes administering the contrast agent non-enterally within 6 hours prior to administration to patients who require it. In this context, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury is to administer one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, to a patient in need of contrast. This includes administering the medication non-enterally within 5, 4, 3, 2, or 1 hour prior to the day. Methods for preventing, mitigating, and / or treating drug-induced acute kidney injury include using trimetazidine alone or a pharmaceutically acceptable salt thereof, or one of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof. When used in combination with one or more other methods, it should be administered non-enterally within 6 hours prior to contrast agent administration to patients who require it. This includes, in one embodiment, a method for preventing, mitigating and / or treating contrast-induced acute kidney injury is to use trimetazidine alone or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof to the patient in need. This includes administering the contrast agent to the patient via non-enteral administration within 5, 4, 3, 2, or 1 hour prior to administration of the contrast agent. In this context, such non-enteral administration is equivalent to intravenous administration.

[0026] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof is administered at least once daily in doses ranging from approximately 0.001 mg / kg to approximately 10 mg / kg per body weight of the patient requiring it, for example, in the range of approximately 0.01 mg / kg to 2.0 mg / kg. For example, the dose includes amounts of trimetazidine or a pharmaceutically acceptable salt thereof in the range of approximately 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 35 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, and includes amounts such as 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2. 75mg, 3mg, 3.5mg, 3.75mg, 4mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 10mg, 11mg, 12mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg , 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg A dose of 200 mg is a specific example of a dosage.

[0027] Typically, the dosage of trimetazidine or a pharmaceutically acceptable salt thereof is administered to patients requiring it 1 to 4 times daily. The methods and compositions described herein reduce adverse events. This may provide reduction and / or increase in efficacy. In one embodiment, the dosage is, for example, approximately 20-100 mg / day, 20-200 mg / day, or 21-100 mg / day, or 22-100 mg / day, or 23-100 mg / day, for example, 21 mg / day, 42 mg / day, 63 mg / day, 22 mg / day, 44 mg / day, 66 mg / day, or 23 mg / day. , 46mg / day, 69mg / day, 24mg / day, 48mg / day, 72mg / day, 25mg / day, 50mg / day, 60mg / day, 75mg / The daily dose is 80 mg / day, 90 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day.

[0028] In some embodiments, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is provided once, twice, or three times daily. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is provided three times daily. In other embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is provided twice daily.

[0029] The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of a fatty acid oxidation inhibitor to a subject in need. The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of trimetazidine or a pharmaceutically acceptable salt, derivative, or analog thereof to a subject in need. The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof to a subject in need. The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof in combination with one or more effective amounts of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof The present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering it to a subject requiring it. An effective dose or therapeutically effective dose may be a dose sufficient to treat, suppress, or alleviate one or more symptoms of contrast-induced acute kidney injury. In one embodiment... The present invention provides a method for preventing contrast-induced acute kidney injury (CI-AKI) in patients with renal failure undergoing diagnostic or therapeutic interventional cardiac procedures requiring the administration of a contrast agent for imaging by computed tomography (CT) or angiography.

[0030] The present invention provides an administration regimen that enables the prevention and / or treatment of contrast-induced acute kidney injury with potentially limited or virtually no negative side effects, such as Parkinson's disease, symptoms of Parkinson's disease, or Parkinson's disease-like symptoms. Those skilled in the art may anticipate that the use and administration regimens provided herein may cause or increase the risk of symptoms of Parkinson's disease. Accordingly, the methods described herein may provide treatment for contrast-induced acute kidney injury that may be considered surprising and unexpected. For example, the present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury in patients requiring treatment, which may not cause Parkinson's disease-like symptoms, such as tremors, rigidity, bradykinesia, and impairments of balance and coordination.

[0031] Trimetazidine or its pharmaceutically acceptable salts may be provided as an acid addition salt, zwitterionic hydrate, zwitterionic anhydride, dihydrochloride, hydrochloride or hydrobromide, or as a zwitterionic monohydrate. Acid addition salts include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, and benzenesulfonic acid. 8-Haloteophyllines, such as 8-bromo- This includes, but is not limited to, theophylline. In one embodiment, inorganic acid addition salts, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitrate addition salts, may be used. In one embodiment, trimetazidine may be provided as a dihydrochloride salt. Those skilled in the art will readily understand that the amount of the active ingredient in the pharmaceutical composition depends on the form of trimetazidine provided.

[0032] Deuteration of pharmaceuticals to improve pharmacokinetic (PK), pharmacodynamic (PD), and toxicity profiles has been demonstrated in several classes of drugs. Therefore, the use of deuterium-enriched trimetazidine is contemplated and is within the scope of the methods and compositions described herein. Deuterium can be synthetically incorporated at any position by hydrogen substitution according to synthetic procedures known in the art. For example, deuterium can be added by proton-deuterium equilibrium exchange. Deuterium can be incorporated at various positions having exchangeable protons, such as min-N-H. Therefore, deuterium can be incorporated selectively or non-selectively by methods known in the art.

[0033] In one embodiment, a method for treating contrast-induced acute kidney injury involves using approximately 20 mg to over 200 mg. The method for treating contrast-induced acute kidney injury includes administering a pharmaceutical composition containing trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, the method for treating contrast-induced acute kidney injury includes administering a pharmaceutical composition containing more than 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, the method for treating contrast-induced acute kidney injury includes administering a pharmaceutical composition containing more than 35 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need.

[0034] One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering a first and second dose regimen of a fatty acid oxidation inhibitor to a patient in need. Another embodiment provides a method for preventing and mitigating contrast-induced acute kidney injury, comprising administering a first and second dose regimen of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. Another embodiment provides one or more trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above. A method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering a first-dose regimen and a second-dose regimen to a patient in need thereof. In one embodiment, the first-dose regimen comprises trimetazidine or a pharmaceutically acceptable salt thereof and The present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering one or more second-dose regimens of trimetazidine, etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0035] For example, the first-dose regimen could be trimetazidine alone, or etomoxyl, oxfenol, or oxfenol. Patients in combination with one or more herring, perhexylline, mildronate, or lanozine. This may be a loading or starting dose to achieve a specific exposure in [location].

[0036] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered several days before contrast agent administration, for example, one, two, three, four, or five days before contrast agent administration. For example, tri Metazidine or a pharmaceutically acceptable salt thereof may be administered for three days prior to contrast agent administration. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need at least 5 days prior to contrast-enhanced treatment.

[0037] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered before contrast agent treatment, for example, to a patient in doses of 2, 3, 4, 6, 9, 10, or 12 of trimetazidine. The administration is performed before contrast agent administration. For example, the method may include administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof three times a day for three days (e.g., 9 doses) before contrast agent administration. In other examples, the method may include administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof three times a day for four days (e.g., 12 doses) before contrast agent administration. In other examples, The method involves taking 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof twice daily for 3 days (e.g.) For example, this may include administering the drug (6 doses) before contrast agent procedures.

[0038] The loading or initiation dose is initiated before contrast agent administration and may provide sufficient exposure to prevent contrast agent-induced acute injury. In one embodiment, the loading dose may be trimetazidine or a pharmaceutically acceptable salt thereof alone, or one of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof. This can be achieved by a bolus injection in combination with the above. In one embodiment, the loading dose is administered over a period of time prior to contrast agent treatment, either by administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof. This can be achieved more effectively. For example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered 6, 12, or 24 hours prior to contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof. It can be administered non-enterally 6, 12, or 24 hours before contrast agent administration. In one embodiment, Trime Tadidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered intravenously 6, 12, or 24 hours prior to contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 6 hours prior to contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered as a contrast agent It may be administered within 5 hours prior to administration of the drug. In one embodiment, trimetazidin or its drug A pharmaceutically acceptable salt alone, or one or more of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any of the pharmaceutically acceptable salts thereof. The combination may be administered within 4 hours before administration of the contrast agent. In one embodiment, Trimeta Trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 3 hours prior to administration of the contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 2 hours prior to administration of the contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 1 hour prior to administration of the contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, for example, For example, within 6 hours, for instance 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 When administered within 0.75 hours, 0.5 hours, or less than 0.25 hours, it may be administered non-enterally. In one embodiment, one or more of trimetazidin, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, are used for, for example, within 6 hours, for example, 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours. It can be administered non-enterally when administered within 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or less than 0.25 hours. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, may be administered within, for example, 6 hours, for example, 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours. 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour It may be administered intravenously when administered within 0.75 hours, 0.5 hours, or less than 0.25 hours. In one embodiment, trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one of any pharmaceutically acceptable salts thereof The above can be administered intravenously, for example, within 6 hours, for example, within 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or less than 0.25 hours. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, may be administered within a given time. Regardless, it may be administered intravenously. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof, etomoxyl, oxfenicin, perhexylline, mildronate, or lanozine may be administered several days before contrast agent treatment, for example, 1, 2, 3, 4, 5, or 6 days before contrast agent treatment. In one embodiment, the loading or initiation dose regimen is administered 3 days before contrast agent treatment.

[0039] The second dosing regimen is trimetazidine, etomoxil, oxphenicin, perhexyl Maintenance doses may be used to achieve and / or maintain specific exposures in patients with phosphorus, mildronate, or lanolazine. Maintenance doses are initiated immediately after contrast agent administration and may provide sufficient exposure to prevent contrast agent-induced acute injury. Maintenance doses may be achieved by administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, over a period of time after contrast agent administration. For example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered 6, 12, or 24 hours after contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered after contrast agent administration. It may be administered over multiple days, for example, 1, 2, 3, 4, 5, 6 days after contrast agent treatment. In one embodiment, the maintenance dose regimen is administered for a certain number of weeks after contrast agent treatment, for example, 6, 8, 10, or 12 weeks. In some examples, the maintenance dose is administered for about 90 days. In a specific example, the maintenance dose is administered for about 87 days. For example, in one embodiment, the initial dose may be administered for 3 days before contrast agent treatment, and the maintenance dose may be administered for 87 days. Therefore, several In that example, the method of disclosure is intended to administer the dosage and profile described herein over a period of 90 days.

[0040] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered for several days after contrast agent administration, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days after contrast agent administration. For example, trimetazidine or a pharmaceutically acceptable salt thereof may be administered for 90 days after contrast agent administration. In one embodiment, a method for preventing, mitigating, and / or treating contrast agent-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need for at least 90 days.

[0041] In one embodiment, the first and second dose regimens consist of trimetazidin alone or a pharmaceutically acceptable salt thereof, or etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one of the pharmaceutically acceptable salts thereof. The combination of one or more drugs may result in the same or different dosages. Therefore, the first administration regimen And the second administration regimen is trimetazidine, eto in the patient as described herein. The same or different profiles of moxyl, oxphenicin, perhexylline, mildronate, or lanozin (e.g., C max、 AUC 0-∞ ) may provide. In one embodiment The first and second dose regimens provide identical exposure to trimetazidine, etomoxyl, oxfenicin, perhexylline, mildronate, or lanozine.

[0042] In one embodiment, the method and pharmaceutical composition contain 21 mg to 25 mg, 21 mg to 23 mg, 21 mg to 35 mg, 20.5 mg to 25 mg, 22 mg to 30 mg, 20 to 45 mg, 21 mg to 75 mg, 21 mg to 50 mg, 21 mg to 45 mg, 22 mg to 75 mg, 22 mg to 50 mg, 22 mg to 45 mg, 22 mg to 35 mg, 21 mg to 30 mg, 23 mg to 75 mg, 23 mg to 55 mg, 23 mg to 40 mg, 23 mg to 55 mg, 24 mg to 35 mg, 24 mg to 50 mg, and 24 mg to 35 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the method and pharmaceutical composition contain 20 mg to 30 mg, 21 mg to 30 mg, 22 mg to 30 mg, 23 mg to 30 mg, 24 mg to 25 mg, 21 mg to 50 mg, 21 mg to 24 mg, 21 mg to 23 mg, or 21 mg to 22 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the method and pharmaceutical composition include, for example, 20.1 mg, 20.25 mg, 20.5 mg, 21 mg, 21.5 mg, 23 mg, 24 mg, 25 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 mg, or 35 mg of trimetazidine or The pharmaceutical composition contains a pharmaceutically acceptable salt or an amount that is a multiple of such a dose. In one embodiment, the pharmaceutical composition contains 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or 26 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0045] The pharmaceutical compositions herein may be provided having immediate-release, delayed-release, sustained-release, or regulated-release profiles. The compositions herein may also be provided for non-enteral administration (e.g., intramuscular, intravenous, subcutaneous, intraperitoneal, or intrathecal). In one embodiment, the pharmaceutical composition may be provided having an immediate-release profile. In one embodiment, pharmaceutical compositions having different drug-release profiles may be combined to create a two-phase or three-phase release profile. For example, the pharmaceutical composition may be provided having both immediate-release and sustained-release profiles. In one embodiment, the pharmaceutical composition may be provided having both sustained-release and delayed-release profiles. Such compositions may be provided as pulse formulations, multilayer tablets, or capsules containing tablets, beads, or granules. The compositions may be manufactured using a pharmaceutically acceptable “carrier” composed of a substance considered safe and effective. The “carrier” is 1 or This includes all components present in a pharmaceutical formulation other than the multiple active ingredients. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, excipients, and coating compositions.

[0046] Non-enteral compositions must be sterile for administration by injection, infusion, or implantation into the body and may be packaged in either single-dose or multi-dose containers. In one embodiment, a liquid pharmaceutical composition for non-enteral administration to a subject comprises an active substance, for example, an inhibitor of fatty acid oxidation. In one embodiment, a liquid pharmaceutical composition for non-enteral administration to a subject comprises an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof, as described herein. The composition is included by volume. In one embodiment, the pharmaceutical composition for non-enteral administration is formulated as a total volume of, for example, approximately 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In one embodiment, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0047] In one embodiment, the pharmaceutical composition for non-enteral administration contains approximately 0.05 mg to approximately 100 mg of active ingredient The substance includes, for example, an inhibitor of fatty acid oxidation. In one embodiment, the pharmaceutical composition for non-enteral administration contains about 0.05 mg to about 100 mg of an active substance, for example, trimetazidin or a pharmaceutically acceptable substance. The salt alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the aforementioned pharmaceutically acceptable salts. Includes. In one embodiment, a pharmaceutical composition for non-enteral administration is, for example, approximately 0.1 mg to 50 mg, 0.1 mg to 40 mg, 0.1 mg to 35 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 35 mg, 1 mg to 35 mg, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 35 mg, 1.5 mg to 30 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 35 mg, 2 mg to 30 mg, 2 mg to 25 mg, 2 mg to 20 mg Active substances in doses of 2mg-15mg, 2.5mg-35mg, 2.5mg-30mg, 2.5mg-25mg, 2.5mg-20mg, 2.5mg-15mg, 3mg-35mg, 3mg-30mg, 3mg-25mg, 3mg-20mg, 3mg-15mg, for example, trimethodi This includes din alone or a pharmaceutically acceptable salt thereof, or a combination of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof.

[0048] In one embodiment, the pharmaceutical composition for non-enteral administration to a subject contains an active substance, such as trimetazidin or a pharmaceutically acceptable salt thereof, alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof, at concentrations ranging from approximately 0.005 mg / ml to approximately 500 mg / ml. In one embodiment, the pharmaceutical composition for non-enteral administration contains, for example, an active substance, such as trimetazidine or a pharmaceutically acceptable salt thereof, alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof, at concentrations of, for example, about 0.05 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 25 mg / ml, about 0.05 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 5 mg / ml, or about 0.05 mg / ml to about 1 mg / ml. In this context, the pharmaceutical composition for non-enteral administration may consist of an active substance, for example, trimetazidin or a pharmaceutically acceptable salt thereof alone, or etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one of any of the pharmaceutically acceptable salts thereof. The above combinations are included at concentrations of approximately 0.05 mg / ml to 15 mg / ml, approximately 0.5 mg / ml to 10 mg / ml, approximately 0.25 mg / ml to 5 mg / ml, approximately 0.5 mg / ml to 7 mg / ml, approximately 1 mg / ml to 10 mg / ml, approximately 5 mg / ml to 10 mg / ml, or approximately 5 mg / ml to 15 mg / ml. In one embodiment, non-enteral administration Pharmaceutical compositions for this purpose, for example, approximately 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, It is formulated as a total volume of 500 ml. In one embodiment, the composition is a bag, glass bag It is packaged and stored in vials, plastic vials, or bottles.

[0049] In one embodiment, the solubility of an active substance in a pharmaceutical composition for non-enteral administration, such as an inhibitor of fatty acid oxidation, may be higher than, for example, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, or about 150 mg / mL when measured in water at 25°C. In one embodiment, the solubility of an active substance in a pharmaceutical composition for non-enteral administration, such as trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof, may be, for example, 25 When measured in water at °C, the solubility may be higher than, for example, approximately 10 mg / mL, approximately 15 mg / mL, approximately 20 mg / mL, approximately 25 mg / mL, approximately 30 mg / mL, approximately 40 mg / mL, approximately 50 mg / mL, approximately 75 mg / mL, approximately 100 mg / mL, or approximately 150 mg / mL. In one embodiment, the solubility of the active substance in the composition, for example, an inhibitor of fatty acid oxidation, may be, for example, approximately 1 mg / mL to approximately 50 mg / mL, approximately 5 mg / mL to approximately 50 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 30 mg / mL, or approximately 10 mg / mL to approximately 45 mg / mL when measured in water at 25 °C.

[0050] In one embodiment, the composition contains an active substance, for example, trimetazidin or a pharmaceutically acceptable salt thereof alone, or one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof. The solubility of this combination, when measured in water at 25°C, is, for example, approximately 1 mg / mL to approximately 50 mg / mL. The dosage may be approximately 5 mg / mL to 50 mg / mL, approximately 10 mg / mL to 50 mg / mL, approximately 20 mg / mL to 50 mg / mL, approximately 20 mg / mL to 30 mg / mL, or approximately 10 mg / mL to 45 mg / mL.

[0051] In one embodiment, the pharmaceutical composition is stable for at least 6 months for non-enteral administration. A pharmaceutical composition is provided. In one embodiment, the pharmaceutical composition for non-enteral administration shows a decrease of about 5% or less of the active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, for example, over 3 or 6 months. In one embodiment, the amount of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof is, for example, The decomposition occurs at approximately 2.5%, 1%, 0.5%, or 0.1% or less. In one embodiment, the decomposition occurs at least 6 months, and is, for example, approximately 5%, 2.5%, 1%, 0.5%, 0.25%, or less than 0.1%.

[0052] In one embodiment, a pharmaceutical composition for non-enteral administration is provided, in which the pharmaceutical composition remains soluble. In one embodiment, a pharmaceutical composition for non-enteral administration is provided, which is stable, soluble, site-compatible, and / or ready for use. In one embodiment, the pharmaceutical composition herein is ready for use for direct administration to a patient in need.

[0053] The non-enteral compositions provided herein include one or more additives, such as solvents and solubility enhancers. It may contain suspending agents, buffering agents, isotonic agents, stabilizers, or antimicrobial preservatives. When used, the additives of the non-enteral composition may be trimetazidine or a pharmaceutically acceptable salt thereof used in the composition alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof. It does not adversely affect the stability, bioavailability, safety, and / or efficacy of the combination. Therefore, it provides a non-enteral composition in which there are no incompatibilities between any of the components of the dosage form.

[0054] In one embodiment, a non-enteral composition comprising trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, is safe It contains at least one additive in a controlled amount. For example, the additive may be a buffer, a solubilizer, or an isotonic agent. It may contain additives, antioxidants, chelating agents, antimicrobial agents and preservatives. Those skilled in the art will know that if one or more additives are present, You will understand that it possesses the above functions and is classified into one or more defined groups.

[0055] In one embodiment, the non-epithelial materials include trimetazidine alone or a pharmaceutically acceptable salt thereof, or a combination of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, and additives. The present invention provides an intestinal composition in which an additive is present in, for example, approximately 10%, 5%, 2.5%, 1%, or less than 0.5% by weight (w / v). In one embodiment, the additive is For example, approximately 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% It exists in weight percentages of %~1%, 0.1%~1%, or 0.5%~1%. In one embodiment... The additives are, for example, approximately 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, and It exists in a weight percentage of 1% to 15%.

[0056] In one embodiment, the non-enteral composition is, for example, once, two, three, or four times a day or more. Alternatively, it may be administered continuously as needed by the patient.

[0057] In one embodiment, a non-enteral composition is provided comprising an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof, wherein the pH of the composition is about 4.0 to about 8.0. In one embodiment, the pH of the composition is, for example, about 5.0 to about 8.0, about 6.0 to about 8.0, or about 6.5 to about 8.0. In one embodiment, the pH of the composition is, for example, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In one embodiment, the pH of the aqueous solution is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0058] In one embodiment, the methods and pharmaceutical compositions described herein are administered 1, 2, 3, or 4 times a day. It may be administered once or every other day. In one embodiment, the pharmaceutical composition described herein , provided to the patient in the morning. In one embodiment, the pharmaceutical composition described herein is provided to the patient once at night and once in the morning.

[0059] In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to the subject over 24 hours is 20 mg to 200 mg. The total amount of trimetazidin or its pharmaceutically acceptable salt administered is 20 mg to 100 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to the subject over 24 hours is 20 mg to 80 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to the subject over 24 hours is approximately 20 mg, 40 mg, or more than 60 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to the subject over 24 hours is approximately 20 mg to more than 60 mg.

[0060] In one embodiment, an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, is used as needed. The present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering the following to patients: An effective dose or therapeutically effective dose is used for one or more symptoms of contrast-induced acute kidney injury. The dose may be sufficient to treat, suppress, or alleviate the condition. For example, an effective dose of trimetazidine may be used to measure the percentage of patients who experience a relative decrease of 30% or more in estimated or measured glomerular filtration rate (GFR) after a certain period of time (e.g., 15, 30, 60, or 90 days) following contrast agent administration. It can be further established. In other examples, an effective dose of trimetazidine, etomoxyl, oxfenicin, perhexylline, mildronate, or lanozine can be established by measuring the percentage of patients who experienced decreased or lost renal function after contrast agent administration. In one embodiment, the method is, for example, 90 mL / min / 1.73 m 2 Less than approximately 15-90 mL / min / 1.73 m 2 , about 60~90mL / min / 1.73m 2 Alternatively, approximately 15-60 mL / min / 1.73 m 2 This includes administering trimetazidine or a pharmaceutically acceptable salt thereof to patients with an estimated glomerular filtration rate of [value missing].

[0061] In one embodiment, a decline or loss of renal function is measured by an absolute increase of 0.3 mg / dL or more in serum creatinine concentration between baseline and any point in time after contrast agent administration (e.g., up to 7 days). This can be determined by setting. In one embodiment, the method involves 0.4 to 1.3 mg / dL of creatinine. This includes administering trimetazidine or a pharmaceutically acceptable salt thereof to patients with tinine levels.

[0062] In one embodiment, the method comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of less than 1.5 mg / dL. In one embodiment, the method comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of 1.5 to 2.0 mg / dL. The method includes administering a pharmaceutically acceptable salt of the same. In one embodiment, the method involves administering trimetazidine or a pharmaceutically acceptable salt of the same to a patient having a creatinine level of 2.0 to 5.0 mg / dL. The method includes administering a salt. In one embodiment, the method involves administering 5.0 to 8.0 mg / dL of creatinine The method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level greater than 8.0 mg / dL. In one embodiment, the method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level greater than 8.0 mg / dL.

[0063] In one embodiment, a decline or loss of renal function is measured by a relative increase of 50% or more in serum creatinine concentration between baseline and any point in time after contrast agent administration (e.g., up to 7 days). This can be determined by: In one embodiment, a decline or loss of renal function is estimated or measured between baseline and any point in time after contrast agent administration (e.g., up to 7 days) by glomerular filtration rate. This can be determined by measuring a relative decrease of 30% or more in GFR.

[0064] One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of a fatty acid oxidation inhibitor to a patient in need before, during, and after a procedure, including the use of a device, e.g., a guidewire and an intracoronary pressure wire; a cardiac catheter, e.g., a balloon catheter; an atherectomy device, e.g., a rotational atherectomy catheter; an intracoronary stent (including bare-metal stents, drug-eluting stents (e.g., sirolimus, paclitaxel, everolimus, and zotarolimus), stents coated with bioabsorbable polymers, and stents having a fully bioabsorbable scaffold); a thrombus aspiration catheter; an embolic protection device; a replacement cardiac valve and / or vascular closure device. In one embodiment, an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, including a device, e.g., a guidewire and an intracoronary pressure wire, a cardiac catheter, e.g., a balloon catheter, an atherectomy device, e.g., a rotational atherectomy catheter, an intracoronary stent (including bare metal stents, drug (e.g., sirolimus, paclitaxel, everolimus, and zotarolimus) eluting stents, stents coated with bioabsorbable polymers, and stents having a fully bioabsorbable scaffold), a thrombus aspiration catheter, an embolic protection device, a replacement cardiac valve and / or a vascular closure device, is administered to a patient in need, before, during, and after the procedure. The present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administration.

[0065] In one embodiment, an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, in combination with or before and / or after the administration of a contrast agent, such as barium sulfate, iodine, and gadolinium, an anticoagulant, such as acetylsalicylic acid, unfractionated heparin, low molecular weight heparin (enoxaparin), synthetic pentasaccharide / Xa factor inhibitor (including fondaparinux), dipyridamole, argatroban, and / or bivalirudin, ticlopidine, cilostazol, and an antiplatelet agent, such as Cangrelol, clopidogrel, prasugrel, ticagrelor, aspirin, and / or a glycoprotein IIb / IIIa antagonist, such as abciximab, eptifibatide, and tirofiban, to prevent, mitigate and / or treat contrast agent-induced acute kidney injury.

[0066] In one embodiment, a method of preventing, mitigating and / or treating contrast agent-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition has a C max in vivo plasma profile greater than about 65 μg / ml.

[0067] In one embodiment, the composition provides an in vivo plasma profile having a C greater than, for example, 75 μg / ml, 85 ng / ml, 90 ng / ml or 100 ng / ml. max In one embodiment, the composition provides an in vivo plasma profile having a C less than, for example, 250 μg / ml, 200 μg / ml, 150 μg / ml or 100 μg / ml. In one embodiment, a method of treating contrast agent-induced acute kidney injury, comprising administering a pharmaceutical composition comprising an active substance, such as trimetazidine or a pharmaceutically acceptable salt, to a patient in need thereof, wherein the composition has a C max in vivo plasma profile greater than about 100 μg / ml. max having an in vivo plasma profile.

[0068] The effective dose of fatty acid oxidation inhibitor required for administration can depend on many factors. The effective dose of trimetazidine or a pharmaceutically acceptable salt required for administration can depend on many factors. The effective dose of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above required for administration can depend on many factors. For example, sufficient to treat, suppress, or alleviate one or more symptoms of contrast-induced acute kidney injury. The appropriate dosage depends on the actual exposure (AUC) the patient receives. Therefore, in some cases... In some cases, subjects with renal failure undergoing diagnostic or interventional cardiac procedures requiring contrast agent administration may require less fatty acid oxidation inhibitors to achieve an effective dose of exposure. In some cases, subjects with renal failure undergoing diagnostic or interventional cardiac procedures requiring contrast agent administration may require less trimetazidine or a pharmaceutically acceptable salt thereof to achieve an effective dose of exposure. In some cases, subjects with renal failure undergoing diagnostic or interventional cardiac procedures requiring contrast agent administration may require less etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof to achieve an effective dose of exposure.

[0069] In one embodiment, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an in vivo plasma profile having an AUC greater than about 500 μg·hr / ml.

[0070] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering a pharmaceutical composition to a patient in need thereof, wherein the AUC is greater than approximately 500 μg·hr / ml. 0-∞ A method is provided for providing a consistent in vivo plasma profile having [a certain characteristic].

[0071] In one embodiment, the composition may be, for example, approximately 550 μg·hr / ml, 600 μg·hr / ml, 650 μg·hr / ml, 850 μg·hr / ml, 800 μg·hr / ml, 750 μg·hr / ml, or 700 μg·hr / ml, 900 μg ·hr / ml, 1000μg·hr / ml, 1250μg·hr / ml, 1500μg·hr / ml, 2000μg·hr / ml, 3000μg·hr / ml, 4000μg·hr / ml or AUC greater than 5000μg·hr / ml 0-∞ It provides an in vivo plasma profile having the following characteristics.

[0072] In one embodiment, a patient requiring it should have AUC more than 48 hours prior to receiving cardiac treatment. 0- ∞ To maintain this state, trimetazidine or a pharmaceutically acceptable salt thereof is administered. For example, the method is, for example, approximately 500 μg·hr / ml, 600 μg·hr / ml, 750 μg·hr / ml or 1000 μg·hr / ml AUC greater than μg·hr / ml 0-∞ It may be possible to provide and maintain an in vivo plasma profile having [specific characteristics].

[0073] In one embodiment, patients who require it have more than 30 days of AUC after receiving cardiac treatment. 0- ∞ To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. In one embodiment, patients requiring this are given a longer AUC than 60 days after cardiac treatment. 0-∞ of To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. In one embodiment, patients requiring this are given a longer AUC for 75 days after cardiac treatment. 0-∞ Maintain To that end, trimetazidine or a pharmaceutically acceptable salt thereof is administered. In one embodiment, a patient requiring it is given AUC for more than 90 days after cardiac treatment. 0-∞ Maintain Therefore, trimetazidine or a pharmaceutically acceptable salt thereof is administered. For example, the method is to administer doses of approximately 500 μg·hr / ml, 600 μg·hr / ml, 750 μg·hr / ml or more than 1000 μg·hr / ml. AUC 0-∞ In one embodiment, an in vivo plasma profile having can be provided and maintained. And for patients who need it, the total 90-day AUC 0-∞ To maintain this, trimetazidine Alternatively, a pharmaceutically acceptable salt thereof is administered.

[0074] In one embodiment, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering more than 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. The patient may be undergoing a cardiac procedure requiring the administration of a contrast agent for imaging. In some embodiments, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof before undergoing the cardiac procedure. For example, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 48 hours before undergoing the cardiac procedure. In some examples, the patient in need may be administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). Trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In some embodiments, the patient in need is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 48 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). In some embodiments, patients are administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after cardiac treatment. In some embodiments, patients who require it are administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 90 days after contrast agent administration. For example, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to a patient over 24 hours may be about 60 mg.

[0075] In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is used before, during, and / or after a surgical procedure, including the use of one or more guidewires, intracoronary pressure wires, cardiac catheters, atherectomy devices, intracoronary stents, thrombus aspiration catheters, embolic protection devices, replacement heart valves, or vascular closure devices. It is administered to the patient. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is administered to the patient before, during, and / or after a cardiac procedure, including contrast agents, anticoagulants and / or antiplatelet agents. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is one of etomoxyl, oxphenicin, perhexylline, mildronate or lanolazine or any of the pharmaceutically acceptable salts thereof. It is administered in combination with one or more other drugs.

[0076] In some embodiments, a method for preventing and / or treating contrast-induced acute kidney injury comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition contains more than about 65 μg / ml of C maxA method is provided for providing an in vivo plasma profile that defines a contrast agent-induced acute kidney injury. In some embodiments, a method is provided for preventing and / or treating contrast agent-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an in vivo plasma profile that defines an AUC greater than about 500 μg·hr / ml. For example, a patient may be undergoing a cardiac procedure that requires the administration of a contrast agent for imaging. In some embodiments, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof for 48 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). In some examples, a patient in need thereof may be administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). Trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In some embodiments, patients requiring it are administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 48 hours prior to cardiac treatment (e.g., administration of a contrast agent). In some embodiments, patients are administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after cardiac treatment. In some embodiments, patients requiring it are administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 90 days after administration of a contrast agent. For example, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to a patient over 24 hours may be about 60 mg.

[0077] In one embodiment, a method for treating and / or preventing contrast agent-induced acute kidney injury is 1 The administration of trimetazidine or its pharmaceutically acceptable salts, derivatives, and / or analogs in combination with one or more other activators. The combination therapy may include administration of activators in the same mixture or in separate mixtures. In one embodiment, the pharmaceutical composition comprises two, three or more activators.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the field to which this disclosure belongs.

[0079] As used herein, the terms “about” or “approximately” mean a range of acceptable error for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined, i.e., on the limits of the measurement system. For example, “about” may mean within 3 or more than 3 standard deviations, according to convention in the art. Alternatively, “about” may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Or, particularly with respect to biological systems or processes, the term may mean within one order of magnitude of the value, preferably up to 5 times, and more preferably up to 2 times.

[0080] As used herein, the terms “to treat” or “treatment” mean reducing, attenuating, or delaying the onset of clinical symptoms of a disease or condition in an object that may have or be predisposed to the disease or condition, but has not yet experienced or shown any clinical or subclinical symptoms of the disease or condition. In one embodiment, “to treat” or “treatment” may mean preventing the onset of clinical symptoms of a disease or condition in an object that may have or be predisposed to the disease or condition, but has not yet experienced or shown any clinical or subclinical symptoms of the disease or condition. “To treat” or “treatment” may also mean suppressing the disease or symptoms, for example, at least one of its clinical or subclinical symptoms. It can refer to preventing or reducing sexual symptoms. "To treat" or "to treat" can also mean alleviating a disease or symptom, for example, a disease or symptom or at least one of them. This refers to causing regression of clinical or subclinical symptoms. The benefit to the treated subject may be statistically significant, mathematically significant, or at least perceptible to the subject and / or the physician. However, prophylactic and therapeutic treatments are two separate embodiments of the disclosure herein.

[0081] An "effective dose" or "therapeutic dose" is the amount of one or more of the disorders, diseases, or symptoms to be treated. This means a dose sufficient to alleviate symptoms or otherwise provide the desired pharmacological and / or physiological effect.

[0082] "MARCE" refers to "Major Adverse Renal and Cardiac Events," including cardiovascular death and non-fatal myocardial infarction. Alternatively, it is defined as one or more of the following events: non-fatal stroke, heart failure, need for renal replacement therapy, hospitalization for cardiac or renal reasons, persistent >25% decline in eGFR, prolonged hospitalization, or readmission. .

[0083] "Medically acceptable" refers to molecular entities and compositions that, when administered to humans, are "generally considered safe," e.g., physiologically acceptable and do not typically cause allergic or similar adverse reactions, such as stomach upset. In one embodiment, this term refers to the FDA or similar lists, the United States Pharmacopeia, or the use in animals, more specifically in humans. This refers to molecular entities and compositions approved by federal or state regulatory authorities as GRAS (Generally Recognized As Safe) under Sections 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, subject to premarket review or approval under a different generally accepted pharmacopoeia.

[0084] The terms "co-administered with," "administered in combination with," "combined with," or "administered together" can be used interchangeably to indicate that two or more drugs are administered during the course of treatment. This means that the drugs may be administered simultaneously or separately at intervals. The drugs may be administered in a single dosage form or in separate dosage forms.

[0085] "Contrast agents" or "contrast media" are iodine, ba This includes, but is not limited to, lium and gadolinium. For example, iodine-based and barium sulfate compounds are commonly used in X-ray and computed tomography (CT) imaging. The methods described herein include any procedure using contrast agents (X-ray imaging, magnetic resonance imaging). It may be used in imaging of the gastrointestinal system (including but not limited to maging), cardiac procedures, and gastrointestinal imaging (including computed tomography, angiography (arterial examination), venography (venous examination), VCUG (voiding cystourethrography), HSG (hysterosalpingography), and IVU (intravenous urography)).

[0086] As used herein, the terms “prevention” or “prevention” refer to the composition of an object or system that is at risk of or predisposed to one or more symptoms caused by a disease or disorder. Administering a substance to discontinue specific symptoms of a disease or disorder, or to alleviate one or more symptoms of a disease or disorder. This means reducing or preventing the disease or disability, reducing its severity, completely resecting the disease or disability, or stabilizing or delaying the epilepsy or progression of the disease or disability.

[0087] As used herein, "prodrug" refers to a pharmacological substance (drug) administered to a target organism in an inactive (or significantly less active) form. Upon administration, the prodrug is metabolized in the body (in vivo) into a compound with the desired pharmacological activity.

[0088] "Analogs" and "derivatives" are interchangeable and have the same nucleus as the parent compound, but differ in bond order, the presence or absence of one or more atoms and / or groups of atoms and their combinations. This refers to compounds that can differ from the compound. Derivatives, for example, have one or more substituents present in the nucleus. Unlike the parent compound, it may contain one or more atoms, functional groups, or substructures. Generally, derivatives can be presumed to be formed from the parent compound, at least theoretically, through chemical and / or physical processes.

[0089] As used herein, "stereoisomer" refers to isomer molecules that have the same molecular formula and bond order (composition) but differ in the three-dimensional orientation of their atoms in space. Examples of stereoisomers include enantiomers and diastereomers. As used herein, an enantiomer refers to one of two enantiomers of an optically active or chiral molecule. A diastereomer (or diastereoisomer) is a stereoisomer that is not an enantiomer (it is a mirror image that cannot be superimposed on each other). A chiral molecule contains a chiral center, also called a stereocenter or stereogenic center, and any two groups can be exchanged to produce a stereoisomer. In molecules possessing a chiral center, it is not necessarily an atom but any point. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, but in organic and inorganic compounds, other atoms can also be the stereocenter. A molecule may have multiple stereocenters and offer many stereoisomers. In compounds where stereoisomerism is due to a tetrahedral stereogenic center (e.g., tetrahedral carbon), the hypothetically possible total number of stereoisomers does not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have a smaller maximum number of possible stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers is one in which one enantiomer is present in greater than 50% of the mixture. The material can be enantiomerically enriched. The enantiomer and / or diastereomer can be divided or separated using techniques known in the art. "Chirality" also includes axial or planar chirality.

[0090] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound described herein, which is modified by forming an acid salt or base salt of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, metal or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts are , including inorganic acids, such as those derived from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts produced from organic acids, such as acetic acid, propionic acid, gojiacin, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetooxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionates. [Examples]

[0091] The examples provided herein are included solely to enhance the disclosure herein and should not be considered limiting in any way.

[0092] Example 1 The following is a hypothetical example: percutaneous coronary intervention or peripheral coronary intervention. This study may be used to evaluate the effect of trimetazidine on the prevention of contrast-induced acute kidney injury in high-risk patients undergoing tubular angioplasty. This multicenter, randomized, double-blind, placebo-controlled trial will be used in patients undergoing planned percutaneous coronary intervention (PCI) or peripheral tubular angioplasty. A triol that reduces the incidence of CI-AKI in high-risk patients undergoing post-to-surgical artery repair (PTA). This can be used to evaluate the efficacy of metazidine. Furthermore, this trial may be used for planned PCI or This refers to the 30-day clinical adverse events (death, RRT, MI, stroke, clinically driven revascularization, or major adverse cardiovascular events) in high-risk patients undergoing PTA. This may be used in some cases to determine the efficacy of trimetazidine in reducing incidence. This trial will assess clinical adverse events (death, RRT, MI, stroke, clinically necessary revascularization, or major adverse cardiovascular events) at 90 days in high-risk patients undergoing planned PCI or PTA. This study may be used to determine the effectiveness of trimetazidine in reducing the incidence of ). Furthermore, this study will assess the 1-year clinical impact of trimetazidine in high-risk patients undergoing planned PCI or PTA. Adverse events (death, RRT, MI, stroke, clinically necessary revascularization, or major adverse cardiovascular events) It may be used in some cases to determine the effectiveness of trimetazidine in reducing the incidence of ).

[0093] The primary efficacy endpoint of this study may include the incidence of CI-AKI at 72 hours post-contrast exposure. CI-AKI may be defined as an increase in serum creatinine >0.5 mg / dl (44.2 μmol / L) or a percentage increase of ≥50% of serum creatinine from baseline blood sample taken before contrast exposure. The primary efficacy endpoint is death, RRT, MI, stroke, and clinically necessary revascularization. This may include a composite of clinical adverse events at 30 days, including reconstruction or major adverse cardiovascular events. Further efficacy endpoints include death, RRT, MI, stroke, clinically required revascularization or major adverse cardiovascular events. This may include a composite of clinical adverse events at 90 days, including adverse cardiovascular events. Further efficacy endpoints include death, RRT, MI, stroke, clinically required revascularization, or major This may include, in some cases, a combination of clinical adverse events over a one-year period, including harmful cardiovascular events.

[0094] Secondary endpoints may include one or more of the following clinical events within 30 days: all-cause mortality; myocardial infarction. Infarction; dialysis-dependent renal failure; unplanned readmission; repeated coronary revascularization of target lesions; massive bleeding (unrelated to coronary artery bypass procedure); major adverse cardiovascular events and stroke. Further secondary endpoints may include the following laboratory-based metrics at 72 hours: percentage of subjects with >0.5 mg / dl (44.2 μmol) SCr increase; percentage of subjects with >25% SCr increase; >100% Percentage of subjects with increased SCr; percentage of subjects with increased SCr > 200%; and average eGFR Equal change.

[0095] Example 2 The following hypothetical example was used to evaluate the effect of trimetazidine on reducing the risk of contrast-induced acute kidney injury (CI-AKI) and related major adverse renal and cardiac events (MARCE). This multicenter, randomized, double-blind, placebo-controlled trial compared the trimetazidine group with the placebo group in determining whether any adverse renal and cardiac events occurred during the 90 days following the day of contrast agent administration (MARCE). MARCE can be used to assess the proportion of subjects who experience cardiovascular death, non-lethal death. This is defined as a heart-related myocardial infarction, heart failure, need for renal replacement therapy, hospitalization for cardiac or renal reasons, and a decrease of ≥25% in eGFR. Further outcome measures include trimetadjusted blood glucose in one or more of the following: This may include differences between subjects treated with gin and placebo: (1) Incidence of CI-AKI based on the KDIGO definition of CI-AKI; (2) Total number of MARCE events, as each subject may experience multiple events; (3) Percentage of subjects experiencing cardiovascular death; (4) Percentage of subjects experiencing non-fatal myocardial infarction; (5) Percentage of subjects experiencing heart failure; (6) Percentage of subjects requiring renal replacement therapy; (7) Percentage of subjects discharged from the hospital. (8) the number of days alive; (9) the percentage of subjects who are readmitted for cardiac or renal reasons; (10) the percentage of subjects who maintain an eGFR decrease of ≥25% at 90 days; and / or (11) the quality of life of the subjects. Change from the baseline.

[0096] Within approximately 48 hours prior to the estimated start of angiography (e.g., arterial sheath insertion), trimetazidine may be administered in a planned range, e.g., 3–6 doses, according to the planned schedule. Administration may continue for up to 120 days from the date of the procedure, e.g., 90, based on the results observed during follow-up visits. It can continue for several days. For example, follow-ups may be after 1, 2, 4, 7, 30, 60, 90, or 120 days. This can occur. The subject may have one or more of the following criteria: Modification of Diet in Renal eGFR <45 mL / min and >15 mL / min as determined by the Disease (MDRD) formula, or eGFR <60 mL / min and ≥45 mL / min as determined by the MDRD formula, and diabetes mellitus, congestive heart failure, or anemia.

[0097] Example 3 The following hypothetical example was used to evaluate the effect of trimetazidine on reducing the risk of contrast-induced acute kidney injury (CI-AKI) and related major adverse renal and cardiac events (MARCE). This multicenter, randomized, double-blind, placebo-controlled trial showed that trimetazidine may reduce major adverse renal and cardiac events (MARCE) and prevent contrast-induced acute kidney injury (CI-AKI). Trimetazidine for evaluating efficacy and / or for reducing individual elements of MARCE It may be used to evaluate the effectiveness of [the drug]. The primary outcome measure may include determining the difference in time to the first major adverse kidney and cardiac event (MARCE) over a certain period (e.g., 90 days) after contrast agent administration between trimetazidine and placebo. The Tocam index may include differences between subjects treated with trimetazidine and placebo in the following: (1) the incidence of CI-AKI based on the KDIGO definition of CI-AKI from baseline to the end of treatment (e.g., day 90); (2) the proportion of subjects experiencing any MARCE event; (3) each subject The body can experience multiple events, therefore: (4) the total number of MARCE events; (5) time to cardiovascular death; (6) non-lethal (6) Time to fatal myocardial infarction; (7) Time to non-fatal stroke; (8) Time to heart failure; (9) Renal (9) Time until alternative therapy is needed; (10) Length of hospitalization; (10) Survival after discharge. (11) the percentage of subjects maintaining an eGFR decline of >20%; (12) the percentage of subjects with prolonged hospitalization or readmission events; and / or (13) the time to readmission for cardiac or renal reasons. During this theoretical trial, subjects may receive either daily doses of trimetazidine (e.g., 20 mg three times daily) or placebo. During index hospitalization, all subjects will be given intravenous isotonic crystalloid solution (normal saline or sodium bicarbonate) in accordance with the standards for conducting clinical trials of the drug. For example, within approximately 48 hours prior to the estimated start of angiography, trimetazidine may be administered in a planned range of 3–6 doses (e.g., 20 mg three times daily for 1–2 days). Thereafter, study subjects may continue to receive trimetazidine for the treatment period (e.g., a further 90 days) from the day of index treatment. One or more outcome measures will be used from the start of the trial. The evaluation can be performed at regular intervals between the total treatment time, for example, after 1, 2, 4, 7, 14, 30, 60 and / or 90 days.

[0098] Those skilled in the art will be able to identify and verify many equivalents to the embodiments and examples described herein by means of routine experiments. Such equivalents are intended to be included in the claims.

Claims

[Claim 1] The method described in the specification.