Method for preventing, treating or relieving myocardial injury using neuregulin and composition therefor

Abstract

To provide a method and a composition for preventing, treating or delaying myocardial injury in mammals.SOLUTION: Provided are an administration method for, an administration frequency of and an administration dosage of a pharmaceutical formulation or composition for reducing myocardial damage, using neuregulin. It can be proved in a rat myocardial damage model that neuregulin can improve the cardiac function after myocardial infarction, suggesting that neuregulin can be used for preventing, treating or delaying myocardial infarction damage.SELECTED DRAWING: None

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the manufacture of a medicament for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention also relates to the use of neuregulin (NRG) for the treatment of cardiac dysfunction in mammals. Methods for administering pharmaceutical preparations or compositions comprising NRG to prevent, treat, or alleviate muscle damage; In particular, the present invention relates to a method for preventing, treating, or alleviating myocardial damage. The present invention relates to a method for preventing myocardial damage in a mammal, a pharmaceutical composition comprising NRG for this purpose, and a method for preventing myocardial damage in a mammal, The method, frequency and administration of pharmaceutical preparations or compositions containing NRG for treating or alleviating and dosage. [Background technology]

[0002] BACKGROUND OF THEINVENTION Cardiovascular problems pose a serious threat to people's lives and health worldwide. There are many types of heart failure, myocardial infarction, coronary arteriosclerosis, arrhythmia, cardiomyopathy, and heart valve disease. Cardiovascular disease includes endocarditis, infective endocarditis, pericardial disease, ischemic heart disease, and congenital heart disease. It tends to cause myocardial damage and affect cardiac function, which makes the body feel unwell. Myocardial infarction is a cardiovascular disease that seriously endangers human health. As the standard of care continues to improve, the incidence of ischemic myocardial infarction has steadily increased. Coronary artery occlusion is a condition in which the coronary blood supply is suddenly reduced or interrupted due to persistent occlusion of the coronary artery. ischemic myocardial necrosis induced by severe and chronic myocardial ischemia caused by Ischemic myocardial infarction causes myocardial cell death and scarring, which leads to cardiac arrest. Affects function.

[0003] When a myocardial infarction occurs, the coronary artery is blocked for 20 to 30 minutes, resulting in a lack of blood and causing myocardial infarction. Part of the cyst becomes necrotic, and the pathological process of myocardial infarction begins. As myocardial necrosis becomes more severe, After 2 hours, most of the affected myocardial cells gradually underwent coagulative necrosis, and at the same time, a large amount of inflammation The myocardial interstitium becomes congested and edematous with infiltration of myocardial cells. The myocardial necrosis process lasts approximately 6–1 The effect is complete after 2 hours. Myocardial fibers dissolve after 1-2 weeks. The necrotic zone is then gradually broken down into fibrils, and finally, after six weeks, the necrotic zone becomes fibrous. In the early stages of myocardial infarction, the scar tissue is replaced completely by a dense scar. This is known as old or resolved myocardial infarction.

[0004] The normal function of the left ventricle is significantly affected after the occurrence of a myocardial infarction. When this occurs, the pumping function of the left ventricle is impaired, resulting in reduced cardiac output, stroke volume, and blood pressure. Concomitantly, end-systolic volume increases and end-diastolic volume may increase within weeks of infarction. .

[0005] Ventricular remodeling is a significant pathological event that occurs after myocardial infarction. The ring is a change in the structure and morphology of the infarcted and non-infarcted areas of the ventricle after myocardial infarction. The changes in the infarcted area mainly include the expansion of the infarct, whereas the changes in the non-infarcted area mainly include the expansion of the infarct. The classic sign of ventricular remodeling is ventricular decompensated hypertrophy. The change in ventricular mass, volume expansion, and morphological changes lead to dysfunction of the ventricular pump. This can lead to heart failure. The underlying mechanism is ventricular remodeling, a condition that occurs as a persistent and progressive event secondary to myocardial infarction. The severity of these changes determines the patient's cardiac function and prognosis. Ventricular remodeling is a major risk factor that affects cardiac function and endangers human life. It is a type of cardiovascular disease.

[0006] Currently, the main treatment for myocardial infarction is reperfusion (thrombolytic therapy and interventional therapy) in the early stages. method), angiotensin II receptor blockers, angiotensin-converting enzyme (ACE) ) inhibitors and β-receptor blockers. These reduce infarct size and prevent recurrent myocardial ischemia. It is effective in reducing the number of ventricles, improving revascularization, and suppressing excessive ventricular dilation, This will reduce the incidence of chronic heart failure.

[0007] The symptoms of myocardial infarction are closely related to the size and location of the infarction and the status of coronary collateral vessels. The main symptoms include pain, fever, tachycardia, nausea, vomiting, hypotension, shock, and arrhythmia. Major complications of myocardial infarction include papillary muscle dysfunction or rupture, cardiac rupture, and ventricular aneurysm. , embolism, and post-infarction syndrome (PMIS).

[0008] Most of the existing drugs or interventional therapies can only alleviate the symptoms of myocardial infarction, but Damage to the organ tissue cannot be repaired. For patients with advanced myocardial infarction, heart transplantation is recommended. is a last-ditch treatment option that can improve cardiac function and save terminally ill patients, but Due to scarcity, surgical complexity, immune rejection, and high costs of treatment, it is difficult to use in clinical practice. This makes it difficult to apply widely.

[0009] In summary, myocardial damage caused by cardiovascular diseases poses serious harm to human health. In particular, myocardial infarction, a fatal disease that seriously endangers human health, is a clinical There is a need to treat with safer and more effective drugs in practice.

[0010] Neuregulin (NG) or heregulin (HRG), a member of the EGF-like family, binds NR Structurally similar to each other, including G1, NRG2, NRG3, and NRG4, and their isomers. This refers to a group of growth differentiation factors (GDFs), which stimulate breast cancer cell differentiation and milk protein secretion. (Lessor T et al., J Cell Biochem. 1998; 70 (4):587-595); Schwannocytes of neural crest cells differentiation into osteoblasts (Topilko et al., Mol Cell Neurosci, 1996; 8 (2-3): 71-75); Stimulation of the synthesis of acetylcholine receptors in skeletal muscle cells (Altiok N et al., EMBO. J. 1995; 14 (17): 4258-4266); promoting cardiomyocyte survival and DM synthesis (Zhao YY et al., I Biol Chem. R. 1998; 273 (17): 10261-10269). In vivo studies performed on mouse embryos carrying the gene deficiency have demonstrated that NRG regulates cardiac and neural development. proved to be necessary.

[0011] NRG receptors are members of the EF receptor family, which also includes FR, ErbB2, ErbB, and ErbB4. NRG receptors play an important role in cell proliferation, differentiation, and survival. Tyrosine kinase consists of a main domain, a transmembrane domain, and an intracellular tyrosine kinase domain. When NRG binds to the extracellular domain of ErbB3 or ErbB4, it There, a transcriptional change occurs, which results in ErbB3 / ErbB4 or ErbB2 / ErbB3 heterodimerization. The ErbB4 / ErbB4 homodimer or ErbB4 / ErbB4 dimer is formed, and its C-terminus is phosphorylated. The modified C-terminus further binds to downstream signaling proteins within the cell, such as AKT and / or activates the EK signaling pathway, ultimately inducing cell proliferation, cell differentiation, cell apoptosis, It can trigger a range of cellular responses, such as stimulating or inhibiting cell migration or cell adhesion. Among these receptors, ErbB2 and ErbB4 are mainly expressed in cardiac tissue (Zhao YY et al. (Ref. Circ Res. 1999; 84 (12): 1380-1387).

[0012] Existing evidence suggests that the EGF-like domain of NRG-1, which contains amino acids 50-64, binds to the receptor and It has been shown that it has a high ability to activate 5; 270 (21): 12857-12863). NRG-1β can bind with high affinity to ErbB3 and ErbB4. B2 can form heterodimers with ErbB3 or ErbB4, and its affinity for ligands The affinity of ErbB3 or ErbB4 homodimers for their ligands is higher than that of ErbB3 or ErbB4 homodimers. Studies have demonstrated that signaling through NRG-1β, ErbB2, and ErbB3 is essential for the formation of the sympathetic nervous system. It has been confirmed that the above-mentioned requirement is met (Britsch S et al., Dienes Dev. 1998; 12 (12): Loss of expression of NRG-1β, ErbB2, or ErbB4 results in impaired cardiac development. It causes embryonic lethality (Gassmann M et al., Nature, 1995; 378(6555): 390-394). Recent studies have demonstrated that NRG-1β, ErbB2, and ErbB4 are not only essential for cardiac development but also It has also been shown to play a crucial role in maintaining adult cardiac function (Kura Mochi Y et al., J Mol Cell Cardiology 1. 2006; 41 (2): 228-235). NRG-1β is a marker of cardiovascular disease in adults. It has been shown that it can enhance the formation of myocardial sarcomeres in various cardiac disorders. In all animal models, administration of the NRG-1β EGF-like domain improved cardiac function, It has been found that cardiac dysfunction can be prevented (Liu et al., J Am Coll Cardiol. 2006; 48: 1438-1447). Clinical trials have also demonstrated that NRG is effective in treating chronic glaucoma caused by a variety of etiologies. It has been shown to have a therapeutic effect on chronic heart failure and significantly enhances cardiac function (CN200910057390.5). In an animal model of cerebral ischemia-reperfusion, NRG-1 showed a significant protective effect on brain cells. , inhibiting the apoptosis of brain cells, enhancing neurological function, and reducing infarct size (Li (Q et al., Neurosci Lett. 2008; 443 (3): 155-159). This induces release of erythrocyte secretion and activates the NRG / ErbB signaling pathway in cardiomyocytes (Kuramochi Y et al., J Biol Chem. 2004; 279 (49): 51141-51147), and NRG-1 inhibits cardiac ischemia-reperfusion There is evidence that it plays a role in the prevention, treatment or mitigation of injury (WO2011091723) .

[0013] Myocardial injury is a fatal disease that seriously endangers human health. The method, frequency and dosage of administration of NRG-1 for the treatment of rheumatoid arthritis have yet to be clearly determined. The present invention provides a method for addressing the above needs and a pharmaceutical composition comprising NRG therefor. It is worth mentioning that the present invention provides a particularly optimized frequency of administration, and the present invention provides a specifically optimized method of administration. The present invention further relates to a method for the prevention, treatment, or amelioration of myocardial injury in a mammal. The present invention relates to the use of NRG for the manufacture of a method for the treatment of myocardial infarction. The present invention provides a particularly optimized dosage and the present invention provides a particularly optimized administration frequency. The present invention provides an improved method of administration. Summary of the Invention

[0014] (Detailed Description) (A. Overview) The present invention relates to the manufacture of a medicament for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention further provides the use of NRG for preventing and treating myocardial injury in a mammal. In relation to the use of NRG for the manufacture of a medicament for the treatment or alleviation of NRG improves cardiac function affected by myocardial injury and reduces cardiac remodeling. It is possible to do so.

[0015] Many cardiovascular diseases, such as heart failure, myocardial infarction, coronary arteriosclerosis, arrhythmia, myocarditis, Valve heart disease, infective endocarditis, pericardial disease, ischemic heart disease, congenital heart disease, etc. can cause myocardial damage. Myocardial damage can affect cardiac function and pose a risk to human health. Infarction is accompanied by persistent coronary artery occlusion, which usually results in apoptosis and necrosis of myocardial cells, massive inflammation, and The myocardial infarction injury is accompanied by the infiltration of inflammatory cells and myocardial fibrosis. It has a tendency to cause cardiac dysfunction and thus affects human health.

[0016] The present invention demonstrates that NRG is essential for cardiac development and plays a crucial role in maintaining cardiac function in adults. The present invention is based on the scientific discovery that NRG plays an important role in the regulation of sarcomere in cardiomyocytes. Based on the scientific discovery that the formation of cytoskeleton and intercellular junctions can be strengthened; The invention demonstrates that NRG inhibits the heart function of animals or patients with heart failure in various animal models and clinical trials. The present invention is based on the scientific discovery that NRG can enhance cerebral ischemia-reperfusion function. Based on the scientific discovery that it exerts a protective effect on brain cells in animal models of hypertension; Akira has reported that NRG exerts a protective effect on brain cells in an animal model of cardiac ischemia-reperfusion. Based on scientific discoveries; NRG, NRG polypeptides, and mutants of NRG or having NRG-like functions All other conjugates which achieve the same effects are within the scope of the present invention.

[0017] In a first aspect, the present invention provides a method for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention further provides a pharmaceutical preparation for preventing damage due to myocardial infarction in a mammal. The present invention provides a pharmaceutical preparation for the prevention, treatment or palliative treatment of a disease in which the mammal is preferably a human. The pharmaceutical preparations contain an effective amount of NRG or a functional fragment thereof, or a nucleic acid encoding NRG. or functional fragments thereof, or substances that increase the production and / or function of NRG, and pharmaceuticals The pharmaceutical preparation includes a carrier, excipient, etc. that is acceptable for use as a pharmaceutical agent for preventing, treating, or preventing myocardial injury. It can be used in combination with other drugs or therapies to alleviate the symptoms of the disease. In such cases, pharmaceutical preparations containing NRG are effective in increasing the EF value of the mammalian left ventricle. In another embodiment, the pharmaceutical preparation comprising NRG is administered to increase the left ventricular end diastolic volume (LVEDV) or left ventricular end diastolic volume (LVADV). In another embodiment, the pharmaceutical preparation comprising NRG is effective in reducing ventricular end systolic volume (LVESV). The formulation is injected subcutaneously via a syringe or other device. In another embodiment, the formulation comprises NRG. The pharmaceutical preparation is injected subcutaneously via a pump, such as an injection pump. In an embodiment, the syringe pump is a micropump. , the micropump is an insulin pump. It is worth mentioning that the present invention is The pharmaceutical preparation may be any preparation available as NRG, and the pharmaceutical preparation may comprise NRG as described above or may comprise NRG. and a pharma- ceutical acceptable excipient, diluent, or carrier. Pharmaceutical preparations that can be used include, but are not limited to, those described herein.

[0018] In a second aspect, the present invention provides a method for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention further provides a method for preventing damage from myocardial infarction in a mammal, The present invention provides a method for treating or alleviating the symptoms of a disease characterized by the above-mentioned, wherein the mammal is preferably a human. an effective amount of NRG or a functional fragment thereof, a nucleic acid encoding NRG or a functional fragment thereof or the production of NRG and / or mitigation of myocardial injury in a mammal. The method includes the use of substances that increase the function of the other drugs, particularly effective amounts of NRG or its derivatives. a nucleic acid encoding NRG or a functional fragment thereof, or a nucleic acid encoding NRG or a functional fragment thereof, Combination of substances that increase the production and / or function of NRG to prevent, treat, or mitigate muscle damage. Can be used in combination.

[0019] In a third aspect, the present invention provides a method for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention further provides a composition for preventing damage from myocardial infarction in a mammal. The present invention provides a pharmaceutical composition for the treatment or amelioration of a disease characterized by a pulmonary edema, wherein the mammal is preferably a human. The pharmaceutical composition comprises a compound according to the present invention for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention includes the use of NRG of the type provided herein, as well as other drugs for preventing, treating, or ameliorating myocardial injury. The pharmaceutical composition includes an EGF-like domain that binds to and activates the receptor. It has been demonstrated that it is possible to However, the NRG provided by the present invention is, for example, a fragment of the NRG-1β2 isomer, 177-2 It contains 37 amino acids. The amino acid sequence of this fragment is: [ka]

[0020] In a fourth aspect, the present invention provides a method for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention further provides a pharmaceutical preparation comprising NRG for use in administering to a mammal. A pharmaceutical product containing NRG for use in preventing, treating, or mitigating damage from myocardial infarction in Dosages of pharmaceutical preparations are provided, and the mammal is preferably a human. This means that one or more beneficial effects can be achieved when the dose is applied to a mammal. The beneficial effects are thought to improve cardiac function in patients with myocardial damage and prevent further deterioration of that cardiac function. and preventing the progression of cardiac dysfunction that may be caused by myocardial damage. The dosage provided to a mammal by the present invention is 0.1 μg / kg / day (protein / body). In one embodiment, the dose is 0.3 μg / kg / day (protein / body weight). / day (protein / body weight) to 50 μg / kg / day (protein / body weight); in one embodiment In one embodiment, the effective dose is 7.5 μg / kg / day; in one embodiment, the effective dose is 15 μg / kg / day. In another embodiment, the effective dose is 30 μg / kg / day.

[0021] In a fifth aspect, the present invention provides a method for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention further provides a method for administering a pharmaceutical preparation comprising NRG to a mammal. Methods of administering pharmaceutical preparations containing NRG to prevent, treat, or reduce damage from myocardial infarction and the mammal is preferably a human. The pharmaceutical preparations may be administered orally, rectally, topically, or intramuscularly. Oral administration, inhalation administration, buccal administration (e.g., sublingual administration), parenteral administration (e.g., subcutaneous injection, intramuscular administration) Intramuscular, intradermal, or intravenous injection), transdermal administration, or any other suitable method In one embodiment, NRG is administered only once a day. In one embodiment, NRG is administered multiple times per day. In another embodiment, NRG is administered daily. In some embodiments, this tolerated dose of NRG is administered within a few days. In another embodiment, NRG is administered two days a week for multiple consecutive days. In another embodiment, NRG is administered two days a week for one day. In another embodiment, NRG is administered subcutaneously three times a day for many consecutive weeks. In another embodiment, NRG is administered subcutaneously three times daily for consecutive days. In another embodiment, NRG is administered subcutaneously three times a day for 38 consecutive days. In another embodiment, NRG is administered subcutaneously three times per day for 49 consecutive days. In another embodiment, NRG is administered subcutaneously three times daily for 60 consecutive days. In another embodiment, NRG is administered three times daily for more than 35 consecutive days. In another embodiment, NRG is administered multiple times per day for many consecutive days. In another embodiment, NRG is administered multiple times a day in multiple consecutive doses. Administered over consecutive days, then slowly discontinued over 3 weeks: 1st week, every other day and every 3 days for the second week; and every 4 days for the third week. NRG was administered subcutaneously three times daily for more than 38 consecutive days and then slowly discontinued. In another embodiment, NRG is administered subcutaneously three times daily for 49 consecutive days, followed by administration over a three week period. Slowly discontinue: 1st week, every other day; 2nd week, every 3rd day; 3rd week, every 4th day. In another embodiment, NRG is administered subcutaneously multiple times per day for multiple consecutive days. In another embodiment, NRG is administered 3 times a day, followed by a slow taper in the daily dose. once for many consecutive days, then the daily dose is slowly tapered. In one embodiment, NRG is administered subcutaneously three times daily for more than 60 consecutive days, and then The daily dose is slowly tapered. In another embodiment, NRG is administered three times a day for 60 consecutive days. Subcutaneous injection for 1 week followed by slow withdrawal over 3 weeks: Daily doses in week 1 are the daily dose in the second week was one-quarter of the continuous dose; the daily dose in the third week was one-quarter of the continuous dose. The daily dose should be one-eighth of the continuously administered dose.

[0022] The present invention also provides a kit for preventing, treating, or ameliorating myocardial damage in a mammal. The present invention also provides a method for preventing, treating, or reducing damage from myocardial infarction in a mammal. The present invention provides a kit for preventing myocardial injury, the mammal being preferably a human. A single or multiple dose of said pharmaceutical preparation or composition for the prevention, treatment, or palliative care of and instructions for use of the pharmaceutical preparation or composition.

[0023] The pharmaceutical preparations or compositions provided by the present invention may be administered before, during, or after the onset of heart disease. When used for prophylaxis, the pharmaceutical preparation or composition generally is administered to When used in therapy, the pharmaceutical preparation or composition generally is administered to treat a heart disease. In one embodiment, the pharmaceutical preparation provided by the present invention is administered during or after the onset of In another embodiment, the present invention provides a method for the treatment of heart disease. Provided pharmaceutical preparations or compositions are administered when a myocardial infarction occurs. In the present invention, the pharmaceutical preparation or composition is administered after the onset of heart disease. do.

[0024] The pharmaceutical preparations or compositions provided by the present invention can be administered orally, rectally, topically, Inhalation administration, buccal administration (e.g., sublingual administration), parenteral administration (e.g., subcutaneous injection, intramuscular injection) The drug may be administered by injection, intradermal, or intravenous injection), transdermal administration, or any other suitable method. Subcutaneous injection can be performed using a syringe, a pump (microinjector pump), or another administration device. The pharmaceutical preparation or composition provided by the present invention may include the following dosage forms: Including, but not limited to, tablets, troches, cachets, dispersions, suspensions, solutions, capsules , ointments, and similar forms.

[0025] (B. Definition) Unless otherwise defined, all scientific and technical terms used herein are understood to be of ordinary skill in the art. All patent documents, patent application documents, Published patent documents and other publications are cited by reference. If any definition of a term has a different meaning from that explained in the above document, the definition given in this section shall apply. The explanation shall take precedence.

[0026] Unless otherwise specified, as used herein, "a / an" means "at least one "one" or "one or more."

[0027] As used herein, "mammal" refers to non-human primates (bovine, porcine, equine, feline, canine, The term refers to animals such as rats, mice, etc., or primates (monkeys, humans), preferably humans.

[0028] As used herein, "myocardial damage" refers to heart failure, myocardial infarction, coronary arteriosclerosis, arrhythmic heart disease, and myocardial infarction. Cardiomyopathy, valvular heart disease, infective endocarditis, pericardial disease, ischemic heart disease, or congenital heart disease It refers to certain types of myocardial damage caused by pathological heart diseases such as myocardial infarction. Myocardial damage tends to cause dysfunction, thereby affecting human health. The causes are oxyradical production, calcium overload, and inflammatory reactions due to neutrophil infiltration into the injured area. Response, apoptosis or necrosis of cardiomyocytes, tissue damage caused by energy supply imbalance metabolic disorders, abnormalities in cardiac signaling, cholesterol accumulation, and atherosclerotic plaque It is associated with multiple pathophysiological changes, including vascular endothelial cell formation.

[0029] As used herein, "neuregulin" or "NRG" refers to any of ErbB2, ErbB3, ErbB4, or Heterologous Neuregulins. A protein or polypeptide capable of binding to and activating a heterodimer or homodimer. NRG refers to a peptide. NRG includes NRG isoforms, NRG EGF-like domains, and NRG EGF-like domains. and a polypeptide comprising the agonist, a mutant or derivative of NRG, and a polypeptide capable of activating said receptor. NRG also includes other gene products of NRG that can The present invention includes, but is not limited to, polypeptides, fragments, and complexes having NRG-like functions. Proteins that can bind to and activate ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimers As an example, and not by way of limitation, The NRG (rhNRG) provided by the invention is a fragment of the NRG-1β2 isomer that contains the EGF-like domain. The amino acid sequence of this fragment is as follows: R: [ka] The NRG used in the present invention activates the above receptor and regulates its biological function. For example, it can stimulate skeletal muscle cells to synthesize acetylcholine receptors; NRGs can promote differentiation, survival, and DNA synthesis. They have substantial effects on biological functions. As will be appreciated by those skilled in the art, conservative NRG mutations that do not confer essential functions are also included. Mutation of a single amino acid in a sequence can result in a loss of biological function of a protein or polypeptide. (Watson et al., "Molecular Biology of the Gene" Gene), 4th edition, 1987, The Bejacmin / Cummings Pub. Co., p. 224). NRGs can be extracted from natural sources or obtained recombinantly, synthetically, or by other means. It can also be obtained.

[0030] As used herein, the term "EGF-like domain" refers to any of ErbB2, ErbB3, ErbB4, or heterodimers thereof. It is capable of binding to and activating a dimer or homodimer, and is disclosed in the following publications: WO 00 / 64400; Holmes et al., Science, 256: 1205-1210 (1992); U.S. Pat. No. 5,530,109 and 5,716,930; Hijazi et al., Int. J. Oncol., 13: 1061-1067 (1998); Chang et al., Nature, 387: 509-512 (1997); Carraway et al., Nature, 387: 512-516 (1998). 97); Higashiyama et al., J. Biochem., 122: 675-680 (1997); and WO 97 / 09425. The polypeptide encoded by the NRG gene has a structure similar to the EGF receptor binding zone described above. In some embodiments, the EGF-like domain refers to a peptide fragment of ErbB2 / ErbB4 or ErbB In some embodiments, E binds to and activates ErbB2 / ErbB3 heterodimers. The GF-like domain comprises amino acids in the receptor binding zone of NRG-1. In the context of the invention, the EGF-like domain refers to amino acids 177-226, 177-237 or 177-240 of NRG-1. In some embodiments, the EGF-like domain is an amino acid sequence in the receptor binding zone of NRG-2. In some embodiments, the EGF-like domain comprises the receptor binding zone of NRG-3. In some embodiments, the EGF-like domain comprises the amino acid sequence of In some embodiments, the EGF-like domain comprises amino acids in the receptor binding zone. , including the amino acid sequence described in U.S. Pat. No. 5,834,229: Ala Glu Lys Glu Lys Thr Phe C ys Val Asn Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro.

[0031] NRG can be administered orally, rectally, topically, by inhalation, bucally (e.g., sublingually), or via a variety of routes. Parenteral administration (e.g., subcutaneous, intramuscular, intradermal, or intravenous injection), transdermal administration, or any other suitable method. The preferred route of administration of the moiety will depend on the condition and severity to be treated, as well as the characteristics of the particular NRG used. The NRG may be administered alone or, more preferably, in combination with It may be administered with any pharma- ceutically acceptable carrier or excipient. Suitable pharma- ceutically acceptable carriers or excipients are provided herein (see Remington: Pharmaceutical Sciences, 1999). Remington: The Science and Practice of Pharmacy, Alfonso R. Gennar o (ed.) Mack Publishing Company, April 1997).

[0032] As used herein, a "pump" refers to a pump that delivers pharmaceutical fluids, drugs, proteins, and / or other compositions. A pump is a device for administering drugs subcutaneously. It is used for continuous, precise, and quantitative administration. The pump is provided with a subcutaneous catheter for continuous subcutaneous infusion. The catheter can be placed externally or the catheter port can be connected to the pump mechanism. Microinjection pumps are portable, easy-to-use devices that can be used for precise injections. For example, an insulin pump is a device that delivers insulin during the treatment of diabetes or other diseases. Insulin pumps are medical devices used to administer insulin or other medications. The insulin pump is thought to be used to deliver insulin subcutaneously continuously. , a disposable thin-walled plastic pipe or catheter can be attached, so that Insulin or other drugs can enter the tissue. Catheters are inserted under the skin and used to The pump can be moved according to the patient's needs. External pumps can be attached to devices that can be implanted in hospitals, clinics, etc. This refers to equipment designed for use in a fixed location, such as a work station, a building, or a similar location. External port refers to a portable or ambulatory device, such as a pump or similar device that can be carried by the patient. The pump includes a reservoir capable of storing a fluid medium, such as, but not limited to, a fluid medium including NRG. Equipped with a reservoir.

[0033] The external pump may be connected to the patient, for example via fluid communication through suitable hollow tubing. The hollow tube can be connected to a hollow needle, which penetrates the patient's skin for injection. Alternatively, the hollow tube may be used to penetrate the patient through a cannula or similar object. An external pump can be worn by the patient or attached to the patient's clothing. The pump can be attached to the patient's clothing or underneath the patient's clothing. A microinfusion pump that can be used for high frequency infusions, such as, but not limited to, the MiniMed Paradigm 522 Insulin pump, MiniMed Paradigm 722 insulin pump, MiniMed Paradigm 515 insulin pump Insulin Pump, MiniMed Paradigm 715 Insulin Pump, MiniMed Paradigm 512R Insulin Pump MiniMed Paradigm 712R insulin pump, MiniMed Paradigm 508 insulin pump, and and a MiniMed Paradigm 508R insulin pump (Medtronic, Northridge, Canada), and This refers to other similar devices known in the art.

[0034] U.S. Patent 11 / 211,095 (filing date: 8 / 23 / 2005, publication number: US2006 / 0264894, registration number US768 6787) and published PCT applications WO01 / 70307 (PCT / US01 / 09139), WO04 / 030716 (PCT / US2003 / 028769 ), WO04 / 030717 (PCT / US2003 / 029019) and WO2013075622 (PCT / CN2012 / 0849 36), U.S. Pat. US2005 / 0065760 (Method for Advising Patients on Insulin Dosage) Consulting Patients Concerning Doses of Insulin) and US6,589,229 (Wearable Implants) Wearable Self-Containing Drug Infusion Device Examples of administration devices, such as external pumps, are cited in this section.

[0035] As used herein, "can be used to prevent, treat, or mitigate myocardial damage" means "Other drugs or therapies applicable to the treatment of myocardial injury" refers to drugs and interventional therapies generally applicable to the treatment of myocardial injury, as well as It refers to drugs and interventional therapies generally applicable to the treatment of myocardial infarction and injury. Medications to treat myocardial infarction include antiplatelet drugs (aspirin, clopidogrel, etc.) , anticoagulants (heparin, bivalirudin, etc.), thrombolytics (alteplase, tenectopy) enzyme, urokinase, recombinant human pro-urokinase, etc.), lipid lowering drugs (statins , cholesterol absorption inhibitors), angiotensin-converting enzyme inhibitors / ANG II receptor blockers , beta-receptor blockers, calcium channel blockers, nitrates, phosphatase inhibitors, Diuretics, renin-angiotensin-aldosterone system (RAS) antagonists, myocardial energy Energy optimizer, ischemic tissue metabolism improver, free radical scavenger Interventional therapies include coronary interventional therapies. [Brief description of the drawings]

[0036] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] 1 shows echocardiographic results of the effect of chronic subcutaneous administration of NRG at various doses in treating rats with acute myocardial infarction. [Diagram 2] 1 shows echocardiographic results of the effect of NRG by chronic subcutaneous administration at various frequencies in treating rats with acute myocardial infarction. [Diagram 3] 1 shows the therapeutic effect of NRG on acute myocardial infarction in rats through chronic subcutaneous administration followed by discontinuation due to reduced frequency. [Figure 4]1 shows the therapeutic effect of NRG on acute myocardial infarction in rats through chronic subcutaneous administration followed by discontinuation with dose reduction. EXAMPLES

[0037] (Example) Example 1: Therapeutic effect of chronic subcutaneous administration of various doses of rhNRG on acute myocardial infarction in rats (Study on the effect-dose relationship of NRG) (1. Purpose) Effects of the left coronary artery ligation-induced myocardial infarction rat model on acute myocardial infarction in rats To investigate the therapeutic effects of various doses of rhNRG in the treatment of acute myocardial infarction in rats. To investigate the dose-effect relationship of NRG to (2. Experimental Drugs) (2.1 Excipients: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.) (2.2 rhNRG: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.)

[0038] (3. Laboratory Animals) 3.1 Strain and source: Wistar rats, Shanghai Sippe-Bk Lab Animal Co., Ltd. (supplied by (3.2 Sex, weight and certificate: Male, 200-270g)

[0039] (4. Experimental materials and equipment) Anesthesia equipment, isoflurane evaporator manufactured by MSS INTERNATIONAL LTD. Isoflurane, 100ml / bottle, manufactured by RWD Life Technologies Co., Ltd. Cardiac ultrasound detector Vivid E95. Ningbo Lingqiao suture needle (with thread) manufactured by Ningbo Medical Needle Co., Ltd.

[0040] (5. Experimental Method) 5.1 Establishment of a rat model of heart failure induced by coronary artery ligation Rats were anesthetized with isoflurane through a gas anesthesia system. Then, the rats were placed in a supine position. After shaving the chest, the skin was disinfected with 75% alcohol. The muscles were bluntly separated to expose the 4th and 5th ribs. Using a hemostat, the 4th and 5th ribs were The muscles between the ribs were bluntly cut. Using both hands, the heart was pushed out of the thoracic cavity, and lung expansion and The heart was fully exposed for observation of the heartbeat. The left atrial appendage and the pulmonary artery cone were fully exposed. The left anterior descending coronary artery (LADCA) between them was ligated with a surgical suture. The organs were quickly returned to their original positions. The pectoral muscles and skin were then sutured. After surgery, the rats were placed in a cage. The animals were then returned to their cages, fed, and observed in detail.

[0041] 5.2 Grouping and Administration Table 1. Grouping of experimental animals and administration schedule [Table 1] Administration was initiated the day after the animal model of myocardial infarction was established.

[0042] (5.3 Observation Indicators) After anesthetization with 4% isoflurane, the rat was fixed in the left lateral position on the operating table. The animals were attached to a gas anesthesia machine and anesthesia was maintained using isoflurane. The skin was disinfected with 75% alcohol and coated with a coupling agent. The left ventricular end diastolic diameter and left ventricular end systolic diameter were measured. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. Ejection fraction (EF) values ​​were also obtained: EF = (EDV-ESV) / EDV × 100%.

[0043] (5.3.2 Data Processing) All experimental data are expressed as ±SD.

[0044] (6. Experimental Results) (6.1 Echocardiogram Results) Echocardiography was performed 60 days after continuous administration of NRG. The results showed that the LVEDd in the vehicle group, LVEDs and EF values ​​were 0.971±0.07cm, 0.832±0.08cm, and 34.6±7.00%, respectively; The LVEDd, LVEDs, and EF values ​​in the μg / kg-NRG group were 0.975 ± 0.07 cm, 0.794 ± 0.10 cm, and 0.81 ± 0.04 cm, respectively. 42.9±11.32%; LVEDd, LVEDs, and EF values ​​in the 7.5 μg / kg-NRG group were 0.965±0.0, respectively. 7 cm, 0.808 ± 0.11 cm, and 38.4 ± 12.17% in the 3.75 μg / kg-NRG group; The EF values ​​were shown to be 0.994 ± 0.08 cm, 0.839 ± 0.12 cm, and 37.0 ± 12.23%, respectively. According to the data on LVEDd and LVEDs, LVEDd and LVEDs may be decreased in the high-dose NRG group. EF The data showed that the cardiac function of rats in the high, medium, and low dose groups was all significantly improved by continuous dosing. The results were improved 60 days after administration, and there was a dose-effect relationship between the three groups. For details, see Table 2 and Figure 1. Please refer to. Table 2. Efficacy of various doses of NRG administered subcutaneously for 60 days in the treatment of acute myocardial infarction in rats. Results of echocardiography. (x±SD) [Table 2]

[0045] (7. Conclusion) After 60 days of treatment with rhNRG, 5 μg / kg, 2.5 μg / kg, or 1.25 μg / kg of NRG were administered subcutaneously three times daily. The EF values ​​of the treatment group were higher than those of the control group, and a specific dose-effect relationship was found among the three doses. there were.

[0046] Example 2: Therapeutic effect of chronic subcutaneous administration of rhNRG at various frequencies on acute myocardial infarction in rats fruit) (1. Purpose) In a rat model of myocardial infarction induced by left coronary artery ligation, The therapeutic effect of specific doses of rhNRG on acute myocardial infarction in rats was evaluated by chronic subcutaneous administration of To research.

[0047] (2. Experimental Drugs) (2.1 Excipients: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.)

[0048] (2.2 rhNRG: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.)

[0049] (3. Laboratory Animals) 3.1 Strain and source: Wistar rats, Shanghai Sippe-Bk Lab Animal Co., Ltd. (supplied by

[0050] (3.2 Sex, weight and certificate): Male, 200-270g.

[0051] (4. Experimental materials and equipment) This is the same as "4. Experimental materials and equipment" in Example 1.

[0052] (5. Experimental Method) 5.1 Establishment of a rat model of heart failure induced by coronary artery ligation Same as "5.1 Establishment of a rat model of heart failure by coronary artery ligation" in Example 1 .

[0053] 5.2 Grouping and Administration Table 3. Grouping of experimental animals and administration schedule [Table 3]

[0054] All experimental animals were randomly divided into groups after coronary artery ligation. The rats were divided into four groups based on body weight: vehicle group (control group), NRG 30 μg / kg / day group, and NRG 30 μg / kg / BIW group. The animals were randomly divided into two groups: 1) NRG 30 μg / kg / day × 7 + QW group, and 2) NRG 30 μg / kg / day × 7 + QW group. For the first three and fourth groups, rats were administered the drug three times a day for the first seven days. The animals were dosed according to body weight at a daily dose of 30 μg / kg / day. For the fourth group, rats were injected with NRG once a week for the final four weeks, with a daily dose of 30 μg / kg. It was decided.

[0055] (5.3 Observation Indicators) 5.3.1 Cardiac Function Tests After anesthetization with 4% isoflurane, the rat was fixed in the left lateral position on the operating table. The animals were attached to a gas anesthesia machine and anesthesia was maintained using isoflurane. The skin was disinfected with 75% alcohol and coated with a coupling agent. The left ventricular end diastolic diameter and left ventricular end systolic diameter were measured. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. Ejection fraction (EF) values ​​were also obtained. EF-(EDV-ESV) / EDV×100%. Echocardiography was performed at weeks 1, 2, 3, and 5 after the onset of myocardial infarction.

[0056] (5.3.2 Data Processing) All experimental data are expressed as ±SD.

[0057] (6. Experimental Results) (6.1 Echocardiogram Results) Echocardiography was performed after 35 days of continuous administration of NRG. , and EF values ​​were 0.925 ± 0.084 cm, 0.756 ± 0.107 cm, and 42.5 ± 10.174%, respectively; NRG The LVEDd, LVEDs, and EF values ​​in the 30 μg / kg / day group were 0.879 ± 0.058 cm, 0.694 ± 0.077 cm, and 0.74 ± 0.077 cm, respectively. and 47.9 ± 8.342%; LVEDd, LVEDs, and EF values ​​in the NRG / 30 μg / kg / BIW group were 0.9 ± 8.342%, respectively. 28±0.084cm, 0.746±0.110cm, and 45.2±10.248% in the NRG / 30μg / kg / day×7+QW group; The VEDd, LVEDs, and EF values ​​were 0.931 ± 0.070 cm, 0.760 ± 0.097 cm, and 42.7 ± 9.892%, respectively. It was.

[0058] As shown in the data for LVEDd and LVEDs, after 35 days of continuous administration, NRG / 30μ g / kg / day significantly reduced LVEDd and LVEDs; EF value data showed that E The F value was significantly higher in the NRG / 30 μg / kg / day group than in the control group; the EF value was significantly higher in the NRG / 30 μg / kg / BIW group than in the control group. The NRG / 30μg / kg group showed a tendency to increase compared to the control group, and the NRG / 30μg / kg group showed a tendency to increase compared to the control group during the first 7 days of continuous administration. The cardiac function of rats in the g / day × 7 + QW group was improved to some extent compared with that of the control group, i.e. The heart function showed a tendency to improve. After that, injections were given every 7 days to maintain the effect. See Table 4 and Figure 2 for the results.

[0059] Table 4. The therapeutic effect of NRG on myocardial infarction in rats through chronic subcutaneous administration at various frequencies. Echocardiogram results (x±SD) [Table 4]

[0060] Example 3: Long-term subcutaneous administration of cyclosporine to acute myocardial infarction in rats and subsequent reduction in frequency Therapeutic effect of rhNRG after discontinuation (1. Purpose) In a rat model of myocardial infarction induced by left coronary artery ligation, The therapeutic effect of rhNRG on acute myocardial infarction in rats through subsequent cessation by reduced frequency Observe the results.

[0061] (2. Experimental Drugs) (2.1 Excipients: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.) (2.2 rhNRG: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.)

[0062] (3. Laboratory Animals) 3.1 Strain and source: Wistar rats, Shanghai Sippe-Bk Lab Animal Co., Ltd. (supplied by (3.2 Sex, weight and certificate): Male, 200-270g.

[0063] (4. Experimental materials and equipment) This is the same as "4. Experimental materials and equipment" in Example 1.

[0064] (5. Experimental Method) 5.1 Establishment of a rat model of heart failure induced by coronary artery ligation This is the same as "5.1 Establishment of a rat model of heart failure induced by coronary artery ligation" in Example 1.

[0065] 5.2 Grouping and Administration Rats were randomly divided into groups and administered medication after coronary artery ligation. They were randomly divided into two groups, including a vehicle group and a NRG 30 μg / kg group. The vehicle group contained 19 rats. There were 18 rats in the NRG group, and 10 rats in the 10μg / kg group were administered three times a day from the day after the model was created. Continuous administration of the drug was started by subcutaneous administration at a dose of 100 mg / kg. All animals were dosed continuously until day 38, and animals in the NRG group were examined by echocardiography. The animals in the NRG group were divided into two subgroups, on average, with one subgroup receiving the induction The animals in the vehicle group continued to receive the drug and the other subgroup was discontinued early. For the subgroup receiving continuous NRG, a 3-week withdrawal schedule was implemented on day 49: NRG was administered subcutaneously every other day during the first week, every third day during the second week, and every fourth day during the third week. Regarding the administration method, rats were injected subcutaneously with NRG three times a day in exactly the same manner as above. For the NRG interruption subgroup, rats were observed for clinical signs. All animals showed no changes in cardiac function. Echocardiograms were performed weekly to monitor changes in function.

[0066] (5.3 Observation Indicators) 5.3.1 Cardiac Function Tests After anesthetization with 4% isoflurane, the rat was fixed in the left lateral position on the operating table. The animals were attached to a gas anesthesia machine and anesthesia was maintained using isoflurane. The skin was disinfected with 75% alcohol and coated with a coupling agent. The left ventricular end diastolic diameter and left ventricular end systolic diameter were measured. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. Ejection fraction (EF) values ​​were also obtained: EF = (EDV-ESV) / EDV × 100%.

[0067] (5.3.2 Data Processing) All experimental data were expressed ± SD. One-way ANOVA analysis was performed using GraphPad Prism6. P<0.05 indicates significant difference between groups. P<0.01 indicates a markedly significant difference between groups.

[0068] (6. Experimental Results) (6.1 Echocardiogram Results) Echocardiography was performed after 35 days of continuous administration of NRG. LVEDd, LVED s, and EF values ​​were 0.988±0.08cm, 0.850±0.10cm, and 33.6±11.36%, respectively; in the NRG group The LVEDd, LVEDs, and EF values ​​were 0.953 ± 0.05 cm, 0.767 ± 0.06 cm, and 44.9 ± 6.09%, respectively. The results showed that NRG significantly reduced LVEDd and LVEDs and enhanced cardiac contractile function. This indicates that LV remodeling can be reversed. The LVEDd, LVEDs, and EF values ​​were 1.020 ± 0.10 cm, 0.881 ± 0.15 cm, and 33.1 ± 14.55%, respectively. The LVEDd, LVEDs, and EF values ​​in the NRG-discontinued subgroup were 0.987 ± 0.05 cm, 0.807 ± 0.06 cm, and 4 2.2±5.48%, while the LVEDd, LVEDs, and EF values ​​in the NRG continuous treatment subgroup were 0.973± 0.07 cm, 0.783 ± 0.08 cm, and 45.0 ± 5.51%; these results suggest that abrupt interruption of NRG reduces the The results indicate that NRG has some effect on cardiac function. The LVEDd, LVEDs, and LVEDs subgroups were randomly assigned to receive NRG and then discontinued. and EF values ​​were 1.043±0.06cm, 0.887±0.06, and 35.4±6.78%, respectively; stepwise NRG interruption The LVEDd, LVEDs, and EF values ​​of the subgroups were 0.989 ± 0.07 cm, 0.814 ± 0.08, and 41.3 ± 4.92%, respectively. A significant difference was observed from the vehicle group. Echocardiography was performed three weeks after discontinuation. The LVEDd, LVEDs, and EF values ​​in the early NRG discontinuation subgroup were 1.010±0.06cm, 0.842+0.06cm, and 38 .9±5.04%; LVEDd, LVEDs, and EF values ​​in the gradual NRG discontinuation subgroup were 0.976±0.0, respectively. 6 cm, 0.805 ± 0.07 cm, and 40.8 ± 4.67%. Compared with the vehicle group, there was no significant difference in cardiac function in the rats. The effect of the gradual discontinuation of NRG on the aging of the aging population was mitigated. See Tables 5 and 6 and Figure 3 for the results. I want to be illuminated. Table 5. Echocardiographic study of the efficacy of NRG administered subcutaneously for 35 days in the treatment of myocardial infarction in rats. Results (x±SD) [Table 5] ***: p<0.001 post-treatment subgroup compared with vehicle group; **: p<0.01 post-treatment subgroup compared with vehicle group; *: p<0.05 post-treatment subgroup compared with vehicle group Table 6. Efficacy of NRG in treating rats with myocardial infarction in two subgroups after 38 days of subcutaneous administration Echocardiogram results (x±SD) [Table 6] ***: p<0.001 post-treatment subgroup compared with vehicle group; **: p<0.01 post-treatment subgroup compared with vehicle group; *: p<0.05 post-treatment subgroup compared with vehicle group

[0069] (7. Conclusion) Through chronic subcutaneous administration followed by discontinuation at reduced frequency, rhNRG has been shown to be a useful marker for the prevention of myocardial infarction. It can improve cardiac function and reduce cardiac remodeling in patients.

[0070] Example 4: Acute administration of 1,2-dichlorophenyl 2-propanediol in rats through chronic subcutaneous administration followed by interruption with dose reduction (Therapeutic effect of rhNRG on chronic myocardial infarction) (1. Purpose) In a rat model of myocardial infarction induced by left coronary artery ligation, The therapeutic effect of rhNRG on acute myocardial infarction in rats through subsequent cessation by reduced frequency Observe the results.

[0071] (2. Experimental Drugs) (2.1 Excipients: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.) (2.2 rhNRG: Developed by Zensun (Shanghai) Sci & Tech Co., Ltd.)

[0072] (3. Laboratory Animals) 3.1 Strain and source: Wistar rats, Shanghai Sippe-Bk Lab Animal Co., Ltd. (supplied by (3.2 Sex, weight and certificate): Male, 200-270g.

[0073] (4. Experimental materials and equipment) This is the same as "4. Experimental materials and equipment" in Example 1.

[0074] (5. Experimental Method) 5.1 Establishment of a rat model of heart failure induced by coronary artery ligation This is the same as "5.1 Establishment of a rat model of heart failure induced by coronary artery ligation" in Example 1. 5.2 Grouping and Administration

[0075] (5.3 Observation Indicators) Rats were randomly divided into groups and administered medication after coronary artery ligation. They were randomly divided into two groups according to body weight. Subcutaneous injections were administered three times daily, and the animals were weighed once daily. The animals were dosed according to their body weight. Echocardiography was performed on the 10th day after model preparation. Echocardiograms were performed every 10 days for the 10-day course, and weekly after dose reduction and completion of the discontinuation. Echocardiograms were then performed every 2 weeks. All animals were continuously dosed until day 60. A dose reduction discontinuation plan was implemented after 3 weeks of treatment. The doses were reduced to 100 mg / kg / day in weeks 1, 2, and 3, respectively. The dose was then reduced to 15μg / kg, 7.5μg / kg, and 3.75μg / kg. The subjects were then administered the drug for 3 weeks to observe the clinical symptoms. After tapering, the drug was discontinued completely.

[0076] 5.3.1 Cardiac Function Tests After anesthetization with 4% isoflurane, the rat was fixed in the left lateral position on the operating table. The animals were attached to a gas anesthesia machine and anesthesia was maintained using isoflurane. The skin was disinfected with 75% alcohol and coated with a coupling agent. The left ventricular end diastolic diameter and left ventricular end systolic diameter were measured. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. Ejection fraction (EF) values ​​were obtained: EF = (EDV-ESV) / EDV x 100%.

[0077] (5.3.2 Data Processing) All experimental data were expressed ± SD. One-way ANOVA analysis was performed using GraphPad Prism6. P<0.05 indicates significant difference between groups; P<0.01 indicates markedly significant difference between groups.

[0078] (6. Experimental Results) (6.1 Echocardiogram Results) Echocardiography was performed after 60 days of continuous administration of NRG. LVEDd, LVED s, and EF were 1.048±0.07cm, 0.910±0.09cm, and 32.1±6.6%, respectively; NRG 30μg LVEDd, LVEDs, and EF in the / kg / day group were 0.981 ± 0.08 cm, 0.794 ± 0.08 cm, and 43.8 ± 8, respectively. 0%. Data on LVEDd and LVEDs showed that LVEDd and LVEDs were significantly higher in the daily NRG group. The EF value data showed a significant difference from the control group (p<0.001). The EF value of the NRG group increased significantly after 60 days of continuous administration, showing a marked difference from the control group. After 60 days, treatment was performed at a lower dose with no change in frequency. An echocardiogram was performed. The LVEDd, LVEDs, and EF values ​​in the control group were 1.038±0.07cm, 0.8 99±0.10 cm and 32.4±9.5%; LVEDd, LVEDs, and EF values ​​in the NRG / 30 μg / kg / day group were 0.9 81±0.08, 0.799±0.08 cm, and 42.3±11.2%. After a 3-week dose reduction for observation, The drug was completely discontinued. The LVEDd, LVEDs, and EF values ​​in the control group were 1.065±0.07cm, 0.9 42±0.10 cm and 28.3±9.4%; LVEDd, LVEDs, and EF values ​​in the NRG / 30 μg / kg / day group were The mean mean mean diameters were 0.994±0.08cm, 0.826±0.10cm, and 39.3±12.7%, respectively. The LVEDd, LVEDs, and EF values ​​in the control group were 1.137±0.08cm, 1.006±0. LVEDd, LVEDs, and EF values ​​in the NRG / 30 μg / kg / day group were 28.0 + 5.7% and 28.0 + 5.7%, respectively. , 1.104±0.08cm, 0.950±0.09cm, and 33.4±7.6%. After 9 weeks of discontinuation, There was still a significant difference in LVEDd and LVEDs between the treatment and control groups; EF values ​​were compared with the control group. The results still showed an upward trend. See Tables 7, 8, 9 and Figure 4 for the results.

[0079] (7. Conclusion) Considering a fixed dose and various administration frequencies, rhNRG reduced myocardial infarction in rats during continuous administration. It exerted some therapeutic effect on the cardiac function of rats with acute myocardial infarction, Improved ventricular remodeling and delayed myocardial infarction-induced aging. It has a significant improving effect on cardiac function in rats with myocardial infarction for a long period after infarction. Table 7. Echocardiographic study of the efficacy of NRG administered subcutaneously for 60 days in the treatment of myocardial infarction in rats. Results (x±SD) [Table 7] ***: p<0.001 post-treatment subgroup compared with vehicle group; **: p<0.01 post-treatment subgroup compared with vehicle group; *: p<0.05 post-treatment subgroup compared with vehicle group Table 8. Treatment of rats with myocardial infarction after 60 days of subcutaneous administration of NRG followed by dose reduction for 3 weeks. Echocardiographic results of the effect in (x ± SD) [Table 8] ***: p<0.001 post-treatment subgroup compared with vehicle group; **: p<0.01 post-treatment subgroup compared with vehicle group; *: p<0.05 post-treatment subgroup compared with vehicle group Table 9. Efficacy of NRG in the treatment of rats with myocardial infarction after discontinuation of subcutaneous administration on day 81. -Test results (x±SD) [Table 9] ***: p<0.001 post-treatment subgroup compared with vehicle group; **: p<0.01 post-treatment subgroup compared with vehicle group; *: p<0.05 post-treatment subgroup compared with vehicle group

Claims

1. 1. Use of neuregulin (NRG) in the manufacture of a medicament for use in a method for preventing, treating, or ameliorating myocardial injury in a mammal, comprising: the method comprising administering the NRG subcutaneously to the mammal multiple times per day at a dose of 15 μg / kg / day to 50 μg / kg / day for consecutive days; and The use comprising slowly discontinuing said NRG after said administration.

2. 2. The method of claim 1, wherein the NRG is administered continuously over multiple days.

3. 2. The method of claim 1, wherein the NRG is administered multiple times per day for 30 to 60 consecutive days.

4. 4. The use of claim 3, wherein the NRG is administered three times a day for 35, 38, 49, or 60 days.

5. 4. The use of claim 3, wherein the NRG is administered three times a day for 60 days.

6. 1. A composition for use in a method for preventing, treating, or ameliorating myocardial injury in a mammal, the composition comprising neuregulin (NRG), the method comprising administering the NRG subcutaneously to the mammal multiple times per day at a dose of 15 μg / kg / day to 50 μg / kg / day for consecutive days; and the composition comprising slowly discontinuing said NRG after said administration.

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