Use of regadenoson in echocardiography

Abstract

A use of regadenoson in the preparation of a drug for detecting a cardiac ischemic disease in echocardiography. The echocardiography is selected from one or more of stress echocardiography, myocardial contrast echocardiography, transthoracic Doppler echocardiography, and two-dimensional speckle tracking echocardiography. The cardiac ischemic disease is selected from one or more of a non-obstructive cardiac ischemic disease or an obstructive cardiac ischemic disease. By administering the drug, diagnosis of the disease in a patient exhibits good accuracy, sensitivity, specificity, and safety.

Description

Application of Reganosane in echocardiography

[0001] The present invention claims the priority of the prior application entitled “Application of Reganosin in Echocardiography” and application number 202410400391.X filed on April 3, 2024, and the priority of the prior application entitled “Application of Reganosin in Echocardiography” and application number 202411294720.3 filed on September 14, 2024. The contents of the above-mentioned prior applications are incorporated into this text by introduction. Technical Field

[0002] The present invention relates to the field of biomedicine, and in particular to the application of Reganosine in echocardiography. Background Art

[0003] Ischemic heart disease is a common cardiovascular disease with a high mortality rate. Causes of ischemic heart disease include coronary artery blockage or lesions, or coronary microvascular dysfunction.

[0004] Cardiac imaging can detect and identify heart disease. For example, coronary angiography (CAG) is considered the gold standard for diagnosing coronary artery disease (CAD). However, clinical findings indicate that the accuracy of diagnosing CAD based solely on coronary artery stenosis, such as the degree of coronary artery stenosis, is limited. This is because there is no clear correlation between coronary artery stenosis and cardiac ischemia. In clinical practice, CAG typically diagnoses CAD based on a coronary artery stenosis ≥70%, requiring interventional treatment. This neglects patients with stenosis but no myocardial ischemia, leading to overtreatment. Furthermore, patients without stenosis undergoing myocardial ischemia testing delay treatment for those with myocardial ischemia. Research over the past two decades has demonstrated that coronary microvascular dysfunction (CMD) and coronary artery spasm (CAS) are important mechanisms leading to myocardial ischemia. However, due to the current inability to visually assess coronary microvascular function, symptoms caused by these dysfunctions are often misattributed to non-cardiac causes, resulting in misdiagnosis and inadequate treatment. Clinically, this condition, characterized by symptoms of ischemic chest pain and objective evidence of myocardial ischemia, but without obstructive coronary artery stenosis detected by CAG, is defined as ischemic non-obstructive coronary artery disease (INOCA). Therefore, selecting appropriate cardiac imaging methods to detect cardiac ischemia in patients is beneficial for a more complete understanding of their cardiac condition, particularly for timely detection and early treatment of INOCA.

[0005] Generally, in the process of detecting ischemic heart diseases, it is often necessary to compare the blood flow at rest with the blood flow during cardiac exercise. However, many patients are unable to exercise due to physical reasons or the exercise load is difficult to reach the expected goal. Drug stress test is an effective supplementary method. Therefore, during the test, it is beneficial to use drugs that increase the patient's blood flow in the short term but do not cause peripheral vasodilation. Commonly used coronary vasodilators are adenosine (such as Adenoscan), which is characterized by subtypes A1 and A 2A 、A 2B The effect is produced by interaction with the adenosine receptor family of A3, among which A 2A Receptors play an important role in regulating myocardial oxygen consumption and coronary blood flow. 2A Side effects caused by interactions with other receptors, such as reduced cardiac conductivity caused by binding to the A1 receptor and bronchoconstriction caused by binding to the A3 receptor, limit the clinical use of adenosine. Furthermore, to ensure the acquisition of imaging data useful for assessing cardiac function, its short half-life necessitates continuous, high-volume administration of the drug to patients in clinical practice. This increases the likelihood of side effects in patients undergoing echocardiographic testing using adenosine, and these side effects can also have uncontrollable effects on test results, reducing their accuracy and sensitivity.

[0006] REGADENOSON (313348-27-5) is a known 2A Receptor agonists have the advantages of fewer side effects and a longer half-life compared to vasodilators such as adenosine. For example, the article "Robert C. Hendel et al., Journal of the American College of Cardiology, Vol. 46, No. 11, 2005: 2069-75" mentions that Reganosine has advantages over adenosine and dipyridamole, such as better patient tolerance, fewer side effects, minimal impact on blood pressure, and simpler administration.

[0007] Furthermore, some clinical studies have shown that Reganosine has a stable performance compared to adenosine in patients with mild to moderate asthma and moderate to severe COPD. For example, "Janet Wei, et al, Cardiovasc Disord Med. 2019; 2019:.doi:10.31487 / j.cdm.2019.01.01" mentioned that adenosine is the default vasodilator, and Reganosine is used if the patient has a history of asthma. This literature also shows that Reganosine is a suitable vasodilator. It is meaningful to study the detection effect of Reganosine in the field of nuclear medicine imaging to improve the accuracy of disease diagnosis. Summary of the Invention

[0008] In view of this, the present invention provides a method for using reganosine in echocardiography to detect cardiac ischemic diseases. When used in echocardiography, the method has better safety and patient compliance than adenosine, and has good accuracy and sensitivity for diagnosing cardiac ischemic diseases compared to adenosine.

[0009] The present invention provides the following technical solutions:

[0010] In a first aspect, the present invention provides the use of Reganosane in the preparation of a medicament for detecting cardiac ischemic diseases in echocardiography.

[0011] Preferably, the echocardiogram is selected from one or more of stress echocardiography, myocardial contrast echocardiography, transthoracic Doppler echocardiography, and two-dimensional speckle tracking echocardiography.

[0012] Preferably, the cardiac ischemic disease is selected from non-obstructive cardiac ischemic disease and / or obstructive cardiac ischemic disease.

[0013] Preferably, the ischemic heart disease is selected from non-obstructive ischemic heart disease.

[0014] Preferably, the non-obstructive cardiac ischemic disease is selected from one or more of ischemia with non-obstructive coronary artery disease, coronary microvascular dysfunction, non-coronary obstructive coronary heart disease, chronic coronary syndrome, non-coronary obstructive myocardial ischemia or coronary microvascular dysfunction-type myocardial ischemia.

[0015] Preferably, the ischemic heart disease is selected from obstructive ischemic heart disease.

[0016] Preferably, the obstructive heart ischemic disease is selected from one or more of coronary artery obstructive myocardial ischemia and coronary artery obstructive coronary heart disease.

[0017] Preferably, the concentration of reganosane in the drug is 0.01-0.2 mg / mL, preferably 0.08 mg / mL.

[0018] In a second aspect, the present invention provides the use of Reganosane in the preparation of a medicament for detecting cardiac ischemic disease in stress echocardiography, wherein the patient with the cardiac ischemic disease exhibits at least one of the following clinical symptoms ① to ⑥ in stress echocardiography:

[0019] ① New onset of 2 or more adjacent ventricular wall segments with abnormal motion, decreased motion, absent motion, or paradoxical motion;

[0020] ② The degree of ventricular wall motion abnormality shown by resting echocardiography worsens; or the previously attenuated segment becomes akinetic or paradoxical after loading, or the previously akinetic segment becomes paradoxical after loading;

[0021] ③ Left ventricular global longitudinal strain (LVGLS) or ejection fraction decreased or did not increase compared with baseline;

[0022] ④ Coronary artery blood flow reserve (CFVR) <3.0, preferably CFVR <2.5;

[0023] ⑤ Left ventricular contractility reserve (LVCR) ≤ 1.1;

[0024] ⑥Other clinically significant manifestations of cardiac ischemic diseases.

[0025] In a third aspect, the present invention provides the use of Reganosant in the preparation of a medicament for detecting coronary artery disease using a combination of coronary angiography and echocardiography. Preferably, the coronary artery disease can be coronary artery disease diagnosed by CAG, coronary artery disease further confirmed on the basis of CAG, or non-obstructive coronary artery disease that cannot be diagnosed by CAG.

[0026] Preferably, the combination of coronary angiography and echocardiography means that the patient first undergoes coronary angiography and then undergoes echocardiography; or, the patient first undergoes echocardiography and then undergoes coronary angiography.

[0027] Preferably, the echocardiogram is a stress echocardiogram.

[0028] In a fourth aspect, the present invention includes providing the use of Reganosine in the preparation of a drug for detecting cardiac ischemic diseases by combining coronary angiography and echocardiography.

[0029] Preferably, the combination of coronary angiography and echocardiography means that the patient first undergoes coronary angiography and then undergoes echocardiography; or, the patient first undergoes echocardiography and then undergoes coronary angiography.

[0030] Preferably, the echocardiogram is a stress echocardiogram.

[0031] Fifthly, the use of Reganosin in the preparation of drugs for reducing the risk of adverse events in patients undergoing echocardiography, wherein the adverse events include at least one of chest discomfort, throat discomfort, dyspnea, hypotension, hot flashes, second-degree atrioventricular block, sinus bradycardia, dry mouth, psychiatric or musculoskeletal discomfort.

[0032] Preferably, the application is the application of Reganosin in the preparation of a drug for reducing the risk of adverse events in patients with coronary heart disease and / or ischemic heart disease detected by echocardiography.

[0033] Sixth, the use of Reganosine in the preparation of drugs for detecting cardiac ischemic diseases and / or coronary heart disease in patients with intolerance to adenosine injections through echocardiography.

[0034] Preferably, the adenosine injection intolerance includes at least one of adenosine injection dose intolerance or adenosine injection time intolerance.

[0035] In a seventh aspect, the present invention provides a method for detecting cardiac ischemic disease, the method comprising: detecting the cardiac ischemic disease using echocardiography, and using Reganosane during the detection process.

[0036] Preferably, the reganoxan acts as a vasodilator.

[0037] Preferably, the administering of Reganosant comprises injecting Reganosant into the patient.

[0038] Preferably, the echocardiogram is selected from one or more of stress echocardiography, myocardial contrast echocardiography, transthoracic Doppler echocardiography, and two-dimensional speckle tracking echocardiography.

[0039] Preferably, the cardiac ischemic disease is selected from non-obstructive cardiac ischemic disease and / or obstructive cardiac ischemic disease.

[0040] Preferably, the ischemic heart disease is selected from non-obstructive ischemic heart disease.

[0041] Preferably, the non-obstructive cardiac ischemic disease is selected from one or more of ischemia with non-obstructive coronary artery disease, coronary microvascular dysfunction, non-coronary obstructive coronary heart disease, chronic coronary syndrome, non-coronary obstructive myocardial ischemia or coronary microvascular dysfunction myocardial ischemia.

[0042] Preferably, the ischemic heart disease is selected from obstructive ischemic heart disease.

[0043] Preferably, the obstructive heart ischemic disease is selected from one or more of coronary artery obstructive myocardial ischemia and coronary artery obstructive coronary heart disease.

[0044] Preferably, the concentration of the reganoxan in the vasodilator is 0.01-0.2 mg / mL, preferably 0.08 mg / mL.

[0045] Preferably, the patient with ischemic heart disease exhibits at least one of the following clinical symptoms ① to ⑥ in stress echocardiography:

[0046] ① New onset of 2 or more adjacent ventricular wall segments with abnormal motion, decreased motion, absent motion, or paradoxical motion;

[0047] ② The degree of ventricular wall motion abnormality shown by resting echocardiography worsens; or the previously attenuated segment becomes akinetic or paradoxical after loading, or the previously akinetic segment becomes paradoxical after loading;

[0048] ③ Left ventricular global longitudinal strain (LVGLS) or ejection fraction decreased or did not increase compared with baseline;

[0049] ④ Coronary artery blood flow reserve (CFVR) <3.0, preferably CFVR <2.5;

[0050] ⑤ Left ventricular contractility reserve (LVCR) ≤ 1.1;

[0051] ⑥Other clinically significant manifestations of cardiac ischemic diseases.

[0052] Preferably, the detection includes detecting at least one clinical symptom among the above ① to ⑥.

[0053] Preferably, the detection further comprises coronary angiography, that is, coronary angiography combined with echocardiography.

[0054] Preferably, the combination of coronary angiography and echocardiography means that the patient first undergoes coronary angiography and then undergoes echocardiography; or, the patient first undergoes echocardiography and then undergoes coronary angiography.

[0055] Preferably, the echocardiogram is a stress echocardiogram.

[0056] Preferably, in the method for detecting cardiac ischemic disease, the risk of adverse events is reduced, wherein the adverse events include at least one of chest discomfort, throat discomfort, dyspnea, hypotension, hot flashes, second-degree atrioventricular block, sinus bradycardia, dry mouth, psychiatric or musculoskeletal discomfort.

[0057] Preferably, the patient is a patient intolerant to adenosine injection.

[0058] Preferably, the adenosine injection intolerance includes at least one of adenosine injection dose intolerance or adenosine injection time intolerance.

[0059] In an eighth aspect, the present invention provides a method for detecting coronary heart disease, the method comprising: using echocardiography and coronary angiography in combination to detect the coronary heart disease, and using Reganosane during the detection process.

[0060] Preferably, the reganoxan acts as a vasodilator.

[0061] Preferably, the administering of Reganosant comprises injecting Reganosant into the patient.

[0062] Preferably, the echocardiogram is selected from one or more of stress echocardiography, myocardial contrast echocardiography, transthoracic Doppler echocardiography, and two-dimensional speckle tracking echocardiography.

[0063] Preferably, the coronary heart disease can be coronary heart disease diagnosed by CAG, or coronary heart disease further confirmed on the basis of CAG, or non-obstructive coronary heart disease that cannot be diagnosed by CAG.

[0064] Preferably, the concentration of the reganoxan in the vasodilator is 0.01-0.2 mg / mL, preferably 0.08 mg / mL.

[0065] Preferably, the combination of coronary angiography and echocardiography means that the patient first undergoes coronary angiography and then undergoes echocardiography; or, the patient first undergoes echocardiography and then undergoes coronary angiography.

[0066] Preferably, the patient is injected with Reganosane before or after coronary angiography, and / or, alternatively, before or after echocardiography.

[0067] Through the above technical solution, the present invention has the following beneficial technical effects:

[0068] 1. The use of Reganosin during the patient testing process has fewer adverse events, fewer side effects, and higher safety, thereby reducing inaccurate test results caused by factors such as uncontrollable sudden changes in the patient's physiological state and improving the sensitivity and accuracy of the test;

[0069] 2. Reganosine can detect various cardiac function indicators in patients during echocardiography, and has better clinical diagnostic accuracy and sensitivity than adenosine;

[0070] 3. Reganosant is widely used as a vasodilator in echocardiography and can be used to diagnose various types of ischemic cardiac diseases. It is particularly suitable for diagnosing non-obstructive ischemic cardiac diseases that cannot be diagnosed by CAG. It can also be used in combination with CAG to help more accurately diagnose ischemic cardiac diseases and / or coronary heart disease and guide clinical treatment.

[0071] 4. The test results of Reganosin in echocardiography have been proven to have important clinical guidance significance and can guide clinical tiered medication and therapeutic intervention measures. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1: Schematic diagram of experimental process 1 and experimental process 2 of the present invention.

[0073] Figure 2: Schematic diagram of the experimental process of the present invention. DETAILED DESCRIPTION

[0074] In the following description, numerous specific details are provided to provide a more thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the present invention may be practiced without one or more of these details. In other instances, certain technical features well known in the art are not described to avoid confusion with the present invention.

[0075] The following describes the implementation of the present invention in detail with reference to the definitions of terms:

[0076] The present invention provides the use of Reganosane in the preparation of a medicine for detecting cardiac ischemic diseases in echocardiography.

[0077] IRegano

[0078] The present invention is a kind of A 2A Receptor agonists have fewer side effects and a longer half-life (33 to 108 minutes) and can be used as coronary vasodilators.

[0079] In a specific embodiment, the Reginaxin of the present invention is Reginaxin injection.

[0080] In a specific embodiment, the concentration of the reganoxan of the present invention in the drug is 0.01-2 mg / mL, 0.02-1.5 mg / mL, or 0.05-1 mg / mL.

[0081] II echocardiography

[0082] The drug prepared using the reganoxan of the present invention plays a role in echocardiography. The echocardiography of the present invention can be one or more of stress echocardiography (SE), myocardial contrast echocardiography (MCE), transthoracic Doppler echocardiography (TTDE), and two-dimensional speckle tracking echocardiography (2D-STE).

[0083] The above detection methods can provide comprehensive information on various cardiac function indicators of patients, including anatomical information, ventricular wall motion information, ventricular function parameters and hemodynamic data.

[0084] The present invention also provides a method for detecting cardiac ischemic diseases by echocardiography, wherein reganosane is used as a vasodilator.

[0085] In one embodiment, the echocardiogram of the present invention is a drug stress echocardiogram.

[0086] In one embodiment, Reganosant is injected into the patient within 2-30 seconds, 5-20 seconds, 8-12 seconds, or 10 seconds before the start of the stress echocardiogram.

[0087] In one embodiment, 0.1-20 mL, 1-10 mL, 3-7 mL, or 5 mL of Reganosant is injected into the patient within 2-30 seconds, 5-20 seconds, 8-12 seconds, or 10 seconds before the start of the stress echocardiogram.

[0088] In one embodiment, the stress test of the stress echocardiogram lasts for 5-60 minutes, 10-50 minutes, 20-40 minutes, 25-35 minutes or about 30 minutes. In one embodiment, dynamic images of the patient are collected by stress echocardiography, including resting echocardiogram images before drug administration and stress echocardiogram images after drug administration.

[0089] In one embodiment, the patient's ventricular wall motion, blood flow, ventricular contractility, etc. are obtained through image analysis.

[0090] III Ischemic heart disease

[0091] The ischemic heart disease of the present invention is a heart disease caused by myocardial ischemia and hypoxia due to changes in cardiac circulation.

[0092] In one embodiment, the cardiac ischemic disease of the present invention is at least one selected from coronary heart disease, coronary artery disease, angina pectoris, myocardial infarction, myocardial infarction, vasospasm, vascular microcirculatory dysfunction, myocardial ischemia, and chronic ischemic heart disease.

[0093] In one embodiment, the cardiac ischemic disease of the present invention particularly refers to a cardiac ischemic disease caused by non-coronary artery stenosis.

[0094] In one embodiment, the cardiac ischemic disease of the present invention may also be selected from one or more of coronary artery obstructive myocardial ischemia and coronary artery obstructive coronary heart disease.

[0095] In one embodiment, the cardiac ischemic disease of the present invention is selected from one or more of ischemia with non-obstructive coronary artery disease (INOCA), coronary microvascular dysfunction (CMD), chronic coronary syndrome, non-coronary obstructive coronary heart disease, non-coronary obstructive myocardial ischemia, or coronary microvascular dysfunction-type myocardial ischemia.

[0096] In a specific embodiment, the patient with ischemic heart disease of the present invention exhibits at least one of the following clinical symptoms in stress echocardiography:

[0097] Abnormal ventricular wall motion, such as: new appearance of abnormal motion, hypokinesis, akinesis, or paradoxical motion in ≥2 (≥3, ≥4, or more) adjacent ventricular wall segments; or worsening of ventricular wall motion abnormality shown on resting echocardiography; or a segment with hypokinesis becoming akinetic or paradoxical after load, or a segment with akinesis becoming paradoxical after load; impaired myocardial contractile function, such as: decreased or no increase in left ventricular global longitudinal strain (LVGLS) or ejection fraction compared to baseline; left ventricular contractile reserve (LVCR) ≤ 1.1 or LVCR ≤ 1.0; abnormal cardiac blood flow function, such as coronary flow reserve (CFVR) < 3.0, or CFVR < 2.5, or CFVR < 2.0, etc.

[0098] IV coronary angiography (CAG) combined with echocardiography (eg, SE)

[0099] The reganosane of the present invention can be used as a vasodilator in a method for detecting cardiac ischemic diseases and / or coronary heart diseases by combining coronary angiography and echocardiography.

[0100] The present invention also provides a method for detecting cardiac ischemic diseases by combining echocardiography and coronary angiography, wherein reganosane is used as a vasodilator.

[0101] The echocardiogram is preferably a stress echocardiogram (SE).

[0102] In a specific embodiment, the combination of coronary angiography and echocardiography means that the patient first undergoes coronary angiography and then undergoes echocardiography; or, the patient first undergoes echocardiography and then undergoes coronary angiography.

[0103] In a specific embodiment, the combination of coronary angiography and echocardiography means that the patient first undergoes coronary angiography and then undergoes echocardiography at an interval of 1-7 days (for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, etc.); or, the patient first undergoes echocardiography and then undergoes coronary angiography at an interval of 1-7 days (for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, etc.).

[0104] If both SE and CAG results are positive, it indicates that the patient has coronary artery stenosis accompanied by ischemia and requires intervention. In the case of a positive CAG result, if the degree of stenosis is low (stenosis ≤ 70%) and the SE result is negative, no intervention is required. If the degree of stenosis is high (stenosis ≥ 70%), interventional treatment is not necessarily required. Conversely, if the CAG result is negative and the SE result is positive, it indicates that the patient has non-obstructive heart ischemic disease and requires further examination, such as coronary artery spasm provocation test and / or microvascular function test, and appropriate intervention is given based on the examination results.

[0105] V Adverse events and discontinuation

[0106] Adverse events in the present invention refer to adverse reactions that occur within 0-30 minutes or 0-15 minutes after the injection of a vasodilator during echocardiography, including disease classifications in the System Organ Class (SOC) of the MedDRA (Medical Dictionary for Regulatory Activities) classification system.

[0107] In one embodiment, the adverse events of the present invention specifically refer to adverse reactions in patients with respiratory system, chest and mediastinal diseases, systemic diseases and various reactions at the administration site, various nervous system diseases, gastrointestinal system diseases, vascular and lymphatic diseases, various examinations, various musculoskeletal and connective tissue diseases, various nervous system diseases, and cardiac diseases.

[0108] In a specific embodiment, the adverse events of the present invention refer to adverse reactions such as chest discomfort, throat discomfort, dyspnea, hypotension, hot flashes, second-degree atrioventricular block, sinus bradycardia, dry mouth, psychosis or musculoskeletal discomfort.

[0109] In a specific embodiment, the throat discomfort comprises at least one of throat discomfort, oropharyngeal discomfort, cough, throat tightness, throat irritation, throat irritation, throat pain, and dry throat.

[0110] In one embodiment, the mental illness comprises at least one of insomnia, anxiety, and dysphoria.

[0111] Drug discontinuation refers to the situation where the patient stops taking the medication due to the severity of the aforementioned adverse events and, based on comprehensive clinical evaluation, is deemed unsuitable for continued testing.

[0112] Hereinafter, the present invention will be further described in detail through examples.

[0113] Purpose of the trial

[0114] Through clinical trials targeting unspecified populations, the accuracy, sensitivity, specificity and safety of Reganosin in detecting cardiac ischemic diseases by echocardiography were verified.

[0115] Experimental drugs

[0116] The experimental group was Reganosan Injection: Nanjing Ruike Health Pharmaceutical Co., Ltd., with a specification of 5mL:0.4mg, and the storage condition was a closed environment not exceeding 25°C.

[0117] The control group was adenosine injection: Penglai Nuokang Pharmaceutical Co., Ltd., with a specification of 30mL:90mg, and the storage condition was a closed environment at 10-30℃.

[0118] Test process

[0119] The experimental flow diagram of the present invention is shown in Figure 1. Disease diagnosis and detection methods: coronary angiography (CAG), stress echocardiography (SE) and myocardial perfusion imaging (MPI).

[0120] Efficacy indicators

[0121] After obtaining the diagnostic results of stress echocardiography and myocardial perfusion imaging (MPI, using single-photon computed tomography, or SPECT) for Reganosine injection / adenosine injection, the accuracy, sensitivity, and specificity of the test results for the two drugs can be calculated using the four-cell table shown in Table 1:

[0122] Table 1

[0123] When the MPI result is positive and the SE diagnosis result is also positive, the “case” is determined to be a true positive;

[0124] When the MPI result is negative and the SE diagnosis result is positive, the “case” is determined to be a false positive;

[0125] When the MPI result is positive and the SE diagnosis result is negative, the “case” is determined to be a false negative;

[0126] When the MPI result is negative and the SE diagnosis result is negative, this "case" is determined to be a true negative.

[0127] Calculation formula:

[0128] Accuracy = (a+d) / (a+b+c+d);

[0129] Sensitivity = a / (a+c);

[0130] Specificity = d / (b+d).

[0131] Example 1 Screening of test subjects

[0132] The inclusion criteria for the study population are as follows: aged 18 to 75 years, regardless of gender; patients with clinically confirmed or suspected coronary heart disease, typical or definite angina attacks, or stable chest pain symptoms.

[0133] Example 2 Clinical trial process 1

[0134] This study adopted a multicenter, randomized, double-crossover design.

[0135] After passing the screening examination, patients were randomly assigned to the Reganosine injection-adenosine injection group (RA group) or the adenosine injection-Reganosine injection group (AR group). After a washout period at the end of the previous dosing phase, they entered the next dosing phase. Subjects who had completed coronary angiography (CAG) before the first dose did not need to repeat Phase 3.

[0136] The dosing regimen is as follows:

[0137] Table 2

[0138] in:

[0139] Dosage and administration of Reganoxan: Inject 0.4 mg / 5 mL into a peripheral vein within 10 seconds, followed by immediate flushing of the line with 5 mL of normal saline.

[0140] Adenosine Dosage: Infusion dose 140 μg / kg / min, administration over 6 minutes, total dose 0.84 mg / kg. The dose should be calculated based on each patient's weight and infused using a microinjection pump.

[0141] 1. Pre-dose inspection

[0142] The subjects' routine physiological and medical history conditions were observed and evaluated within 14 days before the first administration to ensure that their physical condition was suitable for completing the experiment.

[0143] 2. Study Visits

[0144] This study conducted approximately 4 research visits in total, and the specific process was as follows.

[0145] Phase 1

[0146] The subjects were randomly divided into groups after fasting for 4 hours before the stress test.

[0147] Vital signs testing: Vital signs (body temperature, blood pressure, heart rate, respiratory rate) were measured within 30 minutes before drug administration (reganosine for the RA group and adenosine for the AR group) and 30 minutes after the start of SE loading. Blood pressure and heart rate were checked 3 minutes, 6 minutes, and 10 minutes after the start of loading drug administration.

[0148] Check 12-ECG: Check 12-ECG within 30 minutes before drug administration and 3 minutes, 6 minutes, 10 minutes, and 30 minutes after the start of loading.

[0149] During the trial, continuous electrocardiogram monitoring and stress echocardiography images were collected (including resting echocardiography before drug administration and stress echocardiography images after drug administration).

[0150] Phase 2

[0151] After a one-day washout period and safety check, the second dosing cycle began. The dosing and testing methods were the same as in phase 1. The RA group was given adenosine and the AR group was given reganosine.

[0152] Stage 3 Coronary Angiography

[0153] Coronary angiography was performed according to the subjects' conditions.

[0154] Phase 4 Trial End-of-Trial Inspection

[0155] After the trial, the subjects were examined by the following tests: urine pregnancy test / blood pregnancy test, vital signs, physical examination, 12-ECG, and adverse events and concomitant medications of the subjects were recorded.

[0156] Example 3 Clinical trial process 2

[0157] Since SPECT stress myocardial perfusion imaging is of excellent value in diagnosing ischemic heart disease and has a guiding role, as recorded in the literature (Zhang Yuan, Ren Xiaohui, Gu Chao. [J]. Hainan Medicine, 2021, 32(20): 2667-2670.). Therefore, during the test process of the above-mentioned Example 2, when the results of Reganosine injection and adenosine injection SE were inconsistent, Reganosine injection drug stress myocardial perfusion imaging (MPI) was added to detect cardiac blood flow, that is, SPECT examination. Using the SPECT examination results as the standard, the accuracy, sensitivity and specificity of Reganosine SE and adenosine SE in diagnosing myocardial ischemia were evaluated.

[0158] Experimental drug: the aforementioned Reganosen injection.

[0159] Test process:

[0160] After routine vital sign testing, the subjects underwent a drug loading test: 5 ml of injection (containing 0.4 mg of Reganosine) was quickly injected into the patient's vein (about 10 seconds), and the patient was immediately flushed with 5 ml of normal saline.

[0161] The imaging agent 99Tcm-MIBI was then administered intravenously through another intravenous channel. Routine ECG monitoring was then performed. Myocardial tomography was performed and images were acquired 60 to 90 minutes after the injection of the imaging agent.

[0162] Example 4 Test results of Example 2 and Example 3

[0163] The sample size of this study consisted of 24 cases, including 15 males and 9 females, with an average age of 56 years.

[0164] Positive criteria for stress echocardiography in diagnosing cardiac ischemic disease may include any of the following (in Table 3, the presence of at least one of the following conditions in the regorafenone group or adenosine group is considered "+"):

[0165] ① New abnormal motion of ≥2 adjacent ventricular wall segments during stress testing, i.e., decreased motion, absent motion, or paradoxical motion;

[0166] ② During the stress test, the degree of ventricular wall motion abnormality shown by resting echocardiography worsens, that is, the previously attenuated segment becomes akinetic or paradoxical after loading, and the previously akinetic segment becomes paradoxical after loading;

[0167] ③ Left ventricular global longitudinal strain (LVGLS) or ejection fraction decreased or did not increase compared with the baseline state;

[0168] ④Coronary flow reserve (CFVR) <2.5;

[0169] ⑤ Left ventricular contractile reserve (LVCR) ≤ 1.1;

[0170] ⑥Other clinically significant manifestations of myocardial ischemia.

[0171] The positive criteria for CAG detection of coronary heart disease are: stenosis of the left or right coronary artery main branches (right coronary artery, left anterior descending artery, left circumflex artery, left main trunk) or their first-order branches is ≥50%, which is considered to be positive for coronary angiography, and the results are shown as "+" in Table 3.

[0172] Positive criteria for MPI in myocardial ischemia: A pharmacological stress MPI test shows sparse radioactivity distribution or loss in one or more segments of the left ventricle on two or more consecutive slices, indicating a positive result. The results in Table 3 are indicated as "+."

[0173] The results of this experiment are shown in the following table.

[0174] Table 3 Note: “+” represents positive, “-” represents negative, and “ / ” represents not tested.

[0175] The accuracy, sensitivity, and specificity of reganosine and adenosine for diagnosing myocardial ischemia were calculated according to the aforementioned formulas. The results are shown in Table 4 below:

[0176] Table 4

[0177] Example 5 Clinical trial process three

[0178] This study was designed to further validate the efficacy of reganosine and adenosine in the echocardiographic diagnosis of non-obstructive ischemic heart disease. This multicenter, randomized, double-crossover study employed a combined clinical trial procedure (Clinical Trial 1) and stress myocardial perfusion imaging (MPI) with reganosine injection to assess cardiac blood flow, also known as SPECT. Using MPI results as a benchmark, the accuracy of reganosine SE and adenosine SE in diagnosing cardiac ischemic disease, particularly non-obstructive ischemic heart disease, was evaluated. The study drugs and procedures were the same as those used in Clinical Trial 2. First, samples with negative CAG and positive MPI results were screened. A negative CAG indicates the absence of significant coronary artery stenosis, while a positive MPI indicates the presence of cardiac ischemia, making these patients highly likely to have non-obstructive ischemic heart disease. A more detailed echocardiographic analysis of these samples was conducted to compare the differences in the results of reganosine and adenosine (specific types of positive markers detected) and to determine the efficacy and sensitivity of reganosine and adenosine in stress echocardiographic diagnosis of non-obstructive ischemic heart disease. The higher the proportion of positive tests that can be detected, the better the effectiveness; and the more positive indicator types that can be detected, the higher the sensitivity.

[0179] This study included 98 subjects, including 59 males and 39 females, with an average age of 55. A total of 20 groups of samples with negative CAG results and positive MPI results were collected, and the results are shown in Table 5 below.

[0180] Table 5

[0181] Based on the above results, the effectiveness and sensitivity of Reganosine and adenosine for the diagnosis of non-obstructive ischemic heart disease are calculated. Among them, "effectiveness" corresponds to the proportion of positive test results, and in the effective samples (at least one drug detected positive), "sensitivity" corresponds to the proportion of more positive indicators detected for the same patient compared to another drug. For example, patient 15 was tested positive for Reganosine but adenosine was not. For the test of this patient, Reganosine has better effectiveness; for another example, patient 17 was tested three positive indicators by Reganosine but adenosine was only detected two. For this patient, Reganosine has better sensitivity. The results of patients 1-20 in Table 5 are summarized as shown in Table 6 below.

[0182] Table 6

[0183] Example 6 Safety Test 1

[0184] During the aforementioned clinical trials, adverse reactions in patients were evaluated according to the following criteria:

[0185] Grade 1: Mild; asymptomatic or mild; only clinical or diagnostic observations; no treatment required.

[0186] Grade 2: Moderate; minor, local, or noninvasive treatment required; age-appropriate limitation in instrumental activities of daily living.

[0187] Grade 3: Severe or medically significant but not immediately life-threatening; leading to hospitalization or prolonged hospitalization; causing disability; limiting self-care activities of daily living.

[0188] The test results are shown in Table 7 below.

[0189] Table 7

[0190] Among the 24 patients in this study, 18 adverse reactions were associated with reganosant, including 17 Grade 1 and 1 Grade 2. A total of 19 adverse reactions were associated with adenosine, including 16 Grade 1, 2 Grade 2, and 1 Grade 3. The incidence of adverse reactions with reganosant was 75.0%; the incidence of adverse reactions with adenosine was 79.2%.

[0191] Example 7 Safety Test 2

[0192] This study was designed to further investigate the safety of Reginaxin in echocardiographic testing. The experimental procedure was the same as the clinical trial procedure 1 in Example 2. The adverse events described in this example were all detected within 15 minutes after the injection of Reginaxin or adenosine.

[0193] The sample size of this study consisted of 194 cases, including 118 males and 76 females, with an average age of 58 years.

[0194] During the safety testing of this clinical trial, based on the disease classification in the System Organ Class (SOC) of the MedDRA classification system (Medical Dictionary for Regulatory Activities), statistics were collected on adverse reactions and situations leading to drug discontinuation in patients from the aspects of respiratory system, thoracic and mediastinal diseases, systemic diseases and various reactions at the administration site, various nervous system diseases, gastrointestinal system diseases, vascular and lymphatic diseases, various examinations, various musculoskeletal and connective tissue diseases, various nervous system diseases, and cardiac diseases. The results are shown in Tables 8 and 9, among which Table 8 shows the case statistics of some adverse reactions in patients after injection of reganosine or adenosine, and Table 9 shows the case statistics of patients who discontinued the drug due to various serious adverse reactions after injection of reganosine or adenosine.

[0195] Table 8

[0196] Table 9

[0197] Result analysis:

[0198] As can be seen from clinical trial processes 1 and 2 (Tables 3 and 4), when the CAG result was "+," the SE result was "+" in 66.7% of cases, indicating coronary artery stenosis with ischemia; when the CAG result was "+," the SE result was "-" in 33.3% of cases, indicating coronary artery stenosis but no myocardial ischemia; and when the CAG result was "-," the SE result was "+" in 87.5% of cases, indicating no coronary artery stenosis but myocardial ischemia. This shows that diagnosing heart disease based solely on CAG results cannot fully reflect a patient's heart condition, particularly whether they have ischemic heart disease.

[0199] Through the auxiliary examination of Reganosin echocardiography, patients can be classified: if the SE result and CAG result are both "+", it indicates that the patient has coronary artery stenosis accompanied by ischemia and requires intervention. In the case of a "+" CAG result, if the degree of stenosis is low (stenosis ≤ 70%) and the SE result is "-", no intervention is required. If the degree of stenosis is high (stenosis ≥ 70%), direct intervention would be performed in the past. However, after adopting the method of the present invention, if the SE result is "-", such patients may not necessarily require interventional treatment, and a comprehensive judgment on the treatment method should be made based on the severity of symptoms, degree of stenosis, location of stenosis, blood indicators, other examination indicators, etc.; conversely, if the CAG result is "-", the clinic may not have previously considered that the patient has heart disease and requires intervention. However, according to the method of the present invention, if the patient's SE result is "+", it indicates that the patient has non-coronary artery obstructive ischemic heart disease and may need further examination, such as coronary artery spasm provocation test and / or microvascular function test, and appropriate intervention should be given according to the examination results.

[0200] From the clinical trial process three, as shown in Tables 5 and 6, for samples intended to be diagnosed as non-obstructive ischemic heart disease, the overall effectiveness and sensitivity of Reganosine were better than those of adenosine, indicating that Reganosine is of great significance for the clinical diagnosis of SE in non-obstructive ischemic heart disease.

[0201] Safety testing, as shown in Table 7, shows that compared to adenosine, Reganosin has a lower incidence and severity of adverse reactions, suggesting improved safety. Furthermore, Reganosin's one-time administration shortens testing time and improves patient compliance. The aforementioned adverse reactions to adenosine, particularly severe ones, are likely contributing to the decreased accuracy and sensitivity of test results.

[0202] Furthermore, it can be seen from Table 8 that compared with adenosine, Reganosin has better clinical effects, that is, smaller side effects, in reducing adverse reactions in echocardiographic testing (such as chest discomfort, throat discomfort, dyspnea, hypotension, hot flashes, second-degree atrioventricular block, sinus bradycardia, psychiatric or musculoskeletal discomfort), showing higher safety. As can be seen from Table 9, after the patient was injected with Reganosin, even if there were adverse reactions, the adverse reactions were generally mild and patient-friendly. In contrast, some patients were intolerant to adenosine and the symptoms were severe, leading to drug discontinuation. Therefore, Reganosin is suitable for the detection of patients intolerant to adenosine.

[0203] Thus, the method of the present invention is suitable for diagnosing ischemic heart disease, particularly non-coronary artery obstructive ischemic heart disease, and can provide more precise treatment for patients with heart disease in clinical practice. Furthermore, a comparison of efficacy indicators shows that Reganosine has higher detection accuracy, sensitivity, specificity, and safety than adenosine.

[0204] Furthermore, for clinical use, the stress test for Reganosin with stress echocardiography lasts approximately 30 minutes; the stress test for adenosine with stress echocardiography lasts approximately 60 minutes; and the MPI test lasts approximately two days. Because most tertiary hospitals are overcrowded, the simple, one-time administration of Reganosin helps control examination time and is more convenient for crowded examination departments.

[0205] In the above embodiments, all technical solutions that fall within the scope of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, several improvements and modifications that do not depart from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. The use of Reganosin in the preparation of drugs for detecting cardiac ischemic diseases in echocardiography.

2. The method according to claim 1, wherein the echocardiogram is selected from one or more of stress echocardiography, myocardial contrast echocardiography, transthoracic Doppler echocardiography, and two-dimensional speckle tracking echocardiography.

3. The use according to any one of claims 1-2, wherein the ischemic heart disease is non-obstructive ischemic heart disease.

4. The use according to claim 3, wherein the non-obstructive heart ischemic disease is selected from one or more of ischemia with non-obstructive coronary artery disease, coronary microvascular dysfunction, non-coronary obstructive coronary heart disease, chronic coronary syndrome, non-coronary obstructive myocardial ischemia, and coronary microvascular dysfunction-type myocardial ischemia.

5. The use according to any one of claims 1-2, wherein the ischemic heart disease is obstructive ischemic heart disease.

6. The use according to claim 5, wherein the obstructive heart ischemic disease is selected from one or more of coronary artery obstructive myocardial ischemia and coronary artery obstructive coronary heart disease.

7. According to the use according to any one of claims 1-2, the reginaxin is an injection, and preferably the concentration of reginaxin in the drug is 0.01-2 mg / mL.

8. The concentration according to claim 7, wherein the concentration of reganosane in the drug is 0.05-1 mg / mL, preferably 0.08 mg / mL.

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