CN115998737A - Application of amodiaquine in preparation of medicine for treating pressure-loaded myocardial injury - Google Patents
Application of amodiaquine in preparation of medicine for treating pressure-loaded myocardial injury Download PDFInfo
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- CN115998737A CN115998737A CN202211622600.2A CN202211622600A CN115998737A CN 115998737 A CN115998737 A CN 115998737A CN 202211622600 A CN202211622600 A CN 202211622600A CN 115998737 A CN115998737 A CN 115998737A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to the technical field of medicines, in particular to application of amodiaquine in preparing a medicine for treating pressure-loaded myocardial injury. The research of the invention discovers that amodiaquine can inhibit histamine N-methyltransferase (HNMT), and further provides an application technical scheme of amodiaquine in preparing a medicament for treating pressure-loaded myocardial injury. And the amodiaquine has better safety because of rare adverse reactions. The scheme provided by the invention can make up for the defects of the traditional myocardial injury treatment such as heart strengthening, urination promoting and anti-vascular treatment, and can delay the myocardial injury progress and improve the life quality of patients by treating myocardial injury patients after pressure overload by using amodiaquine with extremely rare adverse reactions.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of amodiaquine in preparation of a medicine for treating pressure-loaded myocardial injury.
Background
Pressure overload caused by hypertension, valve disease, etc. is the most common cause of myocardial damage. Currently, beyond treatment for etiology, cardioprotective agents are commonly used to reverse myocardial remodeling caused by pressure overload. Although some medicaments for treating pressure-loaded myocardial injury exist at present, for example, chinese patent publication No. CN102210764A discloses application of sweet almond oil in preparing medicaments for treating myocardial ischemia reperfusion injury, and a pharmacodynamic test shows that the sweet almond oil can improve the hypoxia tolerance of rat myocardial tissues, strengthen the hypoxia tolerance of myocardial tissues to ischemia reperfusion injury, improve the oxidation resistance of myocardial tissues of the ischemia reperfusion rats and reduce the injury degree of myocardial tissues of the rats. The Chinese patent with publication number of CN108567775A discloses a clinic drug lipoic acid for treating pressure-loaded myocardial injury, and lipoic acid is added to patients with pressure-loaded myocardial injury on the basis of standard treatment, so that the activity of myocardial mitochondrial acetaldehyde dehydrogenase 2 (ALDH 2) can be improved, the energy metabolism of myocardial mitochondria can be improved, oxidative stress can be inhibited, the heart protection effect can be exerted, and the occurrence and development of myocardial injury can be delayed.
However, the current myocardial protection drugs cannot completely relieve myocardial cell injury under pressure overload, and new myocardial protection targets are urgently needed to be discovered.
Disclosure of Invention
In order to better play a heart protection role and delay the occurrence and development of myocardial injury, the invention provides an application of amodiaquine in preparing a medicament for treating pressure-loaded myocardial injury.
The aim of the invention can be achieved by the following technical scheme:
the invention first provides the use of histamine N-methyltransferase inhibitors in the manufacture of a medicament for the treatment of pressure-loaded myocardial injury.
Further, the histamine N-methyltransferase inhibitor is selected as amodiaquine, i.e. the present invention provides the use of amodiaquine in the manufacture of a medicament for the treatment of pressure-loaded myocardial injury.
The amodiaquine provided by the invention can inhibit histamine N-methyltransferase (HNMT) to play a role in myocardial protection, and can improve prognosis of patients with pressure-loaded myocardial injury.
In one embodiment of the invention, the agent for treating pressure-loaded myocardial injury is an agent that improves prognosis of a patient with pressure-loaded myocardial injury.
In one embodiment of the present invention, there is provided the use of a histamine N-methyltransferase inhibitor in combination with a standard drug for pressure-loaded myocardial injury in the manufacture of a medicament for the treatment of pressure-loaded myocardial injury.
In one embodiment of the invention, there is provided the use of amodiaquine in combination with a standard drug for pressure-loaded myocardial injury in the manufacture of a medicament for the treatment of pressure-loaded myocardial injury.
The standard drug for pressure-loaded myocardial injury refers to a conventional common drug for pressure-loaded myocardial injury treatment.
In one embodiment of the invention, in the medicament for treating pressure-loaded myocardial injury, amodiaquine is used as a medicinal ingredient in the medicament, and the medicament further comprises pharmaceutically acceptable auxiliary agents.
The invention also provides a pharmaceutical kit for treating pressure-loaded myocardial injury, which comprises a histamine N-methyltransferase inhibitor and a pressure-loaded myocardial injury standard drug, wherein the histamine N-methyltransferase inhibitor and the pressure-loaded myocardial injury standard drug are separated independently.
In one embodiment of the invention, a pharmaceutical kit for treating pressure-loaded myocardial injury comprises amodiaquine and a pressure-loaded myocardial injury standard drug, which are separate independently.
In one embodiment of the invention, the pharmaceutical kit for treating pressure-loaded myocardial injury further comprises instructions describing the use of amodiaquine in an amount selected from the range of 3-10mg/kg per day, preferably 5mg/kg per day.
The invention separates myocardial cells of mice after pressure overload modeling, and discovers that the expression of histamine N-methyltransferase (histamine N-methyl transferase, HNMT) is obviously increased through proteomics. HNMT is a key enzyme responsible for histamine metabolism and uses S-adenosyl-L-methionine as a methyl donor to inactivate histamine after addition of a methyl group to the N-terminus of histamine. But its role in cardiovascular disease has not been elucidated. The invention constructs HNMT myocardial cell specific knockout mice, and discovers that HNMT knockout can relieve myocardial cell injury caused by pressure overload.
Based on the above, the invention provides a technical scheme for inhibiting histamine N-methyltransferase (HNMT), playing a heart protection role and delaying the occurrence and development of myocardial injury.
Amodiaquine (Amodiaquine) is an antimalarial drug that has been widely used clinically, and has been mainly used heretofore for the treatment of malaria. Animal experiments show that amodiaquine can relieve LPS-induced hepatitis.
However, there is no study on the treatment of myocardial injury after pressure overload by amodiaquine, and the prognosis of myocardial injury after pressure overload is still unsatisfactory in the prior art. The research shows that Amodiaquine (Amodiaquine) is an effective and non-competitive histamine N-methyltransferase inhibitor, so the research of the invention shows that Amodiaquine can inhibit histamine N-methyltransferase (HNMT), and further provides an application technical scheme of Amodiaquine in preparing medicines for treating pressure-loaded myocardial injury. And the amodiaquine has better safety because of rare adverse reactions.
Compared with the prior art, the invention has the beneficial effects that:
the study of the invention finds that after TAC operation is carried out on animals, HNMT expression of heart tissues is up-regulated. Animal experiments prove that HNMT knockout can relieve myocardial cell injury caused by pressure overload. Amodiaquine is therefore used to alleviate myocardial injury following pressure overload by inhibiting histamine N-methyltransferase (HNMT). The experimental method, the detection means, the data analysis and the like related to the invention are proven reliable methods which are widely applied, and the result is reliable. Therefore, the invention provides an application technical scheme of amodiaquine in preparing medicaments for treating pressure-loaded myocardial injury, and further provides a clinical outcome of myocardial injury patients after pressure overload is expected to be obviously improved by combining amodiaquine with standard medicament treatment, so as to guide clinical treatment.
Meanwhile, the scheme provided by the invention can make up for the defects of the traditional myocardial injury treatment such as heart strengthening, urination promoting and anti-vascular treatment, and the myocardial injury patient after pressure overload is treated by amodiaquine with extremely rare adverse reaction can delay the myocardial injury progress and improve the life quality of the patient.
Based on the research of the invention, the amodiaquine combined with standard drug treatment is expected to obviously improve the clinical outcome of the patient with myocardial injury after pressure overload, and can be used for guiding clinical treatment.
Drawings
FIG. 1 shows a comparison of ejection fraction between four groups (ns: no statistical difference; P < 0.05; P < 0.01; P < 0.001);
fig. 2. Comparison of the heart-to-tibia ratio between four groups (ns: no statistical difference; P < 0.05; P < 0.01; P < 0.001).
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
Example 1
The following examples used adult male C57BL/6 mice (8 weeks old, 20-25G), which were anesthetized, tracheal cannulated, anesthetized with breathing assistance from a anesthesia respirator, hair from the anterior region of the mice were cut, sterilized, skin was cut between two three ribs on the left edge of the sternum, hemostats separated from subcutaneous muscle, second ribs were cut, chest expander spread the chest wall, aortic arch was separated with microplates, 27G needle was placed across the aortic arch, ligature wire, needle gently withdrawn, and aortic arch constriction (Transverse aortic constriction, TAC) was successfully induced. SHAM group only threading is not ligatured, and the rest processes are the same as TAC group. The treatment groups were randomly divided into a control group and an amodiaquine treatment group, in which amodiaquine (5 mg/kg) was intraperitoneally injected daily, and the control group was continuously intraperitoneally injected for 56 days using an equal volume of sterile physiological saline as a control. The experimental protocol was approved by the ethical committee of the university of double denier animals.
The specific experimental steps are as follows:
1) Experimental animals and animal model preparation: SPF-class male C57BL/6 mice (purchased from Shanghai Jieshijie laboratory animal Co., ltd.) are selected, the week age is 8-10 weeks, the weight is 20-25g, and tracheal intubation articles, fixing adhesive tapes and the like are prepared; the mice are placed in the anesthesia closed box, and are quickly fixed on the operation plate in a supine mode after muscle strength disappears; aiming the cold light source at the neck of the mouse, slightly pulling out the tongue of the mouse by using forceps, and under the irradiation of the cold light source, seeing a tracheal opening with stronger refraction performance consistent with the breathing frequency, rapidly inserting a tracheal cannula into the airway, and rapidly sucking isoflurane again if the mouse has a waking sign in the period; connecting to an anesthesia respirator, and if the intubation is successful, observing the fluctuation of the thoracic cavity of the mouse along with the breathing machine frequency; shearing off the hair in the chest area of the mouse by scissors, and sterilizing by iodophor; the skin is cut off between two third ribs on the left edge of the sternum, subcutaneous muscles are separated by utilizing hemostats, after ribs are exposed, the second ribs are cut off along the left edge of the sternum, and a chest expander is placed in the chest expander in a homeopathic manner and the chest wall is expanded; the blood can be sucked by a sterilized cotton swab or a small cotton ball, and the surgical field is exposed; carefully separating thymus along the middle of bilateral thymus with micropunches to expose ascending aorta and branches; continuing to separate the aortic arch and redundant tissues outside the bifurcation by using the micro forceps, and fully exposing the aortic arch and the first branch and the second branch; a No. 5 silk thread passes through the brachiocephalic trunk and the left common carotid artery by means of a homemade tool, a 27G needle head is transversely arranged on the aortic arch, and ligature silk thread is arranged on the 27G needle head; gently withdraw the needle; after the non-active hemorrhage is determined, the chest wall and the muscle are sutured layer by layer, the chest wall is squeezed lightly at the end of closing the chest to remove the gas in the chest as much as possible, and finally the skin is sutured; the iodophor disinfects skin, is connected to a small anesthesia-free breathing machine, and is put back into a mouse cage after the mouse is completely awake, and the temperature around the mouse can be increased by using a heater to accelerate the mouse to wake up; SHAM group only threading is not ligatured, and the rest processes are the same as operation group.
2) Grouping
Study group 4: sham+saline group; sham+amodiaquine group; tac+saline group; tac+amodiaquine group. The amodiaquine-treated group was given intraperitoneal injection of amodiaquine (5 mg/kg/day); saline is administered the same volume of sterile saline. Each group of mice was normally fed water and was dosed for 56 consecutive days. The body weights of the mice of each group were weighed and recorded daily.
3) Evaluation of mouse cardiac Functions by echocardiography
Echocardiography was examined at 8 weeks with a probe frequency of 30MHz. In particular, after isoflurane-tingling animals, M-mode images were recorded while the heart rate of the mice was maintained between 450 and 550 beats/min. The method is characterized in that a long-axis section beside the sternum and a four-cavity section B-Mode image of the apex of the heart are collected. The parasternal left ventricular short axis was taken, 2D ultrasound was taken to show the left ventricular short axis section, the left ventricular motion was recorded using M-ultrasound at the papillary muscle level, and its Left Ventricular Ejection Fraction (LVEF) was mainly observed. The mice of each group were compared for heart morphology and functional changes. All measurements were averaged over 5 consecutive cardiac cycles and were made by 3 experienced technicians. The results show that: the heart function index of mice in the TAC+normal saline group is obviously lower than that of mice in the SHAM+normal saline group, the heart function of the mice is improved after the injection of amodiaquine in the TAC group, and the LVEF of the mice in the TAC+amodiaquine group is 12.56 percent higher than that of the mice in the TAC+normal saline group (P < 0.05) (see figure 1); the heart to tibia ratio was lower for the tac+amodiaquine group mice than for the tac+saline group mice (see fig. 2).
Through the animal experiments, the research results show that:
the heart ejection fraction of the 1 TAC+amodiaquine group is obviously improved compared with that of the TAC+control group.
The 2 tac+amodiaquine group significantly reduced myocardial hypertrophy (cardiac/tibial ratio) compared to the tac+control group.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. Use of a histamine N-methyltransferase inhibitor in the manufacture of a medicament for the treatment of pressure-loaded myocardial injury.
2. The use according to claim 1, characterized in that amodiaquine is used for the preparation of a medicament for the treatment of pressure-loaded myocardial injury.
3. The use according to claim 1 or 2, wherein the medicament for treating pressure-loaded myocardial injury is a medicament for improving prognosis of a patient with pressure-loaded myocardial injury.
4. The use according to claim 1, wherein the histamine N-methyltransferase inhibitor is used in combination with a standard medicament for pressure-loaded myocardial injury in the manufacture of a medicament for the treatment of pressure-loaded myocardial injury.
5. The use according to claim 4, characterized in that amodiaquine is used in combination with standard medicaments for pressure-loaded myocardial injury for the preparation of a medicament for the treatment of pressure-loaded myocardial injury.
6. The use according to claim 4 or 5, wherein the standard drug for pressure-loaded myocardial injury is a conventional drug commonly used for pressure-loaded myocardial injury treatment.
7. The use according to claim 5, wherein in the medicament for treating pressure-loaded myocardial injury, amodiaquine is used as a medicinal ingredient, and a pharmaceutically acceptable auxiliary agent is further included.
8. A pharmaceutical kit for treating pressure-loaded myocardial injury comprising a histamine N-methyltransferase inhibitor and a pressure-loaded myocardial injury standard drug, wherein the histamine N-methyltransferase inhibitor and the pressure-loaded myocardial injury standard drug are separate.
9. The pharmaceutical kit of claim 8, wherein the pharmaceutical kit for treating pressure-loaded myocardial injury comprises amodiaquine and a pressure-loaded myocardial injury standard drug, the amodiaquine and the pressure-loaded myocardial injury standard drug being separate.
10. The pharmaceutical kit of claim 9, wherein the pharmaceutical kit for treating pressure-loaded myocardial injury further comprises instructions describing the use of amodiaquine in an amount selected from 3-10mg/kg per day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211622600.2A CN115998737B (en) | 2022-12-16 | 2022-12-16 | Application of amodiaquine in preparation of medicine for treating pressure-loaded myocardial injury |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211622600.2A CN115998737B (en) | 2022-12-16 | 2022-12-16 | Application of amodiaquine in preparation of medicine for treating pressure-loaded myocardial injury |
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| Publication Number | Publication Date |
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| CN115998737A true CN115998737A (en) | 2023-04-25 |
| CN115998737B CN115998737B (en) | 2024-03-08 |
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- 2022-12-16 CN CN202211622600.2A patent/CN115998737B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| B GIRARD等: "Human histamine N-methyltransferase pharmacogenetics: cloning and expression of kidney cDNA", MOLECULAR PHARMACOLOGY, vol. 45, no. 3 * |
| 无: "内源性组胺相关基因 C314T突变为高血压带来福音", 中国生物工程杂志, vol. 24, no. 10, pages 89 - 92 * |
| 许莉莉等: "组胺与固有免疫细胞分化在冠心病研究中的新认识", 中国动脉硬化杂志, vol. 27, no. 5, pages 369 - 373 * |
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