Application of palmatine in preparation of anti-hypoxic drugs

Abstract

The invention discloses application of fibrauretine in preparation of an anti-hypoxia drug, and relates to the technical field of medicines. Experimental results for simulating plateau hypoxia show that the palmatine has very remarkable anti-plateau hypoxia activity, can prolong the closed hypoxia tolerance time of mice and the survival rate of acute decompression hypoxia mice, has an obvious protective effect on tissue damage induced by plateau hypoxia, has the effect tending to be better than that of acetazolamide, and can be used for preparing medicines for treating plateau hypoxia. The anti-plateau hypoxia medicine prepared by taking the compound as an active ingredient is used for preventing or treating hypoxia pathological states of heart, brain and lung tissues caused by low pressure and low oxygen.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to the application of flavonoids in the preparation of anti-hypoxia drugs. Background Art

[0002] High altitude is one of the most challenging conditions in the world today. my country has a vast plateau area, and hypoxia is the primary problem encountered in living, working, and traveling in plateau areas. With the development of society and economy, thousands of people go to plateau areas for work, military activities, scientific research, tourism, etc. However, the low-pressure and low-oxygen environment in plateau areas restricts human life activities. There are many factors that lead to hypoxia, which can be divided into physiological hypoxia and pathological hypoxia. Normal pressure hypoxia and plateau low-pressure hypoxia belong to physiological hypoxia. Compared with normal pressure hypoxia, hypoxia caused by the decrease in atmospheric oxygen partial pressure and the decrease in atmospheric pressure in plateau environment will threaten human physiological functions at the same time, making the prevention and treatment of plateau hypoxia damage more difficult. At present, there are many drugs on the market that can treat and improve hypoxia, such as nimodipine, aminophylline tablets, and nifedipine, but the drugs that can actually be used to treat plateau hypoxia are only rhodiola rosea preparations and acetazolamide.

[0003] Fructus palmatine, also known as palmatine or palmatine, is an isoquinoline alkaloid mainly derived from plants of the Menispermaceae family. Its pharmacological activity is mainly concentrated in antibacterial and antiviral effects. In addition, it also has effects on the nervous system and cardiovascular system, as well as anti-inflammatory and antioxidant effects. However, it has not been used in high altitude medicine or hypoxia diseases. The structural formula of Fructus palmatine is as follows: . Summary of the invention

[0004] Based on the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a new use of flavonoids, namely, the use of flavonoids in the preparation of anti-altitude hypoxia drugs.

[0005] To achieve the above object, the present invention adopts the following technical solution: The present invention provides the use of flavonoids in the preparation of anti-hypoxia drugs; the anti-hypoxia drugs are anti-altitude hypoxia drugs.

[0006] The anti-hypoxia drug is prepared into a pharmaceutically acceptable dosage form by adding calendula as an active ingredient to a pharmaceutically acceptable carrier and / or excipient, and the pharmaceutically acceptable dosage form is tablets, granules, capsules, pills, syrups, suspensions, emulsions, powders, oral solutions or injections.

[0007] Huanglongsu can effectively remove the excessive free radicals produced in the hypoxic heart, brain, and lung tissues, improve the antioxidant capacity, relieve lipid peroxidation, and reduce the oxidative stress damage induced by plateau hypoxia; Huanglongsu can reverse the ATP content and Na in the heart, brain, and lung tissues during hypoxia. + -K + -ATP and Ga 2+ -Mg 2+ -Changes in ATPase activity can alleviate energy metabolism disorders induced by plateau hypoxia; jatropha tenuifolia can alleviate the inflammatory response induced by plateau hypoxia by reducing the levels of TNF-α and IL-6 in heart, brain and lung tissues and increasing the content of IL-10; therefore, jatropha tenuifolia can be used in the preparation of drugs for the prevention or treatment of low-pressure and hypoxic injury diseases, including acute mountain sickness caused by high-altitude hypoxia, high-altitude hypoxic brain damage, high-altitude hypoxic myocardial damage and high-altitude hypoxic lung damage.

[0008] The present invention shows, through the whole animal simulation high-altitude hypoxia experiment, that jatropha tenuifolia has significant anti-high-altitude hypoxia activity, can prolong the survival time of mice with normobaric hypoxia, improve the survival rate of mice with acute decompression hypoxia, and has a significant protective effect on tissue damage induced by high-altitude hypoxia. Its mechanism of action is related to alleviating oxidative stress damage, energy metabolism disorders and inflammatory reactions caused by high-altitude hypoxia.

[0009] In summary, flavonoids have significant anti-altitude hypoxia effects, and the effect tends to be better than acetazolamide. The anti-altitude hypoxia drugs prepared with it as the active ingredient are used to prevent or treat the pathological state of hypoxia in the heart, brain and lung tissues caused by low pressure and hypoxia. DETAILED DESCRIPTION

[0010] In order to better understand the essence of the present invention, the excellent anti-altitude hypoxia activity of flavonoids is illustrated by animal experiments and results of flavonoids in the following examples.

[0011] Example 1: Mouse confined hypoxia tolerance experiment 1. Experimental method: 50 SPF BALB / C male mice were randomly divided into 5 groups after adaptive feeding for 3 days: hypoxia model group, acetazolamide group (200 mg / kg), low-dose calendula group (25 mg / kg), medium-dose calendula group (50 mg / kg) and high-dose calendula group (100 mg / kg), with 10 mice in each group. The drug was administered by single intraperitoneal injection with a volume of 0.1 mL / 10g, and the hypoxia model group was given an equal volume of normal saline. 30 minutes after administration, the mice were placed in 250mL wide-mouth bottles containing 5g of soda lime (only one mouse was placed in each bottle), the bottle mouth was smeared with vaseline, sealed to prevent air leakage, and timed immediately until breathing stopped. The survival time of mice in the closed wide-mouth bottle was used as an indicator to compare the hypoxia tolerance time of each drug group. The results are shown in Table 1.

[0012] 2. Experimental results: As shown in Table 1, compared with the hypoxia model group, the three doses of calendula can prolong the survival time of mice in a closed hypoxic environment at normal pressure in a dose-dependent manner. In addition, the survival time of the low, medium and high doses of calendula was significantly higher than that of the acetazolamide positive control group (P<0.05 or P<0.01), and the survival time extension rate of the medium and high doses of calendula was more than 100%.

[0013] Example 2: Acute hypoxia tolerance experiment in mice 1. Sixty healthy Balb / c male mice were randomly divided into three groups after 3 days of feeding adaptation: hypoxia model group, acetazolamide group (200 mg / kg), and calendula group (100 mg / kg), with 20 mice in each group. A single intraperitoneal injection was administered with a volume of 0.2 mL·20 g -1 , the hypoxia model group was given an equal volume of saline. 30 min after administration, the animals were placed in a hypobaric oxygen chamber, the hatch was sealed, and the animals were decompressed at a speed of 1000 m / min to rise to an altitude of 5000 m and 8000 m, where they stayed for 5 min each, and finally rose to an altitude of 10000 m. After maintaining this altitude for 1 h, the inlet valve was adjusted and the animals were slowly lowered to the normal altitude. The hatch was opened, and the mortality rate of the animals within 1 h was observed and counted, and variance analysis was performed on the experimental results. The results are shown in Table 1.

[0014] 2. Experimental results: As shown in Table 1, after exposure to a low-pressure and low-oxygen environment (10,000 m) for 1 h, the mortality rate of the hypoxia model group reached 100%, while the mortality rates of the acetazolamide group and the calendula group were 85% and 60%, respectively, indicating that calendula can effectively reduce the mortality rate of mice under acute hypoxia conditions.

[0015] Example 3: Protective effect of mice on tissue damage in mice induced by simulated high altitude hypoxia 1. Experimental methods 40 healthy male BABL / C mice were randomly divided into 4 groups after adaptive feeding for 3 days: normal control group, hypoxia model group, acetazolamide group (200 mg / kg) and calendula group (200 mg / kg), with 10 mice in each group. The drug was intraperitoneally injected with a volume of 0.2 mL·20 g -1The hypoxia model group was given an equal volume of saline. The mice in the normal group were not hypoxic. 40 minutes after administration, the mice in the other groups were placed in a hypobaric oxygen chamber, the door was sealed, and the altitude was increased to 8000 m at a speed of 10 m / s. After maintaining this altitude for 9 hours, the air inlet valve was adjusted and the altitude was lowered to the local altitude at a speed of 20 m / s. The door was opened and the mice were quickly dislocated and killed. The brain, heart and lung tissues were removed, washed three times with saline, dried with filter paper, and stored in a -80℃ refrigerator for later use. For the determination of biochemical indicators, all operations were performed according to the instructions of the kit.

[0016] 2. Experimental results (1) Effects of calendula on oxidative stress-related indicators in the heart, brain and lung tissues of mice subjected to simulated high altitude hypoxia As shown in Table 3-5, compared with the normal control group, the MDA content in the heart, brain and lung tissues of the mice in the hypoxia model group was significantly increased, and the SOD activity was significantly decreased (P<0.01); compared with the hypoxia model group, the MDA content in the heart, brain and lung tissues of the mice pre-treated with calendula was significantly decreased (P<0.01), and the SOD activity was significantly increased (P<0.01). The above results show that calendula can effectively remove the excessive free radicals produced in the heart, brain and lung tissues of hypoxic mice, improve antioxidant capacity, alleviate lipid peroxidation, and reduce oxidative stress damage induced by high altitude hypoxia.

[0017] (2) Effects of calendula on energy metabolism-related indicators in the heart, brain and lung tissues of mice subjected to simulated high altitude hypoxia As shown in Table 6-8, compared with the normal control group, the ATP content, Na + -K + -ATP and Ga 2+ -Mg 2+ -ATPase activities decreased, while the calendula group was able to reverse the changes in these indicators and alleviate the energy metabolism disorders induced by plateau hypoxia.

[0018] (3) Effects of calendula on inflammatory-related indicators in the heart, brain and lung tissues of mice subjected to simulated high altitude hypoxia As shown in Tables 9-11, compared with the normal control group, the levels of TNF-α and IL-6 in the heart, brain and lung tissues of mice in the hypoxia model group were significantly increased (P<0.01), and the level of IL-10 was significantly decreased (P<0.01), while the levels of TNF-α and IL-6 in the heart, brain and lung tissues of mice in the calendula group were significantly decreased (P<0.01), and the level of IL-10 was significantly increased (P<0.01). The above results show that calendula can alleviate the inflammatory response induced by high altitude hypoxia.

[0019] In summary, flavonoids have significant anti-altitude hypoxia effects, and the effect tends to be better than acetazolamide. The anti-altitude hypoxia drugs prepared with it as the active ingredient are used to prevent or treat the pathological state of hypoxia in the heart, brain and lung tissues caused by low pressure and hypoxia.

[0020] The present invention shows, through the whole animal simulation high-altitude hypoxia experiment, that jatropha tenuifolia has significant anti-high-altitude hypoxia activity, can prolong the survival time of mice with normobaric hypoxia, improve the survival rate of mice with acute decompression hypoxia, and has a significant protective effect on tissue damage induced by high-altitude hypoxia. Its mechanism of action is related to alleviating oxidative stress damage, energy metabolism disorders and inflammatory reactions caused by high-altitude hypoxia.

Claims

1. Application of flavonoids in the preparation of anti-hypoxia drugs.

2. The use according to claim 1, characterized in that: The anti-hypoxia drug is an anti-altitude hypoxia drug.

3. The use according to claim 1, characterized in that: Fructus luteolin effectively removes excessive free radicals produced in hypoxic heart, brain, and lung tissues, improves antioxidant capacity, relieves lipid peroxidation, and reduces oxidative stress damage induced by plateau hypoxia.

4. The use according to claim 1, characterized in that: Fructus luteolin reverses the ATP content, Na + -K + -ATP and Ga 2+ -Mg 2+ -Changes in ATPase activity alleviate energy metabolism disorders induced by plateau hypoxia.

5. The use according to claim 1, characterized in that: Fructus luteolin relieves the inflammatory response induced by high altitude hypoxia by reducing the levels of TNF-α and IL-6 in heart, brain and lung tissues and increasing the level of IL-10.

6. The use according to claim 1, characterized in that: The anti-hypoxia drug is prepared into a pharmaceutically acceptable dosage form by adding flavonoids as an active ingredient to a pharmaceutically acceptable carrier and / or auxiliary material.

7. The use according to claim 6, characterized in that: The pharmaceutically acceptable dosage form is tablet, granule, capsule, pill, syrup, suspension, emulsion, powder, oral solution or injection.

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