CN110101851A - Hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug - Google Patents
Hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug Download PDFInfo
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- CN110101851A CN110101851A CN201910435790.9A CN201910435790A CN110101851A CN 110101851 A CN110101851 A CN 110101851A CN 201910435790 A CN201910435790 A CN 201910435790A CN 110101851 A CN110101851 A CN 110101851A
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- fibrinolysin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21062—Subtilisin (3.4.21.62)
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Abstract
The invention discloses hay bacillus fibrinolysins to treat the application in cerebral ischemia re-pouring injured drug, the hay bacillus fibrinolysin is made by hay bacillus Bacillus subtilis QK02 strain fermentation, the strain oneself be stored in national Type Tissue Collection, bacterium numbering CCTCCNO:M203078；Neurotrosis caused by hay bacillus fibrinolysin of the invention can be significantly improved because of ischemia-reperfusion, it can be substantially reduced cerebral infarction percentage and brain blood Reperfu- sion inflammatory factor IL-1 and brain blood Reperfu- sion inflammatory factor TNF-α content, this all shows that hay bacillus fibrinolysin of the invention has excellent therapeutic effect to cerebral ischemia re-pouring injured.
Description
Technical field
The present invention relates to cerebral ischemia re-pouring injured therapy fields.It is more particularly related to a kind of hay bacillus
Fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug.
Background technique
Cerebral apoplexy is also known as headstroke and cerebrovascular accident, is a kind of Important cause of disease for causing death and disabling.According to brain
Blood supply cerebral apoplexy can be divided into ischemic cerebral apoplexy extremely and hemorrhagic apoplexy, wherein cerebral arterial thrombosis accounts for about 85%,
Hemorrhagic apoplexy accounts for about 15%.It is cerebral ischemia re-pouring injured to refer to that brain tissue restores blood flow hindbrain group in ischemic after a certain period of time
It knits damage to be further aggravated, or even there is a phenomenon where irreversible damages.Blood reperfusion has risen content in brain tissue
High cAMP content further increases, and the content of cGMP then further declines, excitatory amino acid (glutamic acid and asparagus fern ammonia
Acid) extend with the ischemia-reperfusion time and gradually decreases, inhibitory aminoacid (such as alanine, taurine and glycine) is in ischemic
Reperfu- sion early stage is significantly raised；Brain edema and brain tissue necrosis increase.The cell factors such as TNF-α and IL-1 are as important inflammation
The factor promotes the infiltration of leucocyte in process of cerebral ischemia/reperfusion, and stimulation monocyte/macrophage discharges inflammation and is situated between
Matter reinforces local inflammatory reaction, cerebral infarction volume is caused to increase.And clinically drug is mainly anticoagulant and thrombolysis drug,
The damage problem of cerebral ischemia re-pouring is not can effectively solve.
Summary of the invention
In order to achieve the goal above, the present invention provides hay bacillus fibrinolysin in treating cerebral ischemia re-pouring injured drug
Application.
More preferably, the hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug, described withered
Straw bacterium fibrinolysin is made by hay bacillus Bacillus subtilis QK02 strain fermentation, the strain oneself be stored in national allusion quotation
Type culture collection, bacterium numbering CCTCCNO:M203078.
More preferably, the hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug, described withered
Straw bacterium fibrinolysin can be used individually in the form of dry powder, or liquid spray is made with pharmaceutically acceptable auxiliary material cooperation
Agent, liquid drops, capsule, enteric coated tablet or enteric capsule.
The present invention is include at least the following beneficial effects: hay bacillus fibrinolysin of the invention can be significantly improved because of ischemic again
Neurotrosis caused by being perfused, can be substantially reduced cerebral infarction percentage and brain blood Reperfu- sion inflammatory factor IL-1 and brain blood fills again
Infuse inflammatory factor TNF-α content, this all show hay bacillus fibrinolysin of the invention to it is cerebral ischemia re-pouring injured have it is excellent
Therapeutic effect.
Further advantage, target and feature of the invention will be partially reflected by the following instructions, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Detailed description of the invention
Fig. 1 is comparison photo figure of the withered grass bar fibrinolysin to different group rat cerebral infarction volumes；
Fig. 2 illustrates the case where withered grass bar fibrinolysin is to different group rat cerebral infarction volumes.
Specific embodiment
The present invention will be further described in detail below with reference to the embodiments, to enable those skilled in the art referring to specification
Text can be implemented accordingly.
One, the fermentation preparation of hay bacillus fibrinolysin
1, prepared by strain
Bacterial strain is placed in -80 DEG C of low temperature refrigerators and saves, strain using it is preceding with fresh slant activation for 24 hours.It is chosen from inclined-plane
Ring thallus access is taken equipped in the triangular flask of LB liquid medium, in 37 DEG C, 200r/min shaking table shaken cultivation 18h.
2, fermentor (500L) fermented and cultured
1 culture medium prescription of table
Prepare above-mentioned fermentation medium 300L, sterilising conditions are 115 DEG C, 30 minutes, after cooling room temperature, by above-mentioned 3L seed
Liquid is inoculated into fermentation medium according to 1% inoculum concentration, starts fermentation for 24 hours.
3, the preparation of hay bacillus fibrinolytic enzyme powder
After fermentation, fermentation liquid is centrifuged by tube centrifuge, and it is left to obtain concentrate 25L after micro-filtration and ultrafiltration concentration
It is right.Concentrate obtains withered grass bar fibrinolysin raw material spray powder by spray drying.Spray drying condition is 140 DEG C of inlet air temperature, outlet air
Temperature is 63-68 DEG C；
Embodiment 1
1, test animal used: 25 rats, weight 28-36g are randomly divided into 5 groups, are respectively labeled as normal group, model
Group, low dosage test group, middle dosage test group, high dose test group；
2, test method
The equal stomach-filling 0.6ml physiological saline of rat of sham-operation group and model group, low dosage test group, middle dosage examination are given daily
Test group, high dose test group difference stomach-filling 0.6ml concentration 4000IU, 8000IU, 16000IU withered grass bar fibrinolysin medical fluid；
2 times a day, continuous gavage 7 days；
8th day, all rats line brush made middle cerebral artery occlusion 3h, Reperfu- sion 21h；Observation perfusion is deposited after 24 hours
The following index of rat living:
(1) Behavioral change after all survival rats are perfused 24 hours is observed, neurological deficit score is carried out: referring to Zea longa
5 points of standards of grading processed: 0 point be it is normal, impassivity damage；1 point is to be unable to full extension countermeasure fore paw；2 points are to think that outside turns
Circle；3 points are to topple over to opposite side；4 points are that spontaneous cannot walk, the loss of consciousness；
(2) to the influence of cerebral infarct volume
After perfusion 24 as a child, respectively at random from sham-operation group, model group, low dosage test group, middle dosage test group, height
A rat is selected in dosetest group, brain tissue is put into quick-frozen in -20 DEG C of refrigerators by fresh brain tissue immediately after anaesthetizing to it
20-30min is sliced with knife blade, and thickness 2mm or so is advisable (every rat respectively obtains multiple brain sections), and section is neat；
Brain section is placed in TTC Incubating Solution, is put into 37 DEG C of water-baths and is protected from light incubation 15-30min, observe at any time, interval is turned over for 5 minutes
Beat one's brains biopsy tissues, it is made uniformly to touch dyeing liquor；After organizing quality, fixer is added and terminates reaction and saves tissue, claps
According to, comparison, as shown in Figure 1；Sham-operation tissue takes on a red color (i.e. dark color in Fig. 1 of black and white tone), and infarcted region is in pale asphyxia；Brain
Infarction volume=infarcted region volume/ipsilateral brain volume；
(3) to the influence of TNF-α and IL-1 content in brain tissue
After perfusion 24 as a child, sham-operation group, model group, low dosage test group, middle dosage test group, high dose are tested
Remaining rat anesthesia, takes fresh brain tissue immediately in group, and brain tissue is put into quick-frozen 20-30min in -20 DEG C of refrigerators.With life
10% homogenate is made in reason salt water, detects the TNF-α and IL-1 content in brain tissue；
Test result is as follows:
(1) neurological deficit score
The comparison of 2 rats after cerebral ischemic reperfusion neurological deficit score average mark of table
(2) to the influence of cerebral infarct volume
If Fig. 1 is shown, influence of the withered grass bar fibrinolysin to rat cerebral infarction volume, as shown in Figure 1, stomach-filling withered grass bar are fine
The rat of lyase, cerebral infarction volume is all smaller than model group, and low dosage test group, middle dosage test group, high dose test group
In, cerebral infarction volume gradually reduces；
(3) to the influence of TNF-α and IL-1 content in brain tissue
The blood of each group rat is checked, specific data target record is as follows:
Influence of the 3 hay bacillus QK fibrinolysin of table to brain blood Reperfu- sion inflammatory factor IL-1
Influence of the 4 hay bacillus QK fibrinolysin of table to brain blood Reperfu- sion inflammatory factor TNF-α
As can be seen from the above results: the behavior of rats in sham-operated group is all very normal, and anencephaly histic infarct situation
Occur, and apparent cerebral infarction then occur present for model group rats, and neurological deficit score is also very high, shows its abnormal behavior；
Compared with model group, the neurological deficit score of the rat of 3 test groups is all greatly improved, and its cerebral infarction phenomenon has also obtained very
Good improvement, brain blood Reperfu- sion inflammatory factor IL-1 and brain blood Reperfu- sion inflammatory factor TNF-α content have also obtained significantly dropping
It is low；In short, hay bacillus fibrinolysin of the invention can significantly improve because of ischemia-reperfusion caused by neurotrosis, can be obvious
Cerebral infarction percentage and brain blood Reperfu- sion inflammatory factor IL-1 and brain blood Reperfu- sion inflammatory factor TNF-α content are reduced, this all table
Bright hay bacillus fibrinolysin of the invention has excellent therapeutic effect to cerebral ischemia re-pouring injured；
Embodiment 3, acute toxicity test
10 new zealand rabbits, the hay bacillus fibrinolysin medical fluid of weight 4.5-4.8kg, stomach-filling concentration 16000IU, daily 3
Secondary, each 0.6ml observes and records the death condition, changes of weight and other symptoms of new zealand rabbit daily；
It 14th day, puts to death, each organ is taken to carry out pathologic finding；
As a result: at 14 days, whole new zealand rabbit survivals, no death, and each organ pathology is found through histopathological examination
It checks normally, and the respiratory mucosas such as nose, larynx, trachea-bronchial epithelial cell have no damaging variation；
And during this period, significant change does not occur for the weight of rabbit, also without any discomfort symptom；
The above results all show that hay bacillus fibrinolysin not only has a good effect to cerebral ischemia re-pouring injured, and
And in animal experiment, toxic reaction is also not present.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is not limited to specific thin
Section and embodiment shown and described herein.
Claims (3)
1. hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug.
2. hay bacillus fibrinolysin as described in claim 1 is treating the application in cerebral ischemia re-pouring injured drug, special
Sign is that the hay bacillus fibrinolysin is made by hay bacillus Bacillus subtilis QK02 strain fermentation, the strain
Oneself is stored in national Type Tissue Collection, bacterium numbering CCTCCNO:M203078.
3. hay bacillus fibrinolysin as described in claim 1 is treating the application in cerebral ischemia re-pouring injured drug, special
Sign is that the hay bacillus fibrinolysin can be used individually in the form of dry powder, or be matched with pharmaceutically acceptable auxiliary material
Liquid sprays, liquid drops, capsule, enteric coated tablet or enteric capsule is made in conjunction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910435790.9A CN110101851A (en) | 2019-05-23 | 2019-05-23 | Hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910435790.9A CN110101851A (en) | 2019-05-23 | 2019-05-23 | Hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug |
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| CN110101851A true CN110101851A (en) | 2019-08-09 |
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| CN201910435790.9A Pending CN110101851A (en) | 2019-05-23 | 2019-05-23 | Hay bacillus fibrinolysin is treating the application in cerebral ischemia re-pouring injured drug |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111870689A (en) * | 2020-08-12 | 2020-11-03 | 武汉真福医药股份有限公司 | Application of nattokinase in medicine for treating osteoporosis |
| CN111870690A (en) * | 2020-08-12 | 2020-11-03 | 武汉真福医药股份有限公司 | Application of nattokinase in medicine for treating migraine |
| CN115005433A (en) * | 2022-07-19 | 2022-09-06 | 湖北真福医药有限公司 | Bacillus subtilis fibrinolytic enzyme composition with effects of maintaining beauty and keeping young, preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105535950A (en) * | 2016-02-02 | 2016-05-04 | 武汉真福医药股份有限公司 | Method for preparing plasmin composition and application of plasmin composition |
-
2019
- 2019-05-23 CN CN201910435790.9A patent/CN110101851A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105535950A (en) * | 2016-02-02 | 2016-05-04 | 武汉真福医药股份有限公司 | Method for preparing plasmin composition and application of plasmin composition |
Non-Patent Citations (1)
| Title |
|---|
| JIUNN-MIN WANG ET AL: "Nattokinase reduces brain infarction, fibrinogen and activated partial thromboplastin time against cerebral ischemia-reperfusion injury", 《JOURNAL OF FOOD AND DRUG ANALYSIS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111870689A (en) * | 2020-08-12 | 2020-11-03 | 武汉真福医药股份有限公司 | Application of nattokinase in medicine for treating osteoporosis |
| CN111870690A (en) * | 2020-08-12 | 2020-11-03 | 武汉真福医药股份有限公司 | Application of nattokinase in medicine for treating migraine |
| CN115005433A (en) * | 2022-07-19 | 2022-09-06 | 湖北真福医药有限公司 | Bacillus subtilis fibrinolytic enzyme composition with effects of maintaining beauty and keeping young, preparation method and application |
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Application publication date: 20190809 |