CN103877074B - Application of 5,6,7,8- trihydroxy-8-methoxyflavone in preparing anti-hypoxic drug - Google Patents
Application of 5,6,7,8- trihydroxy-8-methoxyflavone in preparing anti-hypoxic drug Download PDFInfo
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Abstract
The invention discloses an application of 5,6,7,8- trihydroxy-8-methoxyflavone in preparing an anti-hypoxic drug which is the drug for preventing and treating hypoxic injury diseases; the hypoxic injury diseases are high-altitude low-pressure oxygen deficit-caused acute high altitude diseases, cerebral ischemia hypoxic diseases or myocardial ischemia hypoxic diseases. The application has beneficial effects as follows: an experiment proves that the 5,6,7,8- trihydroxy-8-methoxyflavone has a remarkable anti-hypoxic effect, and an effect tending to be better than that of acetazolamide; the anti-hypoxic drug prepared by applying the 5,6,7,8- trihydroxy-8-methoxyflavone as an active ingredient can be used for preventing and treating hypoxic injuries or treating various hypoxic pathological states caused by oxygen content drop in external environment, also can be used for preventing or treating hypoxic pathological states of heart, brain, respiratory system, and the like as external normal oxygen cannot sufficiently get to a body due to diseases, and the like, and further can be used for preventing or treating the pathological state that relative oxygen supply is insufficient as oxygen consumption needed for activities of the body exceeds physiological mobilization ability.
Description
Technical field
The present invention relates to field of medicaments, and in particular to 5,6,7- trihydroxy -8- methoxy flavones are preparing anti-anoxic medicine
In application.
Background technology
With the change and rhythm of life quickening of people life style, anoxia has become the fairly common pathology mistake of a class
The reason for journey, generation anoxia, mainly has：In environment, in air, oxygen content or partial pressure of oxygen are too low, with breathing, blood, circulation etc.
Systemic disease causes oxygen supply and oxygen Use barriers occur and body oxygen consumption is more than quantity delivered.The ring of highlandss hypobaric hypoxia
It is acute that border usually makes the first people to plateau headache, cardiopalmus, uncomfortable in chest, shortness of breath, weak, sleep disorder, Nausea and vomiting etc. easily occur
Altitude sickness, there is also the fatal diseases such as plateau pneumochysiss, high altitude cerebral adema when serious, long term hypoxia can also cause chronic
High altitude disease, has a strong impact on high aborigines or sojourner's health.Actively take measures to prevent and treat body anoxia to including anxious
Property altitude sickness has a very important role in the preventing and treating of interior many diseases.Anti-hypoxia injury protection medicine is very deficient at present
Weary, in the urgent need to developing high-efficiency and economic anti-hypoxia injury protection medicine.
Anoxia can cause body active oxygen to generate to be increased, and oxidative stress and free radical damage occurs in body, and flavonoid
Compound can directly remove free radical, improve antioxidant ability of organism, with preferable antioxidant activity and Scavenging ability,
So as to the body oxidative damage caused to anoxia has protective effect.
5,6,7- trihydroxy -8- methoxy flavones are a kind of flavone compounds, but its natural product distribution compared with
Less and content is atomic.Have no that the biological activity about 5,6,7- trihydroxy -8- methoxy flavones is reported at present.
The content of the invention
The purpose of the present invention is aiming at above-mentioned defect of the prior art, there is provided one kind 5,6,7- trihydroxy -8- first
The new application of epoxide flavone, that is, prepare anti-anoxic medicine.
To achieve these goals, the technical scheme of present invention offer is：5,6,7- trihydroxy -8- methoxy flavones are in system
Application in standby anti-anoxic medicine.
5,6,7- trihydroxy -8- methoxy flavones structural formula such as formulas（I）It is shown：
Formulas I
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
The purity of 5,6,7- trihydroxy -8- methoxy flavones is more than 95%.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
Anti-anoxic medicine is the medicine for preventing and treating hypoxic damage disease.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
Hypoxic damage disease is acute high altitude sickness, cerebral hypoxia ischemia disease or myocardial ischemia-anoxemia caused by the low-pressure hypoxia of plateau
Property disease.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
Anti-anoxic medicine is that 5,6,7- trihydroxy -8- methoxy flavones are combined with pharmaceutically conventional adjuvant, is conventionally made
Into oral agents and injection, oral agents include tablet, capsule, dispersant or granule；Injection includes injection or note
Penetrate liquid lyophilized injectable powder.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
In 5,6,7- trihydroxy -8- methoxy flavone tablets, following components by weight is included：Purity more than 95% 5,6,
50 parts of 7- trihydroxy -8- methoxy flavones, 130 parts of filler, 10 parts of disintegrating agent, 6 parts of adhesive, 4 parts of lubricant..
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
In 5,6,7- trihydroxy -8- methoxy flavone capsules, following components by weight is included：Purity more than 95% 5,
6,7- 10 parts of trihydroxy -8- methoxy flavones, 27 parts of filler, 1 part of adhesive, 2 parts of lubricant.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
Filler is starch, and disintegrating agent is Microcrystalline Cellulose, and adhesive is methylcellulose, and lubricant is magnesium stearate.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
In 5,6,7- trihydroxy -8- methoxy flavone dispersible tablets, following components by weight is included：Purity is more than 95%
5,6,7- 5 parts of trihydroxy -8- methoxy flavones, 13 parts of Microcrystalline Cellulose, 2 parts of Croscarmellose Sodium.
Further, application of 5,6, the 7- above-mentioned trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, described
In 5,6,7- trihydroxy -8- methoxy flavone granules, following components by weight is included：Purity more than 95% 5,
6,7- 1 part of trihydroxy -8- methoxy flavones, 1 part of dextrin, 2 parts of cane sugar powder.
The present invention is by the experiment of mice airtight anoxia tolerance, chmice acute decompression tolerance experiment and low-pressure oxygen cabin simulation
The experiment of mice high altitude anoxia confirms that 5,6,7- trihydroxy -8- methoxy flavones have obvious Substituted phenyl-lactic acid, as a result as follows：
Experiment one：Mice airtight anoxia tolerance is tested：
1st, experimental technique：Healthy BALB/C mice 50 is taken, male, adaptability are randomly divided into 5 groups after raising 3d：Anoxia mould
Type group, acetazolamide group（250mg.kg-1）, 5,6,7- trihydroxy -8- methoxy flavone low dose groups（125mg.kg-1）、5,6,
7- trihydroxy -8- methoxy flavone middle dose groups（250mg.kg-1）With 5,6,7- trihydroxy -8- methoxy flavone high dose groups
（500mg.kg-1）, 10 per group.Gastric infusion 5 days, administered volume is 0.4mL20g-1, anoxia model group is to isopyknic
Normal saline.50min after last time administration, mice is respectively put in the 250 mL wide mouthed bottles for filling 5 g sodica calx（Per bottle
1 mice is put only）, bottleneck is smeared with vaseline, seals, be allowed to air tight, immediately timing, until respiratory arrest.Existed with mice
In closed wide mouthed bottle, the time-to-live is index, compares each medicine group hypoxia endurance time.Gavage various dose 5,6,7- trihydroxy -8-
Methoxy flavone is as shown in table 1 to the impact result of airtight anoxia mouse survival time, (x ± s, n=10).
Table 1
。
Note：# P﹤ 0.05,## P﹤ 0.01, compared with anoxia model group.
2nd, experimental result：As shown in 1 result of table, compared with anoxia model group, 5,6,7- trihydroxy -8- methoxy flavones
Basic, normal, high three dosage groups can extend time-to-live of the mice in atmospheric closed anaerobic environment, and be in dose dependent,
The prolonged survival period rate of wherein 5,6,7- trihydroxy -8- methoxy flavone high dose groups reaches 53.10%, with acetazolamide sun
Property matched group is relatively respectively provided with significant difference（P ＜ 0.01）.
Experiment two：Chmice acute hypobaric hypoxia tolerance is tested：
1st, experimental technique：Healthy mice 60 is taken, male, raising property are randomly divided into 3 groups after adapting to 3d：Anoxia model group,
Acetazolamide matched group（250mg.kg-1）, 5,6,7- trihydroxy -8- methoxy flavone high dose groups（500mg.kg-1）, per group
20.Gastric infusion 5 days, administered volume is 0.4mL20g-1, anoxia model group is to isopyknic normal saline.For the last time
Animal is put into lower pressure environment tank by 50min after administration, and closed hatch door rises height above sea level extremely with the speed decompression of 1000 m/min
Each stop 5min is distinguished during 5000m and 8000m, height above sea level 10000m is finally risen to, after maintaining this height 1h, inlet hole is adjusted
Valve, is slowly dropped to normal height above sea level, opens hatch door, and observation counts mortality of animals in 1h, and to the experimental result side of carrying out
Difference is analysed.5,6,7- trihydroxy -8- methoxy flavones are as shown in table 2 to the impact result of chmice acute decompression hypoxia-bearing capability.
Table 2
。
Note： ## P﹤ 0.01, compared with anoxia model group.
2nd, experimental result：As shown in 2 result of table, compare with anoxia model group with acetazolamide group, 5,6,7- trihydroxy -8-
Methoxy flavone high dose group can extend the mice decompression airtight anoxia time-to-live（P﹤ 0.01）, in 1h, mortality rate is 55%, is said
Bright 5,6,7- trihydroxies -8- methoxy flavones can effectively reduce mortality rate of the mice under Conditions of Acute Hypoxia in Human Body.
Experiment three：Protection of the 5,6,7- trihydroxy -8- methoxy flavones to simulated high altitude hypoxia mice brain tissue impairment is made
With：
1st, experimental technique：
Healthy BABL/C mices 40 are taken, male, adaptability are randomly divided into 4 groups after raising 3d：Normal group, anoxia mould
Type group, acetazolamide group (200 mg/kg) and 5,6,7- trihydroxies -8- methoxy flavone high dose groups (75 mg/kg), per group
10.Single tail vein injection is administered, and administered volume is 0.2mL20g-1, normal group and anoxia model group give same volume
Remaining each group mice is put into hypobaric hypoxia animal experimental chamber by normal saline, normal group mice not anoxia, 20min after administration, close
Hatch door is closed, height above sea level is risen to 8000m with the decompression of 10m/s speed, after maintaining this height 9h, adjust air inlet valve, with
20m/s speed is down to height above sea level identical with external atmosphere pressure（Equivalent to 1450m height above sea levels）, hatch door is opened, rapid work is killed
Mice, wins brain, and physiology salt is washed three times, and filter paper is blotted, and -80 DEG C of refrigerator cold-storages are standby.For determining biochemical indicator detection,
Operate according to kit specification.
2nd, experimental result
1. 5,6,7- trihydroxies -8- methoxy flavones are to simulated high altitude hypoxia mice cerebral tissue H2O2, OH and CAT shadow
Ring：
5,6,7- trihydroxy -8- methoxy flavones are to simulated high altitude hypoxia mice cerebral tissue H2O2, OH and CAT impact
As shown in table 3, (x ± s, n=10), compared with Normal group, anoxia model group cerebral tissue H2O2Content is significantly raised（P<
0.01）, scavenging hydroxyl ability significantly reduces（P<0.05）, CAT vigor is without significant changes（P ﹥ 0.05）；With anoxia model group
Compare, in advance with 5, after 6,7- trihydroxy -8- methoxy flavones administrations are processed, Mice brain tissues H2O2Content is significantly reduced（P<
0.01）, scavenging hydroxyl ability, CAT vigor are significantly improved（P<0.01）.
Table 3
。
Note：*P ﹤ 0.05,**P ﹤ 0.01, compared with normal group；
#P ﹤ 0.05,##P ﹤ 0.01, compared with model group.
2. 5,6,7- trihydroxies -8- methoxy flavones to simulated high altitude hypoxia mice cerebral tissue SOD, MDA, T-AOC and
The impact of GSH-px：
5,6,7- trihydroxy -8- methoxy flavones are to simulated high altitude hypoxia mice cerebral tissue SOD, MDA, T-AOC and GSH-
The impact of px is as shown in table 4,（X ± s, n=10）, compared with Normal group, anoxia model group cerebral tissue MDA contents significantly rise
It is high（P<0.01）T-AOC, SOD vigor is significantly reduced（P<0.01）, GSH-px vigor is without significant changes（P ＞ 0.05）；With anoxia
Model group is compared, and in advance with 5, after 6,7- trihydroxy -8- methoxy flavones administrations are processed, Mice brain tissues MDA contents significantly drop
It is low（P<0.01）, SOD, T-AOC and GSH-px vigor is significantly raised（P<0.05 or P<0.01）.
Table 4
。
Note：*P ﹤ 0.05,**P ﹤ 0.01, compared with normal group；
#P ﹤ 0.05,##P ﹤ 0.01, compared with model group.
Experimental result shows that 5,6,7- trihydroxy -8- methoxy flavones can make hypoxia mice cerebral tissue SOD, CAT, GSH-
Px vigor is significantly improved, and T-AOC abilities, OH Scavenging activities are obviously improved, MDA, H2O2Content is significantly reduced.Show 5,6,7-
The excessive free radical that trihydroxy -8- methoxy flavones can be produced in effectively removing hypoxia mice cerebral tissue, improves antioxidation energy
Power, mitigates the caused damage because of anoxia, with good oxygen lack resistant function.
Beneficial effects of the present invention are：It is experimentally confirmed, 5,6,7- trihydroxy -8- methoxy flavones have significant anti-
Anoxia functions, and effect has the trend better than acetazolamide, is anti-anoxic medicine prepared by active component with which, for preventing and treating
The various anoxia pathological states that hypoxic damage or treatment cause because external environment oxygen content is reduced, it can also be used to prevent or control
Treating causes extraneous normal oxygen amount substantially arrive in body because of disease etc., causes the anoxia pathology shape such as the heart, brain and respiratory system
State；Can be also used for preventing or treating causing relative oxygen for not because oxygen consumption needed for body activities has exceeded the physiology ability of mobilization
The pathological state of foot.
Specific embodiment
With 5,6,7- trihydroxy -8- methoxy flavones are active component, are prepared into by the common process on pharmaceuticss various
The anti-anoxic medicine of dosage form.
Medicament source used is as follows：
5,6,7- trihydroxy -8- methoxy flavones：（Purity is more than 95%）, 5,6,7- trihydroxy -8- methoxy flavones according to
It is prepared by the literature method delivered（Chemical reagent, 2013,39（9）：782-784）；
Starch：Filler, Shaanxi omeprazole pharmaceutic adjuvant company limited；
Microcrystalline Cellulose：MCC, disintegrating agent, Shaanxi omeprazole pharmaceutic adjuvant company limited；
Methylcellulose：Adhesive, Anhui Shanhe Medicinal Subsidiary Material Co., Ltd.；
Magnesium stearate：Lubricant, Shaanxi omeprazole pharmaceutic adjuvant company limited.
Embodiment 1：
Tablet：
5,6,7- trihydroxy -8- methoxy flavones（Purity is more than 95%）50.0g,
Starch（Shaanxi omeprazole pharmaceutic adjuvant company limited）130.0g,
Microcrystalline Cellulose（MCC, Shaanxi omeprazole pharmaceutic adjuvant company limited）10.0g,
Methylcellulose（Anhui Shanhe Medicinal Subsidiary Material Co., Ltd.）6.0g,
Magnesium stearate（Shaanxi omeprazole pharmaceutic adjuvant company limited）4.0g,
200.0g altogether.
Prepare by tablet conventional method, make 1000 altogether, contain 5,6,7- trihydroxy -8- methoxy flavone 50mg per piece.
Embodiment 2：
Capsule：
5,6,7- trihydroxy -8- methoxy flavones（Purity is more than 95%）50.0g,
Starch 135.0g,
Methylcellulose 5.0g,
Magnesium stearate 10.0g,
200.0g altogether.
Prepare by capsule conventional method, make 1000 altogether, every capsule contains 5,6,7- trihydroxy -8- methoxy flavones
50mg。
Embodiment 3：
Dispersible tablet：
5,6,7- trihydroxy -8- methoxy flavones（Purity is more than 95%）50.0g,
Microcrystalline Cellulose (MCC) 130.0g,
Croscarmellose Sodium (cCMC-Na) 20.0g,
200.0g altogether.
Prepare by dispersible tablet conventional method, make 1000 altogether, contain 5,6,7- trihydroxy -8- methoxy flavones per piece
50mg。
Embodiment 4：
Granule：
5,6,7- trihydroxy -8- methoxyl groups（Purity is more than 95%）50.0g,
Dextrin 50.0g,
Cane sugar powder 100.0g,
200.0g altogether.
Prepare by granule conventional method, make 1000 bags altogether, per bag contains 5,6,7- trihydroxy -8- methoxy flavones
50mg。
The pharmaceutical dosage form of the present invention is also not limited solely to this, and it can be prepared into more dosage forms, such as drop pill, capsule,
Soft capsule, dispersant, sustained-release preparation, injection etc..
Finally it should be noted that：The preferred embodiments of the present invention are the foregoing is only, the present invention is not limited to,
Although being described in detail to the present invention with reference to the foregoing embodiments, for a person skilled in the art, which still may be used
To modify to the technical scheme described in foregoing embodiments, or equivalent is carried out to which part technical characteristic.
All any modification, equivalent substitution and improvements within the spirit and principles in the present invention, made etc., should be included in the present invention's
Within protection domain.
Claims (6)
- Application of 1.5,6, the 7- trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, it is characterised in that described 5,6,7- The purity of trihydroxy -8- methoxy flavones is more than 95%；The anti-anoxic medicine is the medicine for preventing and treating hypoxic damage disease Thing；The hypoxic damage disease is acute high altitude sickness, cerebral hypoxia ischemia disease or cardiac muscle caused by the low-pressure hypoxia of plateau Ischemic hypoxia disease；The anti-anoxic medicine is 5,6,7- trihydroxy -8- methoxy flavones and pharmaceutically conventional adjuvant With reference to, conventionally made by oral agents and injection, oral agents be tablet, capsule, dispersant or granule；Injection Agent is injection or injection freeze-dried powder injection.
- 2. application of according to claim 15,6, the 7- trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, its It is characterised by, described 5, in 6,7- trihydroxy -8- methoxy flavone tablets, includes following components by weight：Purity More than 95% 5,6,7- 50 parts of trihydroxy -8- methoxy flavones, 130 parts of filler, 10 parts of disintegrating agent, 6 parts of adhesive, lubrication 4 parts of agent.
- 3. application of according to claim 15,6, the 7- trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, its It is characterised by, described 5, in 6,7- trihydroxy -8- methoxy flavone capsules, includes following components by weight：It is pure 5,6,7- trihydroxy -8- methoxy flavone 10 part of the degree more than 95%, 27 parts of filler, 1 part of adhesive, 2 parts of lubricant.
- 4. the 5,6,7- trihydroxy -8- methoxy flavones according to Claims 2 or 3 in anti-anoxic medicine is prepared should It is starch with, it is characterised in that the filler, disintegrating agent is Microcrystalline Cellulose, adhesive is methylcellulose, lubricant is Magnesium stearate.
- 5. application of according to claim 15,6, the 7- trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, its It is characterised by, described 5, in 6,7- trihydroxy -8- methoxy flavone dispersible tablets, includes following components by weight： 5,6,7- trihydroxy -8- methoxy flavone 5 part of the purity more than 95%, 13 parts of Microcrystalline Cellulose, Croscarmellose Sodium 2 Part.
- 6. application of according to claim 15,6, the 7- trihydroxy -8- methoxy flavones in anti-anoxic medicine is prepared, its It is characterised by, described 5, in 6,7- trihydroxy -8- methoxy flavone granules, includes following components by weight：It is pure 5,6,7- trihydroxy -8- methoxy flavone 1 part of the degree more than 95%, 1 part of dextrin, 2 parts of cane sugar powder.
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