CN115645402A - Application of aranidipine in preparation of medicine for treating or preventing acute myocardial infarction - Google Patents
Application of aranidipine in preparation of medicine for treating or preventing acute myocardial infarction Download PDFInfo
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- CN115645402A CN115645402A CN202211464760.9A CN202211464760A CN115645402A CN 115645402 A CN115645402 A CN 115645402A CN 202211464760 A CN202211464760 A CN 202211464760A CN 115645402 A CN115645402 A CN 115645402A
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Abstract
The invention belongs to the field of medicines, relates to a medicine for treating acute myocardial infarction, and particularly relates to application of aranidipine in treatment of acute myocardial infarction. The technical scheme of the invention is as follows: application of aranidipine in preparing medicine for preventing and treating acute myocardial infarction is provided. The invention provides a new application and a drug delivery mode of the aranidipine, which have the protection effect on heart and cerebral ischemia/reperfusion (especially myocardial infarction and ischemic stroke), and reduce ischemia/reperfusion injury; and the function of the cell protection medicine for protecting organs, tissues or cells against cell damage and dysfunction, and the adaptation disease range of the aranidipine is expanded.
Description
Technical Field
The invention belongs to the field of medicines, relates to a medicine for treating acute myocardial infarction, and particularly relates to application of aranidipine in preparation of a medicine for treating or preventing acute myocardial infarction.
Background
Myocardial Infarction (MI): myocardial infarction generally refers to acute myocardial infarction, is myocardial necrosis caused by acute and persistent ischemia and hypoxia of coronary arteries, is accompanied by arrhythmia, shock or heart failure, and can be dangerous to life.
Clinical criteria for myocardial infarction: the clinical definition of myocardial infarction is that abnormal cardiac biomarkers confirm acute myocardial damage, with clinical evidence of acute myocardial ischemia.
Abnormal cardiac biomarker refers to the 99 th percentile of cardiac troponin (cTn) values above the upper normal reference value limit (URL); clinical evidence for acute myocardial ischemia includes at least one of: (1) symptoms of ischemia; (2) newly occurring ischemic electrocardiographic changes; (3) electrocardiogram pathological Q wave formation; (4) imaging evidence indicates a new loss of myocardial activity or a new onset of regional wall motion abnormalities.
About 1800 million people die worldwide each year from cardiovascular disease. This means that every 1.8 seconds one person dies in the world from cardiovascular disease. According to the data of the world health organization, cardiovascular diseases are also the first leading cause of death in the world, and 1770 million people are estimated to die in 2015 [ . The burden of cardiovascular disease is further magnified because it is considered the most expensive disease, with an indirect cost calculated at $ 2370 billion per year, which is expected to increase to $ 3680 billion by 2035. Although acute mortality rates have been decreasing in infarcted patients, reflecting advances in diagnosis and treatment over the past decades, the risk of heart disease remains high, with a 50% risk population generally calculated by the age of 45. According to clinical information, the current myocardial infarction morbidity population presents a younger trend. At present, irregular eating habits, work and rest, excessive working pressure and the like of young people can become the inducement of myocardial infarction.
The treatment of myocardial infarction generally comprises operation treatment, interventional treatment, thrombolytic treatment, drug treatment and the like. The surgical treatment mainly adopts heart transplantation or artificial heart to treat myocardial necrosis, but can be subject to rejection reaction of donor sources and human bodies; interventional therapy mainly comprises percutaneous puncture, coronary angioplasty and coronary bypass, however, focal or diffuse restenosis may occur at a lesion part successfully expanded by a balloon, when myocardial cells are seriously damaged or die, the infarct area is expanded again, and then acute complications such as arrhythmia, heart failure, sudden death and the like occur; thrombolytic therapy is often associated with serious complications, mucosal, subcutaneous and even intracerebral hemorrhage. The drug treatment focuses on preventing and treating ventricular remodeling, the heart function is protected and maintained, the myocardial blood supply is improved, the frequently-dead myocardium is saved, the myocardial infarction range is reduced, the myocardial infarction healing is accelerated, complications are treated, and the sudden death is prevented. Therefore, there is a great need in drug therapy to develop new drugs for patients.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the application of the aranidipine in preparing the medicine for treating or preventing the myocardial infarction. The invention provides a new application and a drug delivery mode of the aranidipine, and enlarges the indication range of the aranidipine.
In order to solve the technical problems, the technical scheme of the invention is as follows:
application of aranidipine in preparing medicine for preventing and treating acute myocardial infarction is disclosed.
The structural formula of the aranidipine is shown as the formula (I):
the formula (I).
The aranidipine is a novel 1, 4-dihydropyridine derivative, has better clinical curative effect on essential hypertension, can reduce peripheral vascular resistance and enhance ejection function. In addition, it can reduce the incidence of stroke, cardiac fibrosis, proliferative fibrosing arteriolar inflammation and malignant nephrosclerosis.
In myocardial ischemia, the energy metabolism is disturbed to reduce the functions of the myocardium, and the sodium pump and the calcium pump are inhibited and the passive transport of calcium is enhanced to accumulate calcium in cells to form calcium overload, so that the cells are subjected to apoptosis and necrosis.
The aranidipine is dihydropyridine calcium channel blocker, and can reduce Ca by blocking voltage-dependent L-type calcium channel (L-VDCC) on cell membrane of cardiac muscle and vascular smooth muscle 2+ Internal flow and decrease of intracellular Ca 2+ The concentration can have obvious effect of protecting cardiac muscle.
In particular, the drug may be a drug that increases the systolic/diastolic capacity of the heart.
In particular, the medicament may be a medicament for improving myocardial fibrosis.
It is another object of the present invention to provide a medicament for treating or preventing acute myocardial infarction.
The technical scheme is as follows:
a medicine for treating or preventing acute myocardial infarction comprises the active ingredient of aranidipine.
Furthermore, the medicine is any pharmaceutically acceptable dosage form.
Further, the preparation comprises one of injection, capsule, tablet, granule, suspension, emulsion, spray, powder, liposome, oral liquid and dripping pill, wherein the preferable preparation is injection.
Further, the aranidipine is a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt is a pharmaceutically commonly used salt, and further the salt is at least one selected from the group consisting of acetate, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzoate, fumarate, maleate, succinic acid, tartaric acid, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2, 5-dihydroxybenzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, laurylsulfonate, hydroquinonesulfonate and p-toluenesulfonate.
Further, the drug is administered by one of intramuscular injection, subcutaneous injection, intravenous injection, oral administration, sublingual buccal administration, intralesional implantation, intracerebral delivery and spray administration, preferably by oral, intramuscular, subcutaneous or intravenous injection.
In conclusion, the invention has the following beneficial effects:
the pathophysiology processes and reasons related to myocardial infarction are relatively diverse, the research on the treatment drugs of myocardial infarction is still in progress, no major breakthrough exists till now, and partial drugs have slow curative effect and large side effect. The inventor finds that the aranidipine also has a good curative effect on acute myocardial infarction. Therefore, the invention provides a safe and effective drug, namely the aranidipine, for treating acute myocardial infarction, and has great significance for improving the life quality of patients with myocardial infarction and family members and reducing social burden.
The invention provides a new application and a drug delivery mode of the aranidipine, which have the protection effect on heart and cerebral ischemia/reperfusion (especially myocardial infarction and ischemic stroke), and reduce ischemia/reperfusion injury; and the function of the cell protection medicine for protecting organs, tissues or cells against cell damage and dysfunction, and expands the indication range of the aranidipine.
Drawings
FIG. 1 is a schematic representation of the effect of aranidipine on the hemodynamics of myocardial infarction rats;
FIG. 2 is an electron micrograph of a Masson-stained pathological section of rat heart tissue.
Detailed Description
The invention is further explained below with reference to the drawings.
This detailed description is to be construed as illustrative only and is not limiting, since modifications will occur to those skilled in the art upon reading the preceding specification, and it is intended to be protected by the following claims.
Example 1 animal experiments: preparation of myocardial ischemia injury rat model
Weighing a rat, carrying out intraperitoneal injection of 20% urethane at a dose of 0.6ml/100g, anesthetizing the rat, fixing the rat on a rat plate in a supine position, carrying out tracheal intubation, and connecting a small animal respirator (the tidal volume is adjusted to be 5ml, and the respiratory frequency is adjusted to be 60-70 times/min). The electrocardiogram is connected, the left lower limb is a positive pole, the right upper limb is a negative pole, and the left lower limb is grounded. The electrocardiogram was observed, and if the mouse with abnormal electrocardiogram appeared, it was not used for the experiment. The left chest of the rat was shaved, skin was disinfected with 75% alcohol, the skin was cut from the left side of the sternum by about 2cm, and subcutaneous and muscular tissues were blunt-separated using hemostats, completely exposing the third four ribs. Separating three or four intercostal muscles by using hemostatic forceps, exposing the heart in a visual field, tearing a pericardium, searching a left anterior descending branch of a coronary artery between an arterial cone and a left auricle, and selecting 7-0 filament to penetrate through the myocardium under the left anterior descending branch of the coronary artery, wherein the depth of the filament penetrating into the myocardium is about 3mm, and the filament possibly penetrates through the left ventricle when being too deep. The silk thread is knotted to tighten the cardiac muscle, the cardiac muscle of the ischemic part becomes white, and the ST segment of the electrocardiogram is lifted up by the arch back, which shows that the myocardial infarction model is successful. After the success of the model building is confirmed, the rib is sutured immediately, and after the rib is sutured, the muscle and the skin are sutured layer by layer. Disinfecting an operation area by using iodophor, injecting 8 ten thousand units of penicillin into the operation area by muscle for three consecutive days, withdrawing the respirator, keeping the tracheal cannula to observe whether the rat recovers spontaneous respiration, pulling out the tracheal cannula if the rat recovers, clearing foreign matters in the oral cavity, and putting the rat on a heat-insulating blanket to be completely recovered. Experimental animals were randomly divided into 5 groups, i.e.: a blank control group, a model group, an Aranidipine (AR) low dose group (0.3 mg/kg), an Aranidipine (AR) medium dose group (1 mg/kg) and an Aranidipine (AR) high dose group (3 mg/kg). The administration time was 4 weeks, once a day.
Example 2 Effect of amlodipine on the hemodynamics of myocardial infarction rats
The anesthetized rat is fixed on a rat board in a supine position, the neck skin is cut, the 4-0 suture line is ligated at the far end of the right common carotid artery by careful separation, and the near end is clamped by a vascular clamp. The V-shaped opening of the right common carotid artery is cut by ophthalmic scissors, the ophthalmic forceps are used for opening the blood vessel and inserting the PE-10 catheter, the vascular clamp is loosened, the aortic pressure is detected, and after the animal state is stable, the PE-10 catheter is continuously inserted into the left ventricle to detect the ventricular pressure. After the measurement is finished, the catheter is carefully taken out and put into normal saline, and the suture line on the right common carotid artery of the rat is tightened to avoid bleeding. And calculating hemodynamic indexes such as LVSP, LVEDP, dp/dtmax, dp/dtmin and the like during data analysis.
Figure 1 is a schematic representation of the effect of aranidipine on hemodynamics of myocardial infarction rats. In the figure, A: after 4w of adripine administration, measuring results of LVSP of myocardial infarction rats; b: after 4w of adripine administration, measuring results of LVEDP of an myocardial infarction rat; c: measuring the result of dp/dtmax of the myocardial infarction rat after 4w of administration of the aranidipine; d: after 4w of adripine administration, the measurement result of dp/dtmin of myocardial infarction rats is obtained. (LVSP: left ventricular systolic pressure; LVEDP: left ventricular end diastolic pressure; dp/dtmax: maximum rate of change in the ascending section of left ventricular pressure; dp/dtmin: maximum rate of decline in the descending section of left ventricular pressure).
The results are shown in FIG. 1:
after coronary artery ligation, LVSP of each group is reduced compared with that before the coronary artery ligation, and LVSP of the model group is obviously reduced compared with that of the control group; compared with the model group, the decrease amplitude of LVSP can be obviously reduced in the high-dose group and the medium-dose group of the aranidipineP< 0.01), the low dose group was statistically insignificant compared to the model group. After ligation, the LVSP of the model group rat is obviously reduced compared with that of a control group, and the contraction function of the heart is obviously damaged under the ischemic condition, and the test result shows that the myocardial contraction capacity of the myocardial ischemic rat can be improved by using both 3mg/kg and 1mg/kg of the aranidipine to maintain the contraction function of the ischemic heart;
after coronary ligation, LVEDP of each group was higher than that before ligation; the model set remained high throughout the experiment; LVEDP did not continue to rise after dosing but instead showed a downward trend in each dosing group compared to the model group, with a significant antagonistic effect on LVEDP rise after dosing with high-dose group of aranidipine (L:)P< 0.01), the differences between the other groups and the model group were not statistically significant. The LVEDP of the model group rat is increased and maintained at a certain level after ligation, the myocardial contractile function of the rat is reflected to be damaged, simultaneously, the cardiac preload is increased due to the reduction of cardiac output so as to lead the diastolic function to reach the limit, and the test result shows that the preload can be reduced by reducing the peripheral vascular resistance of expansion and improving the diastolic capacity by using 3mg/kg, so that the myocardial preload is improvedIschemic rat systolic/diastolic function;
after coronary ligation, dp/dt for each group max 、dp/dt min Are all significantly reduced compared with the pre-ligation; compared with a model group, the each dose group of the aranidipine reduces dp/dt max By a reduction of (a)P< 0.1), while the high-dose group and the medium-dose group of the aranidipine reduce dp/dt min Of decrease amplitude of (a), (b)P< 0.1), reduced dp/dt in the low dose group min The effect of reducing the amplitude is not obviously different from the effect of reducing the amplitude. Indicating that the aranidipine can resist dp/dt max 、dp/dt min The reduction of (a) is effective in improving the cardiac contractile/diastolic ability of the myocardial ischemia rats to maintain the cardiac contractile function.
Example 3 Effect of Alradipine on myocardial fibrosis in myocardial infarction rats
The rat heart is taken out quickly after the rat is killed, the rat heart is washed by ice physiological saline, the rat heart is soaked in 4% paraformaldehyde, cotton is plugged into a bottle containing a specimen, lung tissues are completely immersed in the paraformaldehyde, and after the rat heart is fixed for 24 hours at normal temperature, paraffin-embedded sections of the heart are subjected to Masson staining.
FIG. 2 shows an electron micrograph of a Masson-stained pathological section of rat heart tissue. Masson staining showed that the red fibers of the myocardium were well aligned and the blue fibers of collagen were rare in the control rats. After MI, myocardial cell necrosis and myocardial tissue structural disorder occur, and a large area of blue collagen fibers can be seen in an infarct area. The myocardial tissue structure of rats in the aranidipine administration group is improved to a certain extent, red myocardial cells and blue collagen in an infarct area are distributed in an interactive manner, and the collagen fibers are obviously reduced, which shows that the moderate and high dose of the aranidipine in 4 weeks can reduce the myocardial fibrosis degree after MI.
Claims (4)
1. Application of aranidipine in preparing medicine for preventing and treating acute myocardial infarction is disclosed.
2. The use according to claim 1, wherein the medicament is a medicament for increasing systolic/diastolic capacity.
3. The use according to claim 1, wherein the medicament is a medicament for improving myocardial fibrosis.
4. A medicament for treating or preventing acute myocardial infarction, characterized by: the active ingredient of the medicine is the aranidipine.
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CN116920040A (en) * | 2023-08-31 | 2023-10-24 | 浙江工业大学 | Traditional Chinese medicine composition for treating acute myocardial infarction and preparation and application thereof |
Citations (2)
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CN1931166A (en) * | 2006-09-15 | 2007-03-21 | 天津市中央药业有限公司 | Hypertension treating medicine |
TW201000097A (en) * | 2008-05-30 | 2010-01-01 | Daiichi Sankyo Co Ltd | Medicament for the prophylaxis or treament of hypertension |
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Patent Citations (2)
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CN1931166A (en) * | 2006-09-15 | 2007-03-21 | 天津市中央药业有限公司 | Hypertension treating medicine |
TW201000097A (en) * | 2008-05-30 | 2010-01-01 | Daiichi Sankyo Co Ltd | Medicament for the prophylaxis or treament of hypertension |
Non-Patent Citations (3)
Title |
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DAISUKE SUETA ET AL.: "Clinical roles of calcium channel blockers in ischemic heart diseases", HYPERTENSION RESEARCH, no. 40, pages 423 - 428 * |
李玲;罗振福;丁一;: "阿雷地平的合成", 中国医药工业杂志, vol. 39, no. 01, pages 6 - 8 * |
杨福祯;李宏;何光杰;: "阿雷地平药理作用和临床研究进展", 中国新药杂志, vol. 18, no. 10, pages 867 - 871 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116920040A (en) * | 2023-08-31 | 2023-10-24 | 浙江工业大学 | Traditional Chinese medicine composition for treating acute myocardial infarction and preparation and application thereof |
CN116920040B (en) * | 2023-08-31 | 2024-04-19 | 浙江工业大学 | Traditional Chinese medicine composition for treating acute myocardial infarction and preparation and application thereof |
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