Methods and compositions of neuregulins for preventing, treating or delaying preserved ejection fraction cardiac failure

Abstract

To provide methods for preparing medicine for preventing, treating or delaying preserved ejection fraction cardiac failure in mammals.SOLUTION: The present invention provides methods for preparing medicine using neuregulin.SELECTED DRAWING: None

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a method for preventing, treating, or delaying heart failure with preserved ejection fraction in a mammal. Use of a neuregulin protein in the manufacture of a medicament for the treatment of a mammalian Use of said medicament to prevent, treat, or delay heart failure with preserved ejection fraction In particular, the present invention relates to a method for preventing heart failure with preserved ejection fraction in a mammal, A method for treating or delaying heart failure with preserved ejection fraction, comprising: or neuregulin protein in special populations at risk for heart failure with preserved ejection fraction. In particular, the present invention provides a method for treating cardiovascular disease comprising administering a medicament comprising a medicament containing a protein. , namely, a new indication for neuregulin in the treatment of heart failure with preserved ejection fraction. do. [Background technology]

[0002] BACKGROUND OF THEINVENTION Neuregulin (NRG; heregulin, HRG) is a glial growth factor (GGF) and a novel differentiation factor Also known as NDF, it is a glycoprotein with a molecular weight of 44 KD. As ligands for the ErbB family of receptors, neuregulins play a key role in cell signaling. The NRG family has four members: NRG1, NRG2, NRG3, and NRG4 (Falls et al., 2003). (E. et al., Exp Cell Res. 284:14-30, 2003). NRG1 plays important roles in the nervous system, heart, and thorax. We also hypothesize that NRG1 signaling regulates the development and function of other organ systems, as well as the pathology of human diseases. NRG1 has been shown to play a role in a number of disorders, including schizophrenia and breast cancer. There are isomers of Isomers with different N-terminal regions or different EGF-like domains may have different in vivo functions. It has been shown that the present invention is based on NRG-1β.

[0003] NRG-1β is a transmembrane protein (Holmes et al., Science 256, 1205-1210, 1992). The extracellular domain is the N-terminal region, which contains the immunoglobulin-like domain (Ig-like domain) and the EGF-like domain. The intracellular domain is the C-terminal domain. Under the action of the enzyme, the extracellular domain of NRG is cleaved by the enzyme and becomes free, so that It promotes binding to the ErbB3 receptor on the cell surface and activation of associated cell signaling pathways. do.

[0004] The EGF receptor family is divided into four classes, including ErbB1, ErbB2, ErbB3, and ErbB4. All of these are transmembrane proteins with molecular weights of about 180-185 KD. All except rbB2 contain an extracellular ligand-binding domain in the N-terminal region. All of these proteins have protein tyrosine kinase activity in their intracellular C-terminal regions. ErbB3 and ErbB4 are neuregulin receptors, whereas ErbB4 are epidermal growth factor receptors. Of these neuregulin receptors, only ErbB2 and ErbB4 are highly expressed in the heart (Yarden et al. (Nat Rev Mol Cell Biol, 2: 127-137,2001).

[0005] When NRGs bind to the extracellular domain of ErbB3 or ErbB4, they mediate the secretion of ErbB3, ErbB4, and other ErbB receptors. The formation of heterodimers with ErbB4 (usually containing ErbB2) or homodimers of ErbB4 is induced, This results in phosphorylation of the intracellular domain of these receptors (Yarden et al., Nat Rev Mol Cell 2013). ll Biol, 2: 127-137,2001). The phosphorylated intracellular domain then transmits intracellular signals. binds to signaling proteins, thereby activating downstream AKT or ERK signaling pathways; and a series of cellular responses, such as cell proliferation, cell apoptosis, cell migration, cell differentiation, or cellular Induces stimulation or reduction of cell adhesion.

[0006] NRG plays a particularly important role in cardiac development (WO0037095, CN1276381, WO0309930 0, WO9426298, US6444642, WO9918976, WO0064400, Zhao et al., J. Biol. Chem. 273, 1 During early embryonic development, NRG expression is restricted to the endocardium, where it is expressed in the endocardium. After this, NRG is released into peripheral cardiomyocytes by paracrine mechanisms, and the protein tyrosine It binds to the extracellular domain of the kinase receptor ErbB4, which then undergoes heterodimerization with ErbB2. The formation and activation of the ErbB4 / ErbB2 complex is essential for the early development of spongy heart. Essential for the formation of trabeculae. Genes for three proteins: NRG protein, ErbB4, and ErbB2 If either of these is absent, the embryo will lack trabeculae and die in utero during early development. WO0037095 shows that a certain concentration of neuregulin can sustain the ERK signaling pathway. It activates the sarcoplasmic reticulum and promotes the differentiation and growth of cardiomyocytes, and promotes the adhesion of cardiomyocytes to sarcoplasmic reticulum. Induce remodeling of endothelial membranes and cytoskeleton, improve the structure of cardiomyocytes, and enhance cardiomyocyte contraction. It has also been shown in WO0037095 and WO003099300 that NRG can be used in various It has been shown to be useful in the detection, diagnosis, and treatment of cardiovascular disease.

[0007] The following is a list of some prior art documents related to the present invention: 1. "Function of the myocardium and 1. Cardiac muscle function and manipulation: WO0037095;2. Neuregri "New application of neuregulin and its analogs":C N1276381;3. "Neuregulin-Based Methods and Compositions for the Treatment of Cardiovascular Disease" regulin based methods and composition for treating cardiovascular diseases): WO03099300;4. Zhao YY, Sawyer DR, Baliga RR, Opel DJ, Han X, Marchionni MA, and In the article by Kelly RA and Kelly RA, "Neuregulin promotes cardiomyocyte survival and growth" s Promote Survival and Growth of Cardiac Myocytes)” J. Biol.Chem. 273, 10261-1 0269 (1998);5. "Methods for treating muscle diseases and disorders" ases and disorders: WO9426298:6. "Using neuregulin to form or grow myotubes" Methods of inducing myocyte mitogenesis, differentiation, or survival reasing myotube formation or survival or muscle cell mitogenesis, differentiation 7. "Using neuregulin": US6444642. Therapeutic methods comprising use of a neuregulin: WO9918976;8. "Methods for treating congestive heart failure": WO0 064400;9. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansur In the article by A D, Abadi N, Raab H, Lewis GD, et al., "Identification of heregulin and its specific activity against p185erbB2." Identification of heregulin, a specific activator p185erbB2” Science 256, 1205-1210 (1992);10. Falls DL, Neuregulins: Function, Morphology, and System Neuregulins: functions, forms and signaling strategies" Experimental Mental Cell Research, 284, 14-30 (2003). 11. Yarden Y, Sliwkowski X, "Erb Untangling the ErbB signaling network ” Nature Reviews: Molecular Cell Biology, 2127-137 (2001).

[0008] Heart failure (HF) is classified into various cardiac diseases, including systolic heart failure (SHF) and diastolic heart failure (DHF). In 2008, the European Society of Cardiology (ESC) announced that Diagnosis and treatment guidelines for acute and chronic heart failure and classified DHF as heart failure with preserved ejection fraction (HF-PEF). Systolic heart failure is defined as the inability of the heart, with reduced contractility of the myocardium, to meet metabolic demands. A condition that results in low cardiac output, low perfusion of tissues or organs, and congestion of the pulmonary and / or systemic circulation. Heart failure with preserved ejection fraction (HF-PEF) is often characterized by an impaired left ventricular diastolic relaxation. Interstitial relaxation, decreased myocardial compliance, myocyte hypertrophy, and increased left ventricular stiffness Diastolic heart failure due to chronic fibrosis is characterized by impaired diastolic filling, decreased This results in increased cardiac output, increased left ventricular end-diastolic pressure, and the development of heart failure. According to epidemiological data from 2006, heart failure with preserved ejection fraction or diastolic heart failure is considered to be heart failure. The study showed that heart failure with preserved ejection fraction accounts for more than 50% of the total number of patients. It may also occur with systolic dysfunction. The disease is more likely to occur in older women with hypertension, diabetes, and left ventricular hypertrophy.

[0009] Diastolic and systolic heart failure have similar symptoms and signs. Patients usually have high blood pressure and In the early stages of heart failure, patients may present with fatigue of unknown cause, decreased exercise tolerance, A sustained increase in heart rate of 15 to 20 beats per minute can be an early sign of decreased left ventricular function. Symptoms of dyspnea during sleep, paroxysmal nocturnal dyspnea, and high pillow sleep are Ascites or leg edema may occur in patients as a major or isolated symptom. Concomitantly, impaired exercise tolerance in patients develops over time.

[0010] Diastole is a more complex physiological process than systole, involving multiple factors. Therefore, Diagnosis of heart failure with preserved ejection fraction or diastolic heart failure is more difficult than systolic heart failure. A diagnosis can be made if the following conditions are met: 1. Typical symptoms and signs of heart failure; 2. Normal LVEF (or only slightly reduced ≥45%), normal left ventricular morphology; 3. There is evidence of underlying cardiac disease. For example, a patient with hypertension may have a history of heart failure after undergoing ultrasound examination. have evidence of left ventricular hypertrophy, left atrial enlargement, and left ventricular diastolic dysfunction on cross-section; 4. Increased BNP / NT-proBNP; 5. If echocardiography does not reveal valvular heart disease and there is no evidence of pericardial disease, hypertrophic cardiomyopathy, restrictive cardiomyopathy (invasive Diagnosis and treatment with idiopathic cerebrovascular disease (e.g., pulmonary artery disease) were

[0011] Heart failure with preserved ejection fraction or diastolic heart failure is associated with a variety of causes, including left ventricular dysfunction. Ventricular pressure / volume mechanisms are relatively well recognized etiologies. Hypertension, hypertrophic cardiomyopathy, aortic valve Patients with stenosis had significantly increased ventricular end-diastolic pressure and significantly decreased left ventricular volumes. These affect ventricular filling, resulting in a shift of the pressure-volume curve to the left and a centripetal This leads to the formation of remodeling. Prolonged stress overload leads to diastolic heart failure.

[0012] Ventricular diastolic function involves two phases: relaxation (the primary energy-consuming process) and Ventricular muscle relaxation is the primary energy-consuming process. Compliance of the ventricular muscle is the change in pressure in the heart chambers per unit time during a given diastolic period. is the process of passive filling of the heart cavity caused by changes in unit volume during diastole. Relaxation is the leading ventricular muscle expansion phase in early diastole, and the contraction of the myocardial fibers is The length of the contractile phase and the ability to return to blood pressure, and the energy-dependent Ca 2+ Leading energy transport company Left ventricular relaxation is an energy consuming process that includes isovolumic relaxation and early diastolic rapid filling phases. , isovolumic relaxation (IVRT) duration, maximum blood pressure drop velocity (-dp / dt), mitral E peak deceleration time ( DT) and other parameters are reflected in the two-dimensional echocardiography and hemodynamic examination. These parameters, obtained by the method, are used to evaluate to some extent the diastolic function of the heart. It is possible.

[0013] Furthermore, there is no specific treatment for heart failure with preserved ejection fraction. Dr. Drain is a standard treatment for controlling blood pressure, decreasing heart rate, and reducing fluid retention. For example, angiotensin-converting enzyme inhibitors / angiotensin II receptor inhibitors, beta-blockers These include the use of antihypertensive drugs (hypertensives, sedatives, and diuretics), which can improve the symptoms of systolic heart failure but It is not possible to improve the clinical symptoms and prognosis of heart failure with preserved ejection fraction. Patients with preserved heart failure or diastolic heart failure have a poor prognosis and relatively high rates of relapse. These patients have chronic conditions such as hospitalization and repeated hospitalizations, which increases the burden on the overall health care system. Heart failure is the outcome of the development of diastolic heart failure. How can the heart be in the early stages of diastolic heart failure? Whether or not diastolic outcomes can be improved and further deterioration of diastolic heart failure can be prevented remains to be seen. This is a major challenge in the treatment of heart failure.

[0014] The prior art literature has reported that neuregulin is a nutrient that is involved in heart failure with preserved ejection fraction or diastolic heart failure. The role of the protein in mammalian neural circuits has not been reported. The administration of thrombin significantly improved the symptoms of heart failure with preserved ejection fraction, and The present invention relates to a method for preventing, treating, or delaying heart failure with preserved ejection fraction in a mammal. It has been found that the compound can be used to manufacture a drug for the treatment of Summary of the Invention

[0015] (Contents of the invention) A. Summary of the Invention The present invention demonstrates that NRG is crucial for cardiac development and maintenance of mature cardiac function. The invention is based on scientific discoveries. NRG regulates the sarcomeres, cytoskeleton, and cytoplasmic joints of cardiomyocytes. The present invention is based on the scientific discovery that NRG can enhance the formation of bonds. Animals with heart failure in biological models and the hearts of patients with heart failure in clinical trials Based on scientific findings that neuregulin can improve function. Phosphopolypeptides, Neuregulin Derivatives, or Compounds That Mimic the Activity of Neuregulin are all within the scope of the present invention.

[0016] NRG proteins bind to ErbB receptors on the surface of cardiomyocytes and activate the ERK signaling pathway inside the cells. It can be continuously activated to change the structure of cardiomyocytes, thereby improving their function. Improve performance.

[0017] In a first aspect of the present invention, there is provided a method for treating heart failure with preserved ejection fraction in a mammal, particularly a human. A method for preventing, treating, or delaying heart failure with preserved ejection fraction, comprising: and / or in a mammal, particularly a human, in need of or desiring to treat or delay the onset of an amount of NRG or a functional fragment thereof, or a nucleic acid encoding NRG or a functional fragment thereof; administered substances that increased NRG production and / or function, resulting in preserved ejection fraction. The method includes preventing, treating, or delaying heart failure. can be.

[0018] In a second aspect, the present invention provides a method for treating heart failure with preserved ejection fraction in a mammal, particularly a human. A pharmaceutical preparation for preventing, treating, or delaying atherosclerosis, comprising an effective amount of NRG or its derivatives. A nucleic acid encoding NRG or a functional fragment thereof, or a method for the production and / or development of NRG and a medicament, including a substance that improves or enhances the functionality, and a medicament, a carrier, an excipient, etc. that is medicament acceptable. The pharmaceutical preparation is provided for preventing and treating heart failure with preserved ejection fraction, or in combination with other drug(s) for delaying

[0019] In another aspect, the present invention provides a method for treating heart failure with preserved ejection fraction in a mammal, particularly a human. A composition for preventing, treating or delaying breast cancer, comprising the steps of: Pharmaceutical preparations for preventing, treating, or delaying heart failure with preserved ejection fraction in animals - Patents.com and other drugs to prevent, treat, or delay heart failure with preserved ejection fraction ( The composition may comprise one or more

[0020] The present invention further provides a method for preventing and treating heart failure with preserved ejection fraction in mammals, particularly humans. A kit for preventing or delaying heart failure with preserved ejection fraction comprising one or more doses of Pharmaceutical preparations or compositions used to prevent, treat, or delay The kit is provided further comprising instructions on how to use the product or composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] (B. Definition) Unless otherwise defined, all technical and scientific terms used herein are intended to be understood as meaning the invention. As used herein, the term "common" has the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications cited are incorporated by reference in their entirety. The definitions in this section are incorporated herein by reference in any patents, applications, publications, or other publications. to the contrary or otherwise inconsistent with definitions set forth in the application and other publications. , the definitions set forth in this section take precedence over the definitions incorporated herein by reference.

[0022] As used herein, the singular forms "a," "an," and "the" are "at least one" or "one" unless the context clearly dictates otherwise. It means "more than or equal to."

[0023] As used herein, "neuregulin" or "NRG" refers to any of ErbB2, ErbB3, ErbB4, or Proteins that can bind to and activate these heterodimers or homodimers Protein or peptide, neuregulin isoform, neuregulin EGF-like domain , Polypeptides Containing Neuregulin EGF-Like Domains, Neuregulin Mutants and Derivatives and any kind of neuregulin-like gene product capable of activating the above receptor. Neuregulin also includes the NRG-1, NRG-2, NRG-3, and NRG-4 proteins, neuregulins, and This includes peptides, fragments and compounds that have the function of regulin. Neuregulin binds to and activates ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimers. For example, the present invention is directed to a protein or peptide that can be used to Although not intended to be limiting, the peptides of the present invention are fragments of the NRG-1 β2 isoform, i.e., 177-237. which contains an EGF-like domain having the amino acid sequence: [ka] The NRG protein of the present invention activates the above receptors and regulates their biological functions. For example, it can stimulate the synthesis of acetylcholine receptors in skeletal muscle cells and stimulate cardiac Promotes cell differentiation and survival, as well as DNA synthesis. NRG proteins also play important biological roles. This includes NRG variants with conservative mutations that do not affect the quality of the sequence. A single amino acid mutation in a non-target region of the resulting protein or polypeptide It is well known that these compounds will not alter the biological activity of the compound (see, e.g., Watson et al., "Molecular Biology of the Gene", 4th ed., 1987, The Bejacm (See, e.g., in / Cummings Pub. Co., p. 224). The NRG proteins of the present invention are derived from natural sources. It can be isolated or obtained through recombinant technology, artificial synthesis or other means. Cut.

[0024] As used herein, an "epidermal growth factor-like domain" or "EGF-like domain" refers to any domain that is associated with ErbB2, Binds to and activates ErbB3, ErbB4, or their heterodimers or homodimers The present invention relates to a method for the treatment of various neurodegenerative diseases, the disclosure of which is incorporated herein by reference in its entirety. WO 00 / 64400, Holmes et al., Science, 256:1205-1210 (1992); US Patent Nos. 5,530,109 and 5,716,930; Hijazi et al., Int. J. Oncol., 13:1061-10 67 (1998); Chang et al., Nature, 387:509-512 (1997); Carraway et al., Nature, 387:512-516 (1997); Higashiyama et al., J. Biochem., 122:675-680 (1997); and WO It refers to a polypeptide fragment structurally similar to the EGF receptor binding domain described in 97 / 09425. In certain embodiments, the EGF-like domain is an ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimer. In certain embodiments, the EGF-like domain binds to and activates the receptors of NRG-1. In some embodiments, the EGF-like domain comprises the amino acid sequence of a receptor-binding domain. refers to amino acid residues 177-226, 177-237, or 177-240 of NRG-1. In this case, the EGF-like domain contains the amino acid sequence of the receptor binding domain of NRG-2. In an embodiment, the EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-3. In certain embodiments, the EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-4. In certain embodiments, the EGF-like domain is a polypeptide as described in U.S. Pat. No. 5,834,229. like, [ka] The amino acid sequence of

[0025] As used herein, "heart failure with preserved ejection fraction (HF-PEF)" refers to heart failure with normal left ventricular ejection fraction (LVEF). heart failure with preserved left ventricular ejection fraction (HFNEF), heart failure with preserved left ventricular ejection fraction (HF-PLVEF), and heart failure with preserved systolic function (HF-PLVEF). Heart failure with progressive diastolic function (HF-PSF), also known as diastolic heart failure (DHF), is characterized by cardiomyocyte hypertrophy and interstitial Fibrosis causes impaired left ventricular diastolic relaxation and reduced myocardial compression. liance, impaired left ventricular diastolic filling due primarily to increased stiffness; Decreased normal or decreased cardiac output, increased left ventricular end-diastolic pressure, and the development of heart failure refers to a slightly reduced left ventricular ejection fraction (LVEF). Heart failure with preserved ejection fraction does not exist alone. It may occur either as a result of or may occur simultaneously with systolic dysfunction.

[0026] As used herein, "isovolumic relaxation time (IVRT)" refers to the time it takes for the ventricle to enter a hypotensive isovolumic closing state. In some cases, the ventricles begin to relax while the aortic and atrioventricular valves remain closed If left ventricular relaxation is impaired, IVRT is prolonged. When this occurs, IVRT is reduced.

[0027] As used herein, "pressure drop rate (-dp / dt)" refers to the left ventricular blood pressure during isovolumic relaxation time. The larger the value, the faster the rate of decrease in left ventricular pressure and the better the cardiac diastolic function. The rate of fall in blood pressure is one of the reliable indices for assessing myocardial relaxation.

[0028] As used herein, "mitral E-peak" refers to the early onset of the mitral valve orifice of the heart. Diastolic peak (E) is the maximum blood flow velocity through the valve orifice during the period of rapid filling of the left ventricle. The E peak of the mitral orifice flow curve represents early active diastolic relaxation of the left ventricle. and reflects relaxation of the left ventricle.

[0029] As used herein, "E-peak descent time (DT)" refers to the deceleration time of the descent of the mitral E-peak; In other words, it refers to the slowing of blood flow caused by early diastolic mitral valve movement into the left atrium. , reflects left atrial blood pressure changes during the rapid filling period. The smaller the value, the more rapid the blood pressure changes. Decreased active relaxation usually occurs early in the disease and reduces the early diastolic filling volume of the left ventricle. This manifests as a decrease in β, a decrease in the E peak, and a prolongation of DT >240 ms.

[0030] As used herein, "other drug(s) for the treatment of heart failure with preserved ejection fraction" are angiotensin-converting enzyme inhibitors / angiotensin II receptor inhibitors, β-receptor antagonists agonists, calcium antagonists, cyclic adenosine monophosphate, catecholamines, Nitrates, phosphatase inhibitors, diuretics, renin-angiotensin-aldosterone Treatment of heart failure with preserved ejection fraction, including renal aortic stenosis (RAS) antagonists, and myocardial energy optimization drugs Refers to known drugs for the treatment of allergies. EXAMPLES

[0031] (Example) Example 1: Effects of recombinant human neuregulin on cardiac function in hypertensive heart failure rats test)

[0032] This study demonstrated that recombinant human neuregulin (rhNRG) in SHR hypertensive rats with heart failure Methods: SHR hypertensive rat strain, standard feeding, feeding Monitoring changes in cardiac function during the treatment. After 16 months, the ejection fraction (EF) had decreased to 70%, indicating high risk of heart failure. These results suggest that the rat model of hypertension was successfully established. The rats were divided into a negative control group, an NRG-treated group, and a captopril-treated group. NRG was administered for 5 consecutive days followed by 2 days of rest, and the NRG group underwent 3 treatment cycles. At the end of the third treatment cycle, rats from each group were examined by echocardiography to determine changes in cardiac function. After the third treatment cycle, the hemodynamics of the rats was monitored.

[0033] (1. Laboratory Animals) 1.1 Strain and origin: SHR hypertensive rat strain was obtained from the Animal Center of Chinese Academy of Sciences. The WKY strain was purchased from the Chinese Academy of Sciences, China. They were purchased from the Animal Center of the National Institute of Science.

[0034] 1.2 Sex and age: Male, 6 weeks old.

[0035] 1.3 Feeding: Regular rodent chow, water ad libitum, 12-hour light / dark cycle

[0036] (2. Test Drugs)

[0037] Specifications: Neucardin(TM), 61 amino acids, produced by Shanghai Zensun Sci & Tech Co., Ltd. .

[0038] (3. Test Materials)

[0039] 3.1 Cardiac ultrasound diagnostic equipment: Philips Sonos 5500

[0040] 3.2 Captopril: Sino American Shanghai Squibb Pharmaceutical

[0041] (4. Experimental Method)

[0042] 4.1 Establishment of a rat model of hypertensive heart failure

[0043] SHR hypertensive rat strain, normal feeding, monitoring cardiac function changes during feeding. After 16 months In SHR rats, the ejection fraction (EF) decreased to 70%, and LVDd and LVDs increased significantly, indicating that hypertensive heart It was suggested that the insufficient rat model was successfully established.

[0044] 4.2 Grouping and Dosing

[0045] After the model was successfully established, the rats were randomly divided into a negative control group, an NRG-treated group, and a capsule-treated group. The rats were divided into two groups, one for treatment with Topril and the other for treatment with rhNRG. rhNRG was administered for 5 consecutive days, followed by a 2-day washout period. The treatment cycle consisted of one treatment cycle, and the drug was administered intravenously once daily at a dose of 6.5 μg / kg. At the same time, the NRG group was given drinking water twice a day by intragastric administration. Prill was administered intragastrically at 10 mg / kg twice daily. NRG vehicle was administered for 3 treatment cycles. The negative control group was given drinking water by intragastric administration, and NR was administered intravenously. G Vehicle was given by tail vein injection.

[0046] 4.3 Echocardiography

[0047] Patients were examined by echocardiography before treatment and at the end of the second and third treatment cycles after ketamine anesthesia. Changes in cardiac function were determined.

[0048] 4.4 Hemodynamic measurements

[0049] At the end of the third treatment cycle, rats were anesthetized with 3% pentobarbital by intraperitoneal injection. A midline incision was made in the neck, the left common carotid artery was isolated and intubated, and arterial and left ventricular hemodynamic parameters were recorded. The data was measured.

[0050] (5. Experimental Results)

[0051] Compared with the negative control group, NRG significantly improved hemodynamics in hypertensive rats. The -dp / dt between these groups showed a statistically significant difference (-7467.6±715.8 and - 5488.1±1340.3, P=0.016); and captopril significantly reduced blood pressure in hypertensive rats. (174.5 ± 33.0 vs. 216.5 ± 23.2 and 228.0 ± 26.0; p = 0.029, p = 0.017 ).

[0052] (6. Conclusion)

[0053] A dose of 6.5 μg / kg of rhNRG was administered to hypertensive heart failure rats for 5 consecutive days in one treatment cycle. After 2 or 3 cycles of treatment, rhNRG increased the left ventricular end-diastolic and and further preventing end-systolic volume expansion and improving hemodynamics, Captopril improves cardiac function in hypertensive rats with heart failure. As shown in Table 1, Lowering blood pressure can improve cardiac function in hypertensive rats with heart failure, whereas rhNRG reduces the left ventricular descent velocity during isovolumic diastole, not by lowering blood pressure. Increasing p / dt can improve cardiac function in hypertensive rats with heart failure.

[0054] Table 1. Hemodynamic parameters in each group after three treatment cycles [Table 1]

[0055] Example 2: Effects of recombinant human neuregulin on cardiac function in patients with heart failure with preserved ejection fraction (Testing of effect)

[0056] Effect of recombinant human neuregulin on cardiac function in patients with heart failure with preserved ejection fraction To evaluate the use of the drug, a preliminary clinical trial was conducted at the Sixth People's Hospital affiliated to Shanghai Jiao Tong University. The study was conducted at the Shanghai Jiao Tong University (Shanghai Pital Affiliated to Shanghai Jiao Tong University). There were 2 patients in the placebo group and 2 patients in the experimental group.

[0057] (1) Main entry criteria

[0058] 1.1 Left ventricular ejection fraction (LVEF) ≥ 50% (2D echocardiography);

[0059] 1.2 New York Heart Association (NYHA) level II or III;

[0060] 1.3 Definite diagnosis of chronic heart failure (including history, symptoms, signs, etc.) It was stable;

[0061] 1.4 Patients receiving standard of care for heart failure are receiving the target dose for at least 1 month. or the maximum tolerated dose has been reached or the dose has not been changed within the last month;

[0062] 1.5 Understand and sign the informed consent form.

[0063] (2. Test Drugs)

[0064] Name: Recombinant human neuregulin for injection

[0065] Specifications: 250 g / vial

[0066] Dosage form: Lyophilized powder for injection

[0067] Route of administration: Intravenous drip

[0068] Placebo (zero dose):

[0069] Name: Lyophilized recombinant human neuregulin excipient

[0070] Dosage form: Lyophilized powder for injection

[0071] Route of administration: Intravenous drip

[0072] (3. Route of administration, dosage and course of treatment are shown in Table 2) Table 2. Dosage, route and course of treatment [Table 2]

[0073] (4. Data Collection:) The spectrum of mitral valve flow in two-dimensional echocardiography was measured during the screening period, days 11 to 13. , and was detected on the 30th day.

[0074] (5. Results and Discussion:) Table 3. Numerical changes in IVRT and DT in the spectrum of mitral flow [Table 3]

[0075] From the results in Table 3, the IVRT and DT values ​​of the patients who received the placebo increased gradually, whereas the IVRT and DT values ​​of the patients who received the NRG increased gradually. The IVRT and DT values ​​of patients who underwent this treatment were significantly reduced, and diastolic function was improved to some extent. It was shown that.

[0076] The above examples do not limit the scope of the invention. The present invention can be adjusted and modified by those skilled in the art without the need for any modification. The scope of protection is defined by the claims, not by specific examples. do.

Claims

[Claim 1] Novel products, methods, and methods of manufacture substantially described in this specification.