CN107028979A - A kind of preparation method for anti-acute cerebral ischemia medicine, using and detection device - Google Patents
A kind of preparation method for anti-acute cerebral ischemia medicine, using and detection device Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of preparation method for anti-acute cerebral ischemia medicine, using and detection device, have following steps：1) by 0.11 gram-10.0 grams of vulcanized sodium, 0.9 gram of sodium chloride, 100 grams of water for injection is mixed, and is stirred 3-5 minutes, is deposited 2-3 minutes；2) according to injection small-volume injection specification, parenteral solution is made；3) 100 DEG C of flowing steam, are sterilized 30 minutes；4) the drug test impurity is irradiated using LASER Light Source, and medicine positive and negative image is gathered using industrial camera, carries out control treatment to the impurity image of collection by computer, it is unqualified for there is particle parenteral solution of the diameter more than 15um.The present invention is preferable using parenteral solution medication effect of the present invention after cerebral infarction, has certain effect to reduction blood viscosity, plays the role of highly significant to the tolerance of anoxic, has obvious effect to reduction rat cerebrovascular permeability.
Description
Technical field
The present invention relates to a kind of preparation method for anti-acute cerebral ischemia medicine, application, the present invention relates to a kind of anti-urgency
The detection device of property brain ischemia medicament.
Background technology
It is domestic at present because of cardiovascular and cerebrovascular disease death, it is the main cause of disease.And treatment acute brain is sold in the market
The medicine of ischemia diseases includes flunarizine hydrochloride, thrombus logical, arasaponin, brass class etc..Although there is certain curative effect, have
Carbon elements, and pharmacy cost is high；For the medicine of plant extract, because the medicinal material place of production is different, fief difference, quality standard are received
It is difficult to control to, curative effect has uncertainty.
State Intellectual Property Office on December 30th, 1998, vulcanized with the publication number CN1203080A patent Shen compounds disclosed
Sodium injection；It is prepared by August 30th, 2006, the patent Shen sodium sulfide vein injection liquid disclosed with publication number CN1823815A
Treat the application in cerebral infarction sequela medicament.Although this two patents disclose sodium sulfide injection and are preparing treatment cerebral infarction
Application in sequelae medicament, but without open sodium sulfide injection preparation method, the experimental data of application, medicine detection side
Method and detection device.Particularly this two patent applications do not disclose the experimental data of application, the content of this two patent applications
The actually inreal prior art approved as professional and technical personnel in the field, it is impossible to by the technology people in the field
Member thinks better of and received, and uses.
The molecular formula of the vulcanized sodium：Na2S, molecular weight：78.04；
The structural formula of vulcanized sodium：
The content of the invention
It is an object of the invention to provide a kind of preparation method for anti-acute cerebral ischemia medicine, this hair is used after cerebral infarction
Bright parenteral solution medication effect preferably, has preferable diastole effect to be consistent, to reduction blood viscosity to the in vitro cerebrovascular
There is certain effect, play the role of highly significant to the tolerance of anoxic, to platelet aggregation-against, prevent thrombosis has from showing very much
The effect of work, has obvious effect to reduction rat cerebrovascular permeability, can significantly improve the vigor of original cuiture cranial nerve cell,
There is remarkable effect to reduction Apoptosis；The purpose of the present invention also provides a kind of in the anti-acute cerebral ischemia medicine for the treatment of is prepared
Using；The purpose of the present invention also provides a kind of detection device of anti-acute cerebral ischemia medicine.
In order to achieve the above object, the present invention has following technical scheme：
A kind of preparation method for anti-acute cerebral ischemia medicine of the present invention, there is following steps：
1) by 0.11 gram-10.0 grams of vulcanized sodium, 0.9 gram of sodium chloride, 100 grams of water for injection is mixed, and stirring 3-
5 minutes, deposit 2-3 minutes；
2) according to injection small-volume injection specification, 2 mls/branch, 5 mls/branch, 10 mls/branch, 20 mls/branch or 40 millis are made
The parenteral solution of liter/, is put into cillin bottle or ampoule；The medicine is colourless or faint yellow clear and bright parenteral solution after preparing；
3) 100 DEG C of flowing steam, are sterilized 30 minutes；
4) the drug test impurity uses LASER Light Source parallel radiation, is driven by computer controlled motor control device
Parenteral solution supporting table rotates, and gathers medicine positive and negative image using 5,000,000 pixel industrial cameras, passes through what is be connected with industrial camera
Computer carries out control treatment to the impurity image of collection, and it is unqualified for there is particle parenteral solution of the diameter more than 15um, is rejected.
Application of the medicine made from the above method of the present invention in the anti-acute cerebral ischemia medicine for the treatment of is prepared.
A kind of detection device of anti-acute cerebral ischemia medicine of the present invention, including：
Motor control assembly, computer, fixture, parenteral solution supporting table, laser, industrial camera, the fixture are fixed on
Parenteral solution supporting table side, the parenteral solution is placed in parenteral solution supporting table, fixed by fixture, the computer respectively with motor
Control device, laser, industrial camera connection；
The motor control assembly includes motion control card, X-axis servomotor, X-axis motor servo driver, X-axis servo
Motor encoder, Y-axis servomotor, Y-axis motor servo driver, Y-axis encoder for servo motor, Z axis servomotor, Z axis are watched
Take motor driver, Z axis encoder for servo motor, rotary shaft servomotor, rotary shaft motor servo driver, rotary shaft servo
Motor encoder；
The computer is also connected with motion control card, and motion control card is watched with X-axis motor servo driver, Y-axis respectively
Take motor driver, Z axis motor servo driver, the connection of rotary shaft motor servo driver, X-axis motor servo driver difference
Be connected with X-axis encoder for servo motor, X-axis servomotor, Y-axis motor servo driver respectively with Y-axis encoder for servo motor,
Y-axis servomotor is connected, and Z axis motor servo driver is connected with Z axis encoder for servo motor, Z axis servomotor respectively, is rotated
Axle motor servo driver is connected with rotary shaft encoder for servo motor, rotary shaft servomotor respectively, X-axis servomotor, Y-axis
Servomotor, Z axis servomotor are connected by turbine and worm with parenteral solution supporting table respectively, and rotary shaft servomotor passes through screw rod
Rotary shaft is connected with parenteral solution supporting table, and the X-axis, Y-axis are the axial direction parallel to ground, and X-axis is vertical with Y-axis, the Z axis
For perpendicular to the axial direction on ground.
Wherein, the fixture includes lifting screw, pressing plate, fixed frame, fixing bolt, and the pressing plate hangs down with lifting screw
Directly, pressing plate is used to push down parenteral solution, fixes parenteral solution, pressing plate one end is connected with lifting screw, lifting screw bottom and fixation
Screw connection on frame, fixed frame is fixed on parenteral solution supporting table side, and fixing bolt passes through fixed frame, and fixing bolt can be with liter
Screw rod contact is dropped, and fixing bolt is used to lock lifting screw.
The advantage of the invention is that：
After cerebral infarction using parenteral solution medication effect of the present invention preferably, preferable diastole acts on to the in vitro cerebrovascular
It is consistent, has certain effect to reduction blood viscosity, plays the role of highly significant to the tolerance of anoxic, resist platelet aggregation
Collection, prevents thrombosis from playing the role of highly significant, has obvious effect to reduction rat cerebrovascular permeability, can significantly improve original
It is commissioned to train the vigor of foster cranial nerve cell, has remarkable effect to reduction Apoptosis.
A kind of detection device of anti-acute cerebral ischemia medicine of the present invention, accuracy of detection is high, and can guarantee that the safety of medicine makes
With.
Brief description of the drawings
Fig. 1 is the dose-effect relationship and potency comparison schematic diagram of medicine of the present invention and the anti-rat MCAO of Nimodipine；
Fig. 2 is the integrally-built block diagram of detection device of the present invention；
Fig. 3 is the block diagram schematic diagram of detection device motor control assembly of the present invention.
In figure, 1, computer；2nd, motor control assembly；3rd, parenteral solution supporting table；4th, medicine to be checked；5th, fixture；6th, it is industrial
Camera；7th, laser.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1：A kind of preparation method for anti-acute cerebral ischemia medicine of the present invention, there is following steps：
1) by 0.11 gram of vulcanized sodium, 0.9 gram of sodium chloride, 100 grams of water for injection is mixed, and is stirred 3 minutes, storage 2
Minute；
2) according to injection small-volume injection specification, 2 mls/branch, 5 mls/branch, 10 mls/branch, 20 mls/branch or 40 millis are made
The parenteral solution of liter/, is put into cillin bottle or ampoule；The medicine is colourless or faint yellow clear and bright parenteral solution after preparing；
3) 100 DEG C of flowing steam, are sterilized 30 minutes；
4) the drug test impurity uses LASER Light Source parallel radiation, is driven by computer controlled motor control device
Parenteral solution supporting table rotates, and gathers medicine positive and negative image using 5,000,000 pixel industrial cameras, passes through what is be connected with industrial camera
Computer carries out control treatment to the impurity image of collection, and it is unqualified for there is particle parenteral solution of the diameter more than 15um, is rejected.
Embodiment 2：A kind of preparation method for anti-acute cerebral ischemia medicine of the present invention, there is following steps：
1) by 10.0 grams of vulcanized sodium, 0.9 gram of sodium chloride, 100 grams of water for injection is mixed, and is stirred 5 minutes, storage 3
Minute；
2) according to injection small-volume injection specification, 2 mls/branch, 5 mls/branch, 10 mls/branch, 20 mls/branch or 40 millis are made
The parenteral solution of liter/, is put into cillin bottle or ampoule；The medicine is colourless or faint yellow clear and bright parenteral solution after preparing；
3) 100 DEG C of flowing steam, are sterilized 30 minutes；
4) the drug test impurity uses LASER Light Source parallel radiation, is driven by computer controlled motor control device
Parenteral solution supporting table rotates, and gathers medicine positive and negative image using 5,000,000 pixel industrial cameras, passes through what is be connected with industrial camera
Computer carries out control treatment to the impurity image of collection, and it is unqualified for there is particle parenteral solution of the diameter more than 15um, is rejected.
Embodiment 3：A kind of preparation method for anti-acute cerebral ischemia medicine of the present invention, there is following steps：
1) by 5 grams of vulcanized sodium, 0.9 gram of sodium chloride, 100 grams of water for injection is mixed, and is stirred 4 minutes, storage 2.5
Minute；
2) according to injection small-volume injection specification, 2 mls/branch, 5 mls/branch, 10 mls/branch, 20 mls/branch or 40 millis are made
The parenteral solution of liter/, is put into cillin bottle or ampoule；The medicine is colourless or faint yellow clear and bright parenteral solution after preparing；
3) 100 DEG C of flowing steam, are sterilized 30 minutes；
4) the drug test impurity uses LASER Light Source parallel radiation, is driven by computer controlled motor control device
Parenteral solution supporting table rotates, and gathers medicine positive and negative image using 5,000,000 pixel industrial cameras, passes through what is be connected with industrial camera
Computer carries out control treatment to the impurity image of collection, and it is unqualified for there is particle parenteral solution of the diameter more than 15um, is rejected.
Water for injection, which refers to, meets the lower defined water of Chinese Pharmacopoeia water for injection.Water for injection is distilled water or deionized water
Through the water obtained by distillation, therefore also known as double distilled water.
Application of the medicine made from the above method of the present invention in the anti-acute cerebral ischemia medicine for the treatment of is prepared.
As shown in Figure 1 and Figure 2, the detection device of a kind of anti-acute cerebral ischemia medicine of the invention, including：
Motor control assembly, computer, fixture, parenteral solution supporting table, laser, industrial camera, the fixture are fixed on
Parenteral solution supporting table side, the parenteral solution is placed in parenteral solution supporting table, fixed by fixture, the computer respectively with motor
Control device, laser, industrial camera connection；
Motion control card, X-axis servomotor, X-axis motor servo driver, X-axis encoder for servo motor, Y-axis servo electricity
Machine, Y-axis motor servo driver, Y-axis encoder for servo motor, Z axis servomotor, Z axis motor servo driver, Z axis servo
Motor encoder, rotary shaft servomotor, rotary shaft motor servo driver, rotary shaft encoder for servo motor；
The computer is also connected with motion control card, and motion control card is watched with X-axis motor servo driver, Y-axis respectively
Take motor driver, Z axis motor servo driver, the connection of rotary shaft motor servo driver, X-axis motor servo driver difference
Be connected with X-axis encoder for servo motor, X-axis servomotor, Y-axis motor servo driver respectively with Y-axis encoder for servo motor,
Y-axis servomotor is connected, and Z axis motor servo driver is connected with Z axis encoder for servo motor, Z axis servomotor respectively, is rotated
Axle motor servo driver is connected with rotary shaft encoder for servo motor, rotary shaft servomotor respectively, X-axis servomotor, Y-axis
Servomotor, Z axis servomotor are connected by turbine and worm with parenteral solution supporting table respectively, and rotary shaft servomotor passes through screw rod
Rotary shaft is connected with parenteral solution supporting table, and the X-axis, Y-axis are the axial direction parallel to ground, and X-axis is vertical with Y-axis, the Z axis
For perpendicular to the axial direction on ground.
Wherein, the fixture includes lifting screw, pressing plate, fixed frame, fixing bolt, and the pressing plate hangs down with lifting screw
Directly, pressing plate is used to push down parenteral solution, fixes parenteral solution, pressing plate one end is connected with lifting screw, lifting screw bottom and fixation
Screw connection on frame, fixed frame is fixed on parenteral solution supporting table side, and fixing bolt passes through fixed frame, and fixing bolt can be with liter
Screw rod contact is dropped, and fixing bolt is used to lock lifting screw.
A kind of control method of the detection device of anti-acute cerebral ischemia medicine of the present invention, including step：
1) medicine is placed on parenteral solution supporting table, fixed by fixture；Control to fill by computer controlled motor
Put driving parenteral solution supporting table and move up adjustment in X-axis, Y-axis, three sides of Z axis, realize medicine to be checked in laser output light
Positioned on axle and industrial camera light optical axis；
2) drive parenteral solution supporting table to rotate by computer controlled motor control device, pass through computer controlled laser
Light extraction, enables laser to be irradiated in medicine positive and negative；
3) by controlling industrial camera to gather medicine positive and negative image by computer, the meter being connected with industrial camera is passed through
Calculation machine is compared to the impurity image of collection and the standard picture that has been stored in computer, if there is more than 15um
Grain parenteral solution is then unqualified, rejecting.
Laser of the present invention is semiconductor laser.
Industrial camera：Industrial camera is commonly called as video camera again, and for traditional civil camera (video camera), it has
High picture steadiness, high-transmission ability and high anti-jamming capacity etc., specifically based on CCD (Charge Coupled
Device) the camera of chip.
CCD is the most commonly used imaging sensor of current machine vision.It collects opto-electronic conversion and charge storage, electric charge turn
Shifting, signal-obtaining, in one, are typical solid imaging devices.CCD outstanding feature is, using electric charge as signal, and to be different from
Other devices are using electric current or voltage as signal.This kind of image device is by opto-electronic conversion formation charge packet, then in driving
Shifted in the presence of pulse, amplify output image signal.Typical CCD camera is occurred by optical lens, sequential and synchronizing signal
Device, vertical driver, analog/digital signal process circuit composition.CCD is as a kind of function element, compared with vacuum tube, has
The advantages of without burning, without delayed, low voltage operating, low-power consumption.
Application method of the present invention is：Blown slowly every time in the 5-10 milliliters of glucose solutions of addition 250-500 milliliters 5% by vein
Instill, one time a day, 10 days as one therapeutic course；It is high to impurity requirement in parenteral solution when the present invention is used, i.e., it can not contain in parenteral solution
Diameter 15um particulate matter.
Experimental example：
The influence of the Injection in Rats acute cerebral ischemia of the present invention of experimental example 1.
1.1. experiment purpose
Understand therapeutic action of the parenteral solution intravenously administrable of the present invention to acute cerebral ischemia in rats.
Understand the dosage of the anti-acute cerebral ischemia of parenteral solution intravenously administrable of the present invention and relation, time and the effect relation of effect
Compare with the potency of medicine.
1.2. experiment material
1.2.1. test medicine
The gained parenteral solution of preparation method embodiment 1 of the present invention.
Parenteral solution obtained by preparation method of the present invention, colorless and transparent liquid.
Nimotop vial：The medical joint-stock company's production of the celestial spirit of Bayer Bitterfeld GmbH, specification：50ml：10mg,
Authentication code：Chinese medicines quasi-word J20100002, batch number：BXG2G01.
1.2.2. experiment reagent
Chloraldurate：Chemical Reagent Co., Ltd., Sinopharm Group produces, specification：250g, product batch number：20120522.
2,3, 5-Triphenyltertrazoliumchloride (TTC)：Chemical Reagent Co., Ltd., Sinopharm Group produces, specification：10g/
Bottle, product batch number：20110715, be configured to before use with phosphate buffer 0.5% concentration.
Paraformaldehyde：Chemical Reagent Co., Ltd., Sinopharm Group produces, specification：250g/ bottles, product batch number：20111017.
0.9% sodium chloride injection：Shangdong Hualu Pharmaceutical Co., Ltd. produces, specification：500ml, authentication code：
Chinese medicines quasi-word H37022749, product batch number：A13011703.
1.2.3. dosage sets and is grouped
1.2.3.1. dose-effect relationship test dose sets and is grouped
Solvent control group：Solvent 20ml/kg of the present invention；
By reagent MYNS is set：2.5mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 40mg/kg, totally 5 dosage groups.
Positive control drug nimotop vial is set：25ug/kg、50ug/kg、100ug/kg、500ug/kg、1000ug/
Kg, totally 5 dosage groups.
11 groups altogether, every group of size of animal n≤10.
1.2.3.2. time-effect relationship test dose sets and is grouped
Found by dose-effect relationship experiments, the middle dosage of the anti-acute cerebral ischemia of medicine of the present invention is 10mg/kg, therefore, choosing
With dosages of the 10mg/kg as time-effect relationship.
Administration time point presets 0.5h, 1h, 2h, 4h after acute cerebral ischemia, if 4h administrations are still effective after acute cerebral ischemia,
Continue to extend in units of per hour, until brain infarction area and solvent control group untill, each administration time point difference
Solvent control group is set.
1.2.4. method of administration and administration volume
Method of administration：Constant speed injects the slow intravenously administrable of pump, meets with clinical plan drip-feed method of administration medicine phases.Medicine
Extemporaneous when thing is used, administration volume is 20ml/kg, and administration time is 15min.Administration number of times is single.
1.2.5. experimental animal
Strain：SD rats.Rank：Cleaning grade.Sex：Male.Quantity：190.
Animal productiong licensing number：SCXK (Shanghai) 2008-0016.
The Quality of Experimental Animals quality certification is numbered：2008001628443、2008001629154、2008001630165、
2008001648070、2008001648545、2008001648548。
Body weight：250g±20g.
Source：Western pul-Bi Kai experimental animals the Co., Ltd in Shanghai.
Animal is raised three days after buying back in laboratory point cage adaptability, uses normal rats forage feed, free water, light
12 hours light and shade automatic conversions, 20-22 DEG C of indoor temperature.
1.2.6. laboratory apparatus
Image analysis software：Image J, version 1.41.
MCAO bolt lines：Shadong Biological Technology Co., Ltd., Beijing is produced, production number：2432-A4、2634-A4.Bolt linear diameter
Determined according to rat body weight, see annex 1.
Electronic balance：Shanghai Sunny Hengping Scientific Instrument Co., Ltd. manufactures, model：The types of FA/JA 1003
Electric-heated thermostatic water bath：Changzhou Jintan west of a city Chunlan laboratory apparatus factory produces, model：HH-1.
Two pass micro-injection pump：Zhejiang Prov Smith medicine instrument Co., Ltd, model：WZS-50F6, number of registration Zhejiang food medicine
Supervise tool (standard) word 2007 No. 2540156 (more), factory number：NO：100504447.
Polyethylene pipe：PE10, internal diameter 0.3mm, external diameter 0.5mm；PE50, internal diameter 0.58mm, external diameter 0.96mm, France
Biotrol companies.
Operating scissors, surgical forceps, the conventional operating theater instruments such as surgical thread.
1.3. experimental method
Chloraldurate 300mg/kg intraperitoneal injection of anesthesia is used after rat weight, is lain on the back after anesthesia and is fixed on operating table, neck
Skin cropping, 75% ethanol disinfection, surgical exposure side jugular vein does jugular vein and is intubated for being administered.Separation opposite side neck is always moved
Arteries and veins simultaneously ligatures arteria carotis communis proximal part, and along the up separation external carotid artery of arteria carotis communis, artery is placed in the distal end of arteria carotis communis
Press from both sides blocking blood flow, an osculum cut with ophthalmologic operation in artery clamp rear, insertion one in spherical shape bolt line (bolt line according to
Rat body weight is selected, and sees annex 1), slowly it is pushed into bolt line to arteria cerebri anterior (depth about 20mm) and draws about 2mm further back i.e.
To arteria cerebri media mouthful, gim peg line records the plug wire time and starts administration, administrable constant speed is injected pump and slowly injected, medicine
Prepare and prepared according to the method for isometric(al) not isoconcentration, administration volume 20ml/kg, intravenously administrable time 15min.Administration knot
Beam extracts duct of Arantius, skin suture.Extracted out after arterial embolism line 2h, rat, which is put back in cage, to continue to raise.
Postoperative 24h carries out neurological deficit score to rat.Sacrificed by decapitation rat after scoring, takes out brain, is put into mould and cuts
Into 7.Brain piece is put into temperature for 37 DEG C, in the TTC dye liquors of concentration 0.5%, gently shaken frequently, the normal brain activity after about 5min
Tissue is dyed to red, and necrotic brain tissues are not colored.Dyeing is put into brain piece in 4% paraformaldehyde to soak about 12 hours and taken after terminating
Go out, be that brain piece is taken pictures with digital camera, image is handled with Image J softwares, calculate the infarct size per a piece of brain piece
And calculating and the ratio of normal cerebral tissue's area.
1.4. observation index
The dosage of the anti-acute cerebral ischemia of the present invention and the relation of effect.
The time of the anti-acute cerebral ischemia of the present invention and the relation of effect.
The anti-acute cerebral ischemia of the present invention is compared with the potency of nimotop vial.
Acute cerebral ischemia neurology behavior scoring after 24 hours.
5 points of standards of grading processed of Zea Longa：0 point：Impassivity injury symptoms；1 point：It is unable to full extension offside fore paw；2
Point：Turn-taked to offside；3 points：Topple over to offside；4 points：Spontaneous it can not walk, the loss of consciousness；5 points：It is dead.
1.5. statistical disposition
Experimental result is represented with mean ± standard deviation (_ x ± s), statistical analysis is carried out with 18.0 groups of SPSS, with P<
0.05 is with statistical significant difference standard.
1.6. experimental result
1.6.1. the relation of dosage and effect research of the anti-acute cerebral ischemia in rats of gained parenteral solution of the embodiment of the present invention 1
In this experiment, vein gives corresponding test medicine immediately after rat MCAO.By reagent medicine 2.5mg/kg of the present invention
Group (F=3.625, P=0.073) is compared no difference of science of statistics with solvent control group, with the increase of Test Drug Dosages, this hair
Bright medicine 5mg/kg (F=13.0, P=0.002), 10mg/kg (F=38.4, P=0.000), 20mg/kg (F=51.5, P=
0.000) with 40mg/kg (F=56.9, P=0.000), rat cerebral infarction area also reduces therewith, poor with solvent control group
Different highly significant.
When drug dose of the present invention is to 20mg/kg, brain infarction area narrows down to 24.5%, is further added by this basis tested
The dosage of medicine, brain infarction area is but without accordingly (table 1-1) is reduced, accordingly it was determined that drug-treated rats of the present invention are acute
The basic, normal, high dosage of cerebral ischemia is respectively 5mg/kg, 10mg/kg and 20mg/kg.
The dosage and effect of anti-acute cerebral ischemia in rats are have also been made to positive drug nimotop vial using same method
Relationship experiments are answered, in order to compare the potency of by reagent and the ceiling effect of medicine；Compared with solvent control group, Ni Modi
Flat parenteral solution 25ug/kg (F=7.08, P=0.016), 50ug/kg (F=14.8, P=0.01), 100ug/kg (F=40.2, P
=0.000), 500ug/kg (F=55.3, P=0.000), 1000ug/kg (F=62.1, P=0.000), difference highly significant
(being shown in Table 1-1).
Influence (unit of the gained parenteral solution parenteral solution liquid of the table 1-1 embodiment of the present invention 1 to acute cerebral ischemia in rats：Cerebral infarction
Unleavened dough is accumulated)
*P<0.05, * * P<0.01,***P<0.001vs solvent control groups
1.6.2. the potency of the anti-acute cerebral ischemia in rats of gained parenteral solution of the embodiment of the present invention 1 compares
The obvious medicine more of the present invention of potency that can be seen that the anti-acute cerebral ischemia of Nimodipine from table 1-1 is strong, that is, exists
Brain infarction area is on the basis of, and dosage used in Nimodipine is substantially less than medicine of the present invention, but lacks with regard to anti-acute brain
The medicine ceiling effect of blood, medicine of the present invention is slightly better than positive control drug nimotop vial.
1.6.3. the relation of the gained parenteral solution of the embodiment of the present invention 1 anti-acute cerebral ischemia in rats time and effect
For understand by reagent treat acute cerebral ischemia time window, rat after MCAO 0.5h, 1h, 2h and 4h injection by
Reagent thing.As a result find, 2h injects medicine (F=8.82, P=0.008) of the present invention after MCAO, remains to significantly reduce cerebral infarction
Unleavened dough is accumulated；The effect being less than to the effect for reducing brain infarction area within 2h is administered after 4h (F=0.112, P=0.741) again.Cause
This, the Best Times window of drug therapy acute cerebral infarction is within 2h.
The anti-acute cerebral ischemia in rats of gained parenteral solution of the table 1-2 embodiment of the present invention 1 time-effect relationship research ( )
**P<0.01,***P<0.001vs solvent control groups
1.7. experiment conclusion
1.7.1. the gained parenteral solution intravenously administrable of the embodiment of the present invention 1 has the work of the anti-acute cerebral ischemia in rats of highly significant
With.
1.7.2. the anti-acute cerebral ischemia in rats of gained parenteral solution intravenously administrable of the embodiment of the present invention 1 has good dose-effect to close
System.
1.7.3. the maximum drug titers of the anti-acute cerebral ischemia in rats of gained parenteral solution intravenously administrable of the embodiment of the present invention 1 are excellent
In positive control drug nimotop vial.
1.7.4. the time window of the anti-acute cerebral ischemia in rats of gained parenteral solution intravenously administrable of the embodiment of the present invention 1 is within 2h
Effect is preferable.
1.7.5. the low middle high dose of the suitable rat experiment of the gained parenteral solution intravenously administrable of the embodiment of the present invention 1 is respectively
5mg/kg, 10mg/kg and 20mg/kg.
Influence of the parenteral solution of 2. embodiment of the present invention of experimental example 2 to Beagle dog cerebral blood flow (CBF)s
2.1. experiment purpose
Parenteral solution intravenously administrable of the present invention is understood to anesthesia Beagle dogs cerebral blood flow (CBF) and the influence of cerebral vascular resistance.
2.2. experiment material
2.2.1. test medicine
The parenteral solution of the embodiment of the present invention 2.
Nimotop vial：The medical joint-stock company's production of the celestial spirit of Bayer Bitterfeld GmbH, specification：50ml：10mg,
Authentication code：Chinese medicines quasi-word J20100002, batch number：BXG2G01.
2.2.2. experiment reagent
Yellow Jackets：German Merck biotech companies production, import packing, specification：25g/ bottles, product batch number：
WS20130112。
Liquaemin：Chemical Reagent Co., Ltd., Sinopharm Group produces, specification：1g/ bottles, technical conditions meet Q/CYDZ66-
2012, product batch number：20130617.
2.2.3. dosage sets and is grouped
Dosage sets as follows：
Solvent control group：The solvent of the embodiment of the present invention 2；Positive controls：Nimotop vial：30ug/kg；
The parenteral solution low dose group of the embodiment of the present invention 2：1.5mg/kg；The middle dose group of the embodiment of the present invention 2：3mg/kg；
The parenteral solution high dose group of the embodiment of the present invention 2：6mg/kg；
Every group of size of animal is 6.
2.2.4. method of administration and administration volume
Method of administration is injects the slow intravenously administrable of pump using constant speed, equivalent to clinical vein dropleting medicine-feeding.Volume is administered
1ml/kg。
2.2.5. experimental animal
Kind：Healthy Beagle dogs.Source：Shanghai Jia Gan bio tech ltd.Quantity：30.Sex：It is male female simultaneous
With.Body weight：8~10kg.Licensing：SCXK (Shanghai) 2010-0028.
The certification of fitness is numbered：2010002800929.
2.2.6. laboratory apparatus
PowerLab data acquisition and analysis systems：AD companies, model：ML870/P types, the place of production：Australia.
Ultrasonic blood flow instrument：Transonic companies, model：T420 types (U.S.), S Series Precision flow probes MA4PSB,
MA6PSB。
Animal respirator：Shanghai Alcott bio tech ltd is produced, model：ALC-V8 types.
Constant speed injects pump：The auspicious graceful RM-500I types single track syringe pump in Shanghai.
2.3. experimental method
Beagle dogs are injected intravenously without barbital sodium with 3% and anaesthetized, and dorsal position is fixed, operative region shaving, sterilization.Use ovum
Circle pincers involve tongue outside oral cavity causes asphyxia to prevent glossoptosis.Side femoral artery insertion conduit recording blood pressure is separated, separation is same
Side femoral vein insertion conduit is used for intravenously administrable.Needle electrode insertion four limbs are subcutaneously recorded into electrocardiogram.Take neck center slightly to
Upper bit cuts skin, separates right common carotid artery, is separated upwards along arteria carotis communis, find the bifurcated of external carotid artery and internal carotid
Place, ligation external carotid artery and other parteriole branches, stay internal carotid.Skin is cut in breastbone upper end, separating muscle finds gas
Pipe, the bone mark of a projection, as sixth cervical vertebra are touched immediately below tracheae, can be touched in the lower outside of sixth cervical vertebra
To sutura, it is vertebral artery that can have been touched at blood vessel pulse in sutura, is carefully peeled off.The flow that will be matched with blood vessel diameter
Probe is hung in arteria carotis communis and vertebral artery, and daubing coupling agent connects ultrasonic blood flow instrument, and flow instrument and PowerLab are connected
Connect, pass through Real time vision CBF curve.
System after connecting stable 15min record value based on an index, be then administered, record be administered after 15,30,
60th, 90, the change of 120min blood pressures, side arteria carotis communis and vertebral artery amount.Animal is put to death with aeroembolism method after record end,
Brain is taken to weigh immediately.The full cerebral blood flow (CBF) of 2 representatives (CBF) is multiplied by with right common carotid artery CBF+vertebral artery flow.
2.4. observation index
Record index：Forward backward averaging angiosthenia, heart rate, internal carotid artery flow amount and vertebral artery amount is administered.Calculating refers to
Mark：
Cerebral blood flow (CBF)：Brain blood
Pipe resistance：R=MBP (mmHg)/[CBF (ml/min) 100g brain].
2.5. statistical analysis
Experimental result represents with mean ± standard deviation (_ x ± s), compares statistical with before and after being carried out in 18.0 pairs of groups of SPSS
Analysis, with P<0.05 is with statistical significant difference standard.
2.6. experimental result
2.6.1. to the influence of Beagle dogs heart rate and mean arterial pressure
Influence to heart rate：The heart rate of solvent control group dog is arrived after administration in 120min before administration, and heart rate stabilization is average
Heart rate is at 150 times points or so；Heart rate significantly slows down in 60min after the administration of positive drug Nimodipine, heart rate before being administered 168
Secondary/min, compares decreased heart rate very before dropping to the 137 times/min of 15min 148 times/min and 30min after administration, and administration
Significantly.And Each point in time does not influence Beagle dogs to basic, normal, high three dosage groups of the embodiment of the present invention 2 upon administration
Heart rate.
Influence to blood pressure：Most notably positive control drug nimotop vial is influenceed on blood pressure after administration, it is average
127mmHg of the angiosthenia before being administered is reduced to 86mmHg minimum after administration, and blood pressure reduction is acted on clearly, until experiment
Terminate (120min after administration) blood pressure still significantly lower than level before administration.The embodiment of the present invention 2 is can be seen that from table 3-2 to inject
After vena axillaris administration, the mean arterial pressure of basic, normal, high three dosage groups is all highly stable compared with before administration, illustrates the present invention
Embodiment 2 is smaller on the blood pressure influence of Beagle dogs after being administered.
Influence (unit of the parenteral solution of the table 2-1 embodiment of the present invention 2 to Beagle dog hearts rate：Secondary/min)
*P<0.05, * * P<0.01 before administration with being compared
Influence (unit of the parenteral solution of the table 2-2 embodiment of the present invention 2 to Beagle dog mean arterial pressures：mmHg
)
*P<0.05, * * P<0.01, * * * P<0.001 before administration with being compared
2.6.2. to the influence of Beagle dog cerebral blood flow (CBF)s
Compare before and after administration, the cerebral blood flow (CBF) of solvent control group dog is reduced as time went on and gradually；Positive control drug
The cerebral blood flow (CBF) increase of dog is notable after nimotop vial administration；The parenteral solution low dosage of the by reagent embodiment of the present invention 2 is given,
Unobvious is acted on to the cerebral blood flow (CBF) for increasing dog, the cerebral blood flow (CBF) for giving dog after the parenteral solution middle dosage of the embodiment of the present invention 2 increases
Plus, hold time about 60min, to cerebral blood flow (CBF) at the end of experiment is reduced close to that preceding level is administered again；When to the embodiment of the present invention 2
After parenteral solution high dose, the experiment that is increased up of cerebral blood flow (CBF) terminates, and higher level is constantly in, therefore, it can be seen that this hair
The not only effect of increase anesthesia Beagle dog cerebral blood flow (CBF)s, and with the presence of obvious dose-effect relationship of the bright parenteral solution of embodiment 2.
Influence (ml/min/100g brain tissue of the parenteral solution of the table 2-3 embodiment of the present invention 2 to Beagle dog cerebral blood flow (CBF)s )
*P<0.05, * * P<0.01 before administration with being compared
2.6.3. to the influence of Beagle dog cerebral vascular resistances
Compare before and after medication, solvent control group dog is due to having before and after medication blood pressure stabilization but cerebral blood flow (CBF) is as time went on
And the phenomenon reduced, therefore, its cerebral vascular resistance can also be raised as time went on upon administration；To cerebral vascular resistance reduction
Most notably positive control drug nimotop vial, cerebral vascular resistance is constantly in reduced levels after administration；And it is of the invention
Though embodiment 2 is low, Each point in time cerebral vascular resistance has reduction to middle dose group upon administration, reduction level is not reaching to statistics
Notable meaning is learned, only cerebral vascular resistance is gradually reduced more obvious and differed with comparing reduction before administration after the administration of high dose group
Significantly.
The table 2-4 embodiment of the present invention 2 to Beagle dog cerebral vascular resistances influence (mmHg ﹒ min ﹒ 100g/ml,)
*P<0.05, * * P<0.01 before administration with being compared
2.7. experiment conclusion
2.7.1. the parenteral solution intravenously administrable of the embodiment of the present invention 2 does not influence the heart rate and mean arterial pressure of Beagle dogs.
2.7.2. the parenteral solution intravenously administrable of the embodiment of the present invention 2 plays the role of increase anesthesia Beagle cerebral blood flow (CBF)s.
2.7.3. the parenteral solution intravenously administrable of the embodiment of the present invention 2 can significantly reduce the cerebral vascular resistance of anesthesia Beagle dogs.
Influence of the parenteral solution of the present invention of experimental example 3. to acute cerebral hypoxia：
3.1. experiment purpose
Understand whether the intravenously administrable of the embodiment of the present invention 3 can increase tolerance of the animal subject to acute anoxia.
3.2. experiment material
3.2.1. test medicine
The parenteral solution of the embodiment of the present invention 3；
Nimotop vial：The medical joint-stock company's production of the celestial spirit of Bayer Bitterfeld GmbH, specification：50ml：10mg, authentication code：
Chinese medicines quasi-word J20100002, batch number：BXG2G01.
3.2.2. experiment reagent
0.9% sodium chloride injection：Shangdong Hualu Pharmaceutical Co., Ltd. produces, authentication code：Chinese medicines quasi-word
H37022749, product batch number：A13011703.
3.2.3. experimental animal
Experiment is related to two kinds of animals of SD rats and ICR mouse, and ICR mouse, hypoxic hypoxia SD are used in hypobaric hypoxia experiment
Rat.
3.2.3.1. hypobaric hypoxia is tested：
Strain：ICR mouse ranks：Cleaning grade.
Sex：Male Body Weight：18-20g.Quantity：60.
Source：The western pul Bi Kai experimental animals Co., Ltd in Shanghai.
Production licence：SCXK (Shanghai) 2008-0016.
The treatment of animals quality certification is numbered：2008001631372.
3.2.3.2. hypoxic hypoxia is tested：
Strain：SD rats.Rank：Cleaning grade.
Sex：Male.Body weight：200g.Quantity：50.
Source：The western pul Bi Kai experimental animals Co., Ltd in Shanghai.
Production licence：SCXK (Shanghai) 2008-0016,
The treatment of animals quality certification is numbered：2008001632340.
Animal is raised three days after buying back in our unit's experimental animal room point cage adaptability, uses normal rats forage feed, from
By drinking water, 12 hours light and shade automatic conversions of light, 20-22 DEG C of indoor temperature.
3.2.4. dosage sets and is grouped
Solvent control group：The solvent of the embodiment of the present invention 3；
Positive controls：Nimotop vial, mouse 150ug/kg, rat 100ug/kg.
The dosage of the SD rats embodiment of the present invention 3 is respectively：5mg/kg；10mg/kg；20mg/kg totally three dosage groups.
Every group of size of animal 10.
The dosage of the ICR mouse embodiment of the present invention 3 is respectively：7.5mg/kg；15mg/kg；30mg/kg totally three dosage groups.
Every group of size of animal 12.
3.2.5. method of administration and administration volume
Tail vein is administered, and administration time is 15min.Administration number of times is single.Volume is administered：Mouse 10ml/kg, rat
20ml/kg。
3.3. experimental method
Laboratory mice and rat are carried out respectively, and the experiment of mouse hypobaric hypoxia is that mouse is put into 250ml wide-mouth bottle,
10g soda limes are placed in bottle to absorb moisture and CO2, bottleneck smear vaseline with ensure sealing, mouse is put into bottle and covered tightly
Bottle cap starts timing, stops and dead, the time that record is survived in closed environment to breathing.
The experiment of rat hypoxic hypoxia is that rat is put into homemade closed lucite cage relatively, one end of cage
There is an air inlet, the other end has a gas outlet, continue to fill the mixing of 97% nitrogen and 3% oxygen into cage from air inlet
Gas, rat is put into cage and starts timing, and record rat stops and the time of death from cage is put into breathing.
3.4. observation index
The life span of rat and mouse in anaerobic environment.
3.5. statistical disposition
Experimental result is with mean ± standard deviationRepresent, statistical analysis is carried out with 18.0 groups of SPSS, with P<0.05
For with statistical significant difference standard.
3.6. experimental result
3.6.1. to the influence of mouse life span in hypobaric hypoxia environment
Solvent control group mouse life span average out to 41.2min in the environment of airtight anoxia；Positive controls Buddhist nun is not
Horizon parenteral solution (F=21.4, P=0.000) average out to 52.2min, life span extends 26.7% than solvent control group, with
Solvent control group compares difference highly significant；The injection of the embodiment of the present invention 3 liquid energy significantly improves tolerance of the mouse to anoxic,
In the environment of anoxic, low dosage (F=6.63, P=0.017), middle dosage (F=15.2, P=0.001) and high dose (F=
15.4, P=0.001) the mouse survival time of three groups is compared with solvent control group, and 15.6%, 16.6% and has been respectively increased
24.7%, the result shows that the parenteral solution of the embodiment of the present invention 3 can significantly extend time-to-live of the mouse in anaerobic environment, and
There is obvious dose-effect relationship between basic, normal, high dosage in the extension of time-to-live.
The influence of life span when the table 3-1 embodiment of the present invention 3 is to chmice acute anoxic
*P<0.05***P<0.001vs solvent control groups
3.6.2. to the influence of rat life span in anaerobic environment
Rat hypoxia endurance test is carried out in the environment for having gas to flow, but oxygen content only has 3%, and remaining is nitrogen
Gas, in this context the rat mean survival time of solvent control group there was only 6.24min, positive controls nimotop vial
The rat mean survival time of (F=29.7, P=0.000) is 8.25min, is compared life span with solvent control group and extended
32.2%.By the parenteral solution low dosage (F=1.40, P=0.253) of the test product embodiment of the present invention 3 and middle dose group (F=3.67, P
=0.0.071) though being compared life span with solvent control group has extension, it is not statistically significant.But the embodiment of the present invention 3 is high
The surviving rats time of dosage group (F=11.8, P=0.003) has reached 7.43min, and life span extends 19.0%, significantly
Higher than solvent control group.
The influence of life span when the table 3-2 embodiment of the present invention 3 is to rat acute anoxic
**P<0.01***P<0.001vs solvent control groups
3.7. experiment conclusion
3.7.1. the parenteral solution of the embodiment of the present invention 3 is remarkably improved life span of the mouse in hypobaric hypoxia environment.
3.7.2. the parenteral solution high dose of the embodiment of the present invention 3 is remarkably improved existence of the rat in hypoxic hypoxia environment
Time.
The Injection in Rats of the present invention of experimental example 4. is in the thrombotic influence of body
4.1. experiment purpose
Understand influence of the parenteral solution of the embodiment of the present invention 2 to blood platelet function in physiological conditions.
4.2. experiment material
4.2.1. test medicine
The parenteral solution of the embodiment of the present invention 2, colorless and transparent liquid.
Aspirin：Zhengzhou Chen Xu chemical products Co., Ltd produces, bulk drug, white needles or plate crystal or powder
End, stable in dry air, water-soluble 3.3g/L is directly dissolved in physiological saline when using.Product batch number：20120518.
4.2.2. experiment reagent
0.9% sodium chloride injection：Shangdong Hualu Pharmaceutical Co., Ltd. produces, authentication code：Chinese medicines quasi-word
H37022749, product batch number：A13011703.
4.2.3. dosage sets and is grouped
Solvent control group：The solvent of the embodiment of the present invention 2；
Positive controls：Aspirin, 20mg/kg；
The parenteral solution low dose group of the embodiment of the present invention 2：5mg/kg；
The parenteral solution middle dose group of the embodiment of the present invention 2：10mg/kg；
The parenteral solution high dose group of the embodiment of the present invention 2：20mg/kg；
Totally 5 groups, every group of size of animal is 10.
4.2.4. method of administration and administration volume
Method of administration is administered for femoral vein, meets clinical existing with method of administration is injected intravenously, administration volume is 20ml/kg.
Administration time is 15min.Administration number of times is single.
4.2.5. experimental animal
Strain：SD rats.Rank：Cleaning grade.
Sex：Male.Quantity：60.
Body weight：200g±20g.
Source：The western pul Bi Kai experimental animals Co., Ltd in Shanghai.
Animal productiong licensing number：SCXK (Shanghai) 2008-0016.
The Quality of Experimental Animals quality certification is numbered：2008001637729.
Animal is raised three days after buying back in our unit's experimental animal room point cage adaptability, uses normal rats forage feed, from
By drinking water, indoor temperature is controlled in 20-22 DEG C, 12 hours light and shade automatic conversions of light.
4.2.5. instrument and material
No. 4 operation silk threads：Shanghai Pudong Jinhuan Medical Products Co., Ltd. produces.
Electronic scale：Upper current chart level instruments and meters Co., Ltd production, model JA2003.
Polyethylene pipe：PE10, internal diameter 0.3mm, external diameter 0.50mm, French Biotrol companies production.
4.3. experimental method
No. 4 operation silk threads that 6cm length is measured before experiment are some, and trimming makes silk thread weight consistent.
Preparation is about No. 4 operation silk threads that a long 6cm is placed in 10cm silicone tube, pipe, and the connection of silicone tube two ends gathers
50u/ml heparin salines are full of in vinyl tube, the fixed backward pipe of ligation, it is standby.
With 15% chloraldurate 300mg/kg intraperitoneal injection of anesthesia after rat weight.Dorsal position is fixed on mouse platform, operation point
From rat side femoral vein, for venous cannula administration.Right carotid and left side vena jugularis externa are separated, heparinate is will be filled with
Right carotid and left side vena jugularis externa are inserted in the polyethylene pipe two ends of water respectively, open artery clamp, and blood is always moved from right neck
Arteries and veins flows through pipeline and returns to left vena jugularis externa.Blocking blood flow after open 15 minutes, takes out silk thread and weighs, gross weight subtracts silk thread dry weight
Amount is wet weight of thrombus.
4.4. observation index
In body thrombus weight.
4.5. statistical disposition
Experimental result is represented with mean ± standard deviation (_ x ± s), statistical analysis is carried out with 18.0 groups of SPSS, with P<
0.05 is with statistical significant difference standard.
4.6. experimental result
With conduit by after arteria carotis communis and jugular vein short circuit, artery clamp is unclamped, artery blood flow enters jugular vein through conduit, by
It can be attached in the blood platelet being fixed with conduit in silk thread, blood on silk thread rapidly and form thrombus, adhered within the unit interval
More, the weight of thrombus is heavier, if medicine plays the role of platelet aggregation-against attachment, the weight of thrombus will be lighter.It is real
Issue after examination and approval now, blood is after arteriovenous shunt flowing 15min, the wet weight of thrombus average out to 43.5mg of solvent control group, and positive
The weight average of comparison medicine aspirin group (F=66.9, P=0.000) silk thread is 26.5mg, and thrombus weight reduces by 39.1%,
It is significantly less than solvent control group.Low middle high three dosage groups of the parenteral solution of the embodiment of the present invention 2 also have extraordinary antiplatelet to glue
Attached effect, low dose group thrombus weight average out to 40.5mg is can be seen that from table 6-1, as the embodiment of the present invention 2 injects liquor
The increase of amount, the weight of thrombus mitigates therewith, in (F=8.14, P=0.011), high dose group (F=33.8, P=0.000)
Thrombus average weight in wet base 36.1mg and 31.3mg, thrombus weight reduces by 17.0%, 28.0% respectively, with solvent control group comparing difference
Highly significant, illustrates that the embodiment of the present invention 2 has significantly anti-thrombosis function.
Influence of the Injection in Rats of the table 4-1 embodiment of the present invention 2 in body thrombus weight
*P<0.05, * * * P<0.001vs solvent control groups
4.7. experiment conclusion
The middle and high dosage group of the parenteral solution of the embodiment of the present invention 2 have very significantly anti-rat in the thrombotic effect of body.
The influence of the Injection in Rats cerebrovascular permeability of the present invention of experimental example 5.
5.1. experiment purpose
Understand the influence of the Injection in Rats cerebrovascular permeability of the embodiment of the present invention 1.
5.2. experiment material
5.2.1. test medicine
The parenteral solution of inventive embodiments 1, colorless and transparent liquid, lot number：130501.
Nimotop vial：The medical joint-stock company's production of the celestial spirit of Bayer Bitterfeld GmbH, specification：50ml：10mg,
Authentication code：Chinese medicines quasi-word J20100002, batch number：BXG2G01.
5.2.2. experiment reagent
Formamide：Chemical Reagent Co., Ltd., Sinopharm Group produces, specification：500ml/ bottles, product batch number：20130515.
0.9% sodium chloride injection：Shangdong Hualu Pharmaceutical Co., Ltd. produces, authentication code：Chinese medicines quasi-word
H37022749, product batch number：A13011703.
Evans blue：By Chemical Reagent Co., Ltd., Sinopharm Group, import is dispensed, lot number：Lot No W20100705, rule
Lattice：10g/ bottles.Injection dosage：50mg/kg, be configured to when using 5% concentration.
5.2.3. dosage sets and is grouped
Solvent control group：The medicine solvent of the embodiment of the present invention 1；
Positive controls：Nimodipine, 100ug/kg；
The medicine low dose group of the embodiment of the present invention 1：5mg/kg；
The medicine middle dose group of the embodiment of the present invention 1：10mg/kg；
The medicine high dose group of the embodiment of the present invention 1：20mg/kg；
Totally 5 groups, every group of size of animal is 10.
5.2.4. method of administration and administration volume
Femoral vein is administered, and meets clinical existing with method of administration is injected intravenously, administration volume is 20ml/kg.Administration time is
15min.Administration number of times is single.
5.2.5. experimental animal
Strain：SD rats.Rank：Cleaning grade.Sex：Male.Quantity：60.Body weight：200g±20g.Source：Shanghai
Western pul Bi Kai experimental animals Co., Ltd.
Animal productiong licensing number：SCXK (Shanghai) 2008-0016.
The Quality of Experimental Animals quality certification is numbered：2008001633403.
Animal is raised three days after buying back in our unit's experimental animal room point cage adaptability, uses normal rats forage feed, from
By drinking water, indoor temperature is controlled in 20-22 DEG C, 12 hours light and shade automatic conversions of light.
5.2.6. instrument and material
ELIASA：Sai Mo flies generation that (Shanghai) Instrument Ltd., model：multiskan MK3.
5.3. experimental method
Fixed after rat administration 1h with 15% chloraldurate 300mg/kg intraperitoneal injection of anesthesia, dorsal position, surgical incision neck
Portion's skin separation exposure bilateral common carotid arteries.Evans blue 50mg/kg is injected through sublingual vein, Bilateral Cervical is ligatured after 5 minutes total
Artery, sacrificed by decapitation animal after 3 hours takes out brain, is soaked in respectively by group label after weighing molten equipped with 10ml formamides
In the bottle of liquid, incubated 72 hours in 45 DEG C of insulating boxs, the Evans blue in brain tissue can be leached into formamide solution, take color
Plain liquid adjusts wavelength in 492nm measure absorbances (OD values) with ELIASA, and intracerebral Evans blue is calculated according to standard curve
Content, is represented with ug/g brain wet weights.
5.4. observation index
Evans blue content in per Borneo camphor tissue
5.5. statistical disposition
Experimental result is with mean ± standard deviationRepresent, statistical analysis is carried out with 18.0 groups of SPSS, with P<0.05
For with statistical significant difference standard.
5.6. experimental result
Yi Wen in the content discovery of Evans blue, the every Borneo camphor tissue of solvent control group is leached in each group brain tissue by determining
It is 0.084ug to think blue content；Compare with solvent control group, in low middle high three dosage groups of parenteral solution of inventive embodiments 1,
Evans blue leaching content is reduced with the increase of dosage, is shown between each group with the presence of good dose-effect relationship；Wherein originally
The medicine low dose groups (F=1.32, P=0.265) of inventive embodiments 1 though reduction Evans blue leaching content, and solvent control
Compare no statistical significance；Middle dosage (F=5.07, P=0.037) and high dose group (F=8.15, P=0.011) Evans blue
Leaching content is further reduced, and shows significant difference, points out the medicaments injection of the embodiment of the present invention 1 to lead to reduction blood vessel
Permeability has preferable effect.
The Injection in Rats cerebrovascular permeability of table 5-1 inventive embodiments 1 influence ( )
*P<0.05vs solvent control groups
5.7. experiment conclusion
The parenteral solution intravenously administrable of inventive embodiments 1 can significantly reduce the cerebrovascular permeability of rat, reduce Evans blue
From the leaching content of brain tissue.
Breviary vocabulary
As described above, just more can sufficiently realize the present invention.It the foregoing is only the relatively reasonable implementation of the present invention
Example, protection scope of the present invention includes but is not limited to this, and those skilled in the art is any to be based on the technology of the present invention side
Unsubstantiality denaturation change is included within the scope of the present invention includes in case.
Claims (4)
1. a kind of preparation method for anti-acute cerebral ischemia medicine, it is characterised in that have following steps：
1) by 0.11 gram-10.0 grams of vulcanized sodium, 0.9 gram of sodium chloride, 100 grams of water for injection is mixed, and stirs 3-5 points
Clock, is deposited 2-3 minutes；
2) according to injection small-volume injection specification, 2 mls/branch, 5 mls/branch, 10 mls/branch, 20 mls/branch or 40 mls/branch are made
Parenteral solution, be put into cillin bottle or ampoule；The medicine is colourless or faint yellow clear and bright parenteral solution after preparing；
3) 100 DEG C of flowing steam, are sterilized 30 minutes；
4) the drug test impurity uses LASER Light Source parallel radiation, is driven and injected by computer controlled motor control device
Liquid supporting table rotates, and gathers medicine positive and negative image using 5,000,000 pixel industrial cameras, passes through the calculating being connected with industrial camera
Machine carries out control treatment to the impurity image of collection, and it is unqualified for there is particle parenteral solution of the diameter more than 15um, is rejected.
2. application of the medicine according to made from claim 1 method in the anti-acute cerebral ischemia medicine for the treatment of is prepared.
3. a kind of detection device of anti-acute cerebral ischemia medicine for claim 1, including motor control assembly, its feature exist
In including：
Computer, fixture, parenteral solution supporting table, laser, industrial camera, the fixture are fixed on parenteral solution supporting table side,
The parenteral solution is placed in parenteral solution supporting table, is fixed by fixture, the computer respectively with motor control assembly, laser,
Industrial camera is connected；
The motor control assembly includes motion control card, X-axis servomotor, X-axis motor servo driver, X-axis servomotor
Encoder, Y-axis servomotor, Y-axis motor servo driver, Y-axis encoder for servo motor, Z axis servomotor, Z axis servo electricity
Machine driver, Z axis encoder for servo motor, rotary shaft servomotor, rotary shaft motor servo driver, rotary shaft servomotor
Encoder；
The computer is also connected with motion control card, and motion control card is electric with X-axis motor servo driver, Y-axis servo respectively
Machine driver, Z axis motor servo driver, rotary shaft motor servo driver connection, X-axis motor servo driver respectively with X
Axle encoder for servo motor, X-axis servomotor connection, Y-axis motor servo driver respectively with Y-axis encoder for servo motor, Y-axis
Servomotor is connected, and Z axis motor servo driver is connected with Z axis encoder for servo motor, Z axis servomotor respectively, rotary shaft
Motor servo driver is connected with rotary shaft encoder for servo motor, rotary shaft servomotor respectively, and X-axis servomotor, Y-axis are watched
Take motor, Z axis servomotor to be connected with parenteral solution supporting table by turbine and worm respectively, rotary shaft servomotor is revolved by screw rod
Rotating shaft is connected with parenteral solution supporting table, and the X-axis, Y-axis are the axial direction parallel to ground, and X-axis is vertical with Y-axis, and the Z axis is
Axial direction perpendicular to ground.
4. a kind of detection device of anti-acute cerebral ischemia medicine according to claim 3, it is characterised in that：The fixture includes rising
Screw rod, pressing plate, fixed frame, fixing bolt drop, the pressing plate is vertical with lifting screw, pressing plate is used to push down parenteral solution, makes injection
Liquid is fixed, and pressing plate one end is connected with lifting screw, and lifting screw bottom is connected with the screw on fixed frame, and fixed frame is fixed on note
Liquid supporting table side is penetrated, fixing bolt passes through fixed frame, and fixing bolt can be contacted with lifting screw, fixing bolt, which is used to lock, to be risen
Screw rod drops.
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Citations (4)
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|---|---|---|---|---|
| CN1203080A (en) * | 1997-01-15 | 1998-12-30 | 杨里颖 | Compound sodium sulfide injection |
| US20030235571A1 (en) * | 2002-06-19 | 2003-12-25 | Gabriel Gojon-Romanillos | Systemic treatment of pathological conditions resulting from oxidative stress and/or redox imbalance |
| CN1823815A (en) * | 2005-02-26 | 2006-08-30 | 杨云 | Application of sodium sulfide vein injection liquid in preparation of medicine for treating sequela of cerebral embolism death |
| CN104887701A (en) * | 2015-05-29 | 2015-09-09 | 邓学峰 | Novel fast hemorrhoid removal medicament, namely sodium sulfide-menthol composition and preparation method of novel fast hemorrhoid removal medicament |
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|---|---|---|---|---|
| CN1203080A (en) * | 1997-01-15 | 1998-12-30 | 杨里颖 | Compound sodium sulfide injection |
| US20030235571A1 (en) * | 2002-06-19 | 2003-12-25 | Gabriel Gojon-Romanillos | Systemic treatment of pathological conditions resulting from oxidative stress and/or redox imbalance |
| CN1823815A (en) * | 2005-02-26 | 2006-08-30 | 杨云 | Application of sodium sulfide vein injection liquid in preparation of medicine for treating sequela of cerebral embolism death |
| CN104887701A (en) * | 2015-05-29 | 2015-09-09 | 邓学峰 | Novel fast hemorrhoid removal medicament, namely sodium sulfide-menthol composition and preparation method of novel fast hemorrhoid removal medicament |
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