CN102526193A - Musk heart-protecting pills and application thereof to preparation of medicines for treating and preventing transient cerebral ischemia of mammals - Google Patents
Musk heart-protecting pills and application thereof to preparation of medicines for treating and preventing transient cerebral ischemia of mammals Download PDFInfo
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Abstract
The invention provides application of musk heart-protecting pills to preparation of medicines for treating and/or preventing transient cerebral ischemia of mammals. The musk heart-protecting pills are formed by combining seven medicinal materials such as musk, a ginseng extract, calculus bovis factitious, cinnamon, styrax, venenum bufonis and borneol or extracts of the medicinal materials. An animal test proves that the musk heart-protecting pills have an obvious effect of treating the transient cerebral ischemia and can be applied to clinical medicines for treating the transient cerebral ischemia.
Description
Technical field
The invention belongs to the new purposes of Chinese medicine preparation, especially relate to Heart pill of Musk and treat and/or prevent the application in the medicine of mammal transient ischemic attack in preparation.
Background technology
In recent years, the sickness rate of cerebrovascular raises year by year, has become with myocardial infarction, malignant tumor to be listed as one of three the highest big diseases of fatality rate.
Transient ischemic attack is a kind of common ACVD, mainly is the of short duration limitation disordered brain function that is caused by cerebrovascular lesion (forming the brain blood spasm that microemboli causes because of the outer atheromatous plaque of cranium comes off).Clinical manifestation is relevant with the cerebral ischemia happening part, visible dizziness, headache, quadriplegia, speech disorder, inpairment of vision, in a certain state of delirium, convulsions, stupor etc.General lasting several minutes to several hours, in 24 hours, accomplish at most and alleviate, do not stay any sequela, but can show effect repeatedly, further develop cerebral infarction can take place in the several years.
In the patient of cerebral infarction, most of cases occur on the basis of hypertension, hyperlipidemia, and the blood viscosity increases.Slow blood flow, platelet aggregation, microthrombusis etc. are the main causes of cerebral infarction.Effectively reducing blood viscosity plays an important role in treatment of cerebral and prevention.
Early stage at cerebral infarction, local neuron's albumen is synthetic to stop film ion transport function stop, neuron generation depolarization, Ca
2+Inner flow guide causes the irritability amino alcohol---and paddy ammonia alcohol discharges.This type of material can quicken Ca again conversely
2+Interior stream and neuron depolarization, thus neuronal damage is increased the weight of.The formation of free radical also can aggravate neuronic infringement.Therefore, use Neuroprotective Agents significant in early days to the recovery prognosis of cerebral infarction.
Below at present clinical Neuroprotective Agents commonly used roughly can be divided several types:
1.Ca
2+Antagonist: ability is the diastole cerebrovascular significantly, the cerebral blood flow increasing amount.Be mainly used in treatment transient ischemic attack, cerebral thrombosis and cerebral embolism.Oral headache, flushing, gastrointestinal upset and the blood pressure drops of causing, intravenously administrable can occur that blood pressure slightly descends, heart rate quickening, phlebitis etc.Its choice drug is representative with nimodipine (Nimodipine), but clinical efficacy is unsatisfactory;
2. glutamate receptor inhibitor: the rising of neurocyte synaptic space glutamic acid is one of major reason of nerve cell death behind the ischemia, reduces the release of glutamic acid or block its receptor acting to have neuroprotective.For example, before clinical, in the animal experiment study, prove that MK-801 has good anti-cerebral ischemia damnification effect, but can't go on the market because of serious adverse reaction in clinical experiment, occurring.At present, studying a kind of new release inhibitor of glutamic acid safely and effectively sieve pyrazoles (Lubeluzole) abroad, it can effectively stop the release of glutamic acid.Glutamate receptor inhibitor C errstat proves that after deliberation glutamate receptor is had the obvious suppression effect, but effect remains further to be observed;
3.NO synthase inhibitor: increasing research confirms that NO is a kind of novel neurotransmitter; Has neurocyte toxicity when excessive; Contain neuron excessive release NO of meeting under abnormal conditions of NO synthase (NOS) among the central nervous system, the neuron that will contain NOS destroys 85%-95%.The medicine of weakened NO toxic action commonly used is a NG position nitro L-arginine (INNA), but clinical use curative effect neither be very definite, and because early stage release has a protective effect to brain injury is counter;
4. free radical scavenger: can prevent lipid peroxidation and reduce infarct size, but clinical result of use and imprecise;
5. neurotrophy reinforcing agent: this type of medicine can promote oxidation, the reduction of brain cell, regulates metabolism, the excited downtrod nervus centralis of neurocyte, promotes the reparative regeneration of injured neuron, but clinical efficacy is not certainly.
The therapeutic purposes of cerebrovascular disease are the control disease progress, promote the injured nerve function to recover as early as possible, improve prognosis.Although its Therapeutic Method is a lot, still there is not great breakthrough so far, curative effect is still very not sure, and also there is different views in some just under study for action, need wait to improve.Ultra early recovery blood supplies, and improves blood circulation state, cooperates comprehensive intervention and brain protection treatment to neuronal death different mechanisms behind the ischemia, will be the key of treatment undoubtedly.
Summary of the invention
Heart pill of Musk (the accurate word Z31020068 of traditional Chinese medicines) mainly contains Moschus, Radix Ginseng extract, artificial Calculus Bovis, Cortex Cinnamomi, Styrax, Venenum Bufonis and Borneolum Syntheticum.Heart pill of Musk is the representative of the herbal mixture medicine of the aromatic herbs activating YANG class treatment thoracic obstruction (coronary heart disease, angina pectoris), because of its determined curative effect, safe ready, price economy, and becomes one of treatment coronary heart disease, anginal common drug.According to statistics, Heart pill of Musk is sure to occupy the first in the Chinese medicine of the aromatic herbs activating YANG class treatment thoracic obstruction, be unique big kind of exclusive Chinese medicine that has higher popularity in the whole nation.
The objective of the invention is to develop the new purposes of Heart pill of Musk, provide Heart pill of Musk to treat and/or prevent the application in the medicine of mammal transient ischemic attack in preparation.
Preferably, said Heart pill of Musk is formed by seven flavor medicine materials such as Moschus, Radix Ginseng extract, artificial Calculus Bovis, Cortex Cinnamomi, Styrax, Venenum Bufonis, Borneolum Syntheticum or extract combination.
Preferably, said mammal behaviour, rat and Canis familiaris L. preferably are the people.
Preferably, transience ischemia that said transient ischemic attack is the local prominent cerebral ischemia that causes with fixed attention of middle cerebral artery electricity, line bolt method causes or bilateral vertebral artery obstruction add the bilateral common carotid arteries folder and close the GBI due to opening again.
Preferably, the consumption of said Heart pill of Musk is 1.125～24mg/kg.When said mammal is a man-hour, the consumption of said Heart pill of Musk is 1.125～2.25mg/kg.When said mammal was rat, the consumption of said Heart pill of Musk was 6～24mg/kg, more preferably 12～24mg/kg.When said mammal was Canis familiaris L., the consumption of said Heart pill of Musk was 2～8mg/kg, is preferably 8mg/kg.
Preferably, said medicine is oral formulations, for example pill.
The local prominent cerebral ischemic model of the present invention through duplicating the middle cerebral artery electricity and cause with fixed attention, transience ischemia-reperfusion injury model that line bolt method causes and bilateral vertebral artery obstruction add the bilateral common carotid arteries folder and close the GBI reperfusion injury model due to opening again, have studied prevention and the therapeutical effect of medicine pill (being Heart pill of Musk) 6～24mg/kg oral administration to rat ischemia property cerebral infarction.
Experimental result shows; Compare with the feminine gender group; Medicine pill various dose group all can make GBI pour into behind the ischemia of rat that the electroencephalogram extinction time prolongs again and perfusion back electroencephalogram recovery time and righting reflex are obviously shortened recovery time, and therapeutic effect and dosage are proportionate.Wherein, medicine pill low dose group (6mg/kg) does not show significant difference (P＞0.05) though each item index is compared with the feminine gender group makes moderate progress; Electroencephalogram extinction time behind dose groups in the medicine pill (12mg/kg) ischemia, irritate back electroencephalogram recovery time, righting reflex again and compare with the feminine gender group recovery time and all to have significant difference (P＜0.05); Electroencephalogram extinction time behind medicine pill high dose group (24mg/kg) ischemia, irritate back electroencephalogram recovery time, righting reflex is compared with the feminine gender group recovery time all has utmost point significant difference (P＜0.01) again.The cerebral edema situation that medicine pill various dose group all can make GBI pour into rat again improves, and wherein, the brain moisture content of middle dosage and high dose group is lower than negative group (P＜0.05) significantly.Local cerebral ischemia-reperfusion injury model result shows that receiving the reagent thing can significantly improve behavioristics's defective that line bolt method causes the focal cerebral ischemia in rats model marks, and reduces the brain necrosis percentage rate.Receive the reagent thing proportional to the improvement effect and the dosage of cerebral ischemia.The middle and high dose groups of medicine pill relatively has utmost point significant difference (P＜0.01) with negative group.Permanent local cerebral ischemia model result shows, receives the reagent thing can significantly improve behavioristics's defective that electrocoagulation causes the focal cerebral ischemia in rats model and marks, and reduces the brain necrosis percentage rate.Receive the reagent thing proportional to the improvement effect and the dosage of cerebral ischemia.Wherein, medicine pill low dose group and negative group more only behavioristics's defective mark significant difference (P＜0.05) arranged; Middle dose groups compares two indexs with negative group all has significant difference (P＜0.05); High dose group compares two indexs with negative group all has utmost point significant difference (P＜0.01).
Test of pesticide effectiveness result confirms, medicine pill 12～24mg/kg oral administration to rat experimental cerebral and ischemia after again the tissue injury that causes of perfusion tangible prevention and therapeutical effect are arranged.
In the medicine pill study on mechanism, Pedis Canitis blood flow experimental result shows that medicine pill 2～8mg/kg administration has the trend that increases dog internal carotid artery flow and reduction cerebral vascular resistance than negative control group, but the statistics there was no significant difference.Medicine pill 2～4mg/kg does not have tangible influence to the arteriotony of anesthetized dog.8mg/kg dose groups administration 60min after-contraction pressure, mean pressure decrease, but do not have significance with the negative control group comparing difference.The anesthetized dog heart rate decreases after each dose groups administration of medicine pill 2～8mg/kg, but does not relatively have significant difference with negative control group.Pia mater encephali model of microcirculation obstacle result shows; Medicine pill also can improve the blood stasis symptom that the macromolecule right rotary glycoside intravenous injection causes rat in dose dependent ground; Show as that site counting increases, the stasis of blood stream state obviously improves, but compares difference not statistically signigicant (P＞0.05) with the feminine gender group; There is not significant change around each experimental group rat brain microcirculatory vascular color and the blood vessel.Results suggest medicine pill treating cerebral ischemia, maybe part with to improve the brain microcirculation relevant.Whole blood and plasma viscosity result show, receive reagent thing medicine pill also can reduce WBV, and when high dose, have significance ground to be lower than negative control group (P＜0.05), but plasma viscosity is not had obvious influence.The effect of Mechanism Study results suggest medicine pill anti-cerebral ischemia property brain injury maybe with reduce cerebral vascular resistance and WBV, it is relevant to improve the brain microcirculation.
Compared with prior art, there is following beneficial effect at least in the present invention:
The present invention is according to the clinical treatment characteristics; Adopt the anti-GBI reperfusion injury of Heart pill of Musk medicine pharmacodynamic study, Heart pill of Musk medicine cause focal cerebral ischemia in rats to line bolt method therapeutical effect, Heart pill of Musk to electrocoagulation cause the therapeutical effect, Heart pill of Musk of focal cerebral ischemia in rats damage to the research of anesthetized dog periphery and cerebral blood flow influence, Heart pill of Musk to the influence of the experimentation of cerebral microcirculation disturbance influence, Heart pill of Musk to hemorheology of rat; The result shows that Heart pill of Musk has obvious effect to the treatment transient ischemic attack; New purposes of the present invention has enlarged the indication of Heart pill of Musk; As further confirm through clinical trial, can be applicable to the clinical treatment and the prevention of transient ischemic attack.
Through the experiment proof; Heart pill of Musk 6～24mg/kg can make GBI pour into behind the ischemia of rat that the electroencephalogram extinction time prolongs again and perfusion back electroencephalogram recovery time and righting reflex are obviously shortened recovery time; The cerebral edema situation be improved significantly; Can obviously reduce the cerebral infarction weight of local prominent cerebral ischemia and ischemia reperfusion injury rat, improve behavioristics's defective, and therapeutic effect and dosage are proportionate.Its anti-cerebral ischemia damnification mechanism possibly partly and reduce WBV, and it is relevant to improve the brain microcirculation.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the influence of Heart pill of Musk duodenal administration to the anesthetized dog cerebral vascular resistance;
Fig. 2 is the influence of Heart pill of Musk duodenal administration to anesthetized dog internal carotid artery flow;
Fig. 3 is the influence of Heart pill of Musk duodenal administration to anesthetized dog periphery mean arterial pressure; And
Fig. 4 is the influence of Heart pill of Musk duodenal administration to the anesthetized dog heart rate.
The specific embodiment
Specify the present invention through embodiment below, should be appreciated that following embodiment only is used to explain the present invention, and the scope that does not limit the present invention in any way.
The anti-GBI reperfusion injury of embodiment 1 Heart pill of Musk pharmacodynamic study
1.1 test material
1.1.1 confession test agent
Title: Heart pill of Musk; Source: Hehuang Pharmaceutical Co., Ltd., Shanghai; Lot number: G070103;
Specification: 42 balls/bottle/box, the heavy 22.5mg of every ball; Character: the glossy watered pill of pitchy
Dosage: adult's ball every days 3～6, according to becoming body weight for humans 60kg meter, the dosage of then being grown up is 1.125～2.250mg/kg.According to the body surface area conversion, rat unit body weight dosage is generally 6 times of adult.According to conversion rat low dosage after adult's low dosage round numbers is 6mg/kg, and middle high dose is respectively 12 and 24mg/kg.
Preparation: get certain ball number in mortar, add 0.5% sodium carboxymethyl cellulose (CMC-Na) solution and be ground to the desired concn suspension.
1.1.2 positive control sample
Title: nimodipine raw material; Source: Zhengzhou Rui Kang pharmaceutical factory; Lot number: 20060106; Character: light yellow crystalline powder
Preparation: precision weighing is placed in the mortar, adds 0.5%CMC-Na solution and is ground to the desired concn suspension.
1.1.3 negative control sample
Title: sodium carboxymethyl cellulose (CMC-Na); Source: Chemical Reagent Co., Ltd., Sinopharm Group; Lot number: F20060608; Character: white fiber sprills
Preparation: add distilled water behind the precision weighing and be mixed with concentration 0.5% solution.
1.1.4 experimental animal
Strain: Wistar rat; Sex: male; Body weight: 250～300 grams; Source: Shanghai Si Laike laboratory animal responsibility company limited; The animal quality certification: SCXK (Shanghai) 2003-0003
Raise: animal feeding in positive pressure purification ventilation Animal House, 23 ± 2 ℃ of room temperatures, humidity 40～70%, artificial lighting's simulation changes ad lib and drinking-water round the clock.
1.2 test apparatus
SW-30 radio frequency bipolar coagulator, detecting instrument factory of Shanghai Detecting Technology Inst..
The MP150 polygraph, BIOPAC Systems, Inc..
The DHG-9070A Constant Temp. Oven, Shanghai China connects the medical apparatus and instruments company limited.
Sartorius BS 110S electronic balance, Beijing Sai Duolisi balance company limited
1.3 test method
Establish 5 groups altogether, negative control group (0.5%CMC-Na 5ml/kg), Heart pill of Musk low dose group (6mg/kg), middle dose groups (12mg/kg), high dose group (24mg/kg) and positive controls (nimodipine 5mg/kg).In preceding 30 minutes gastric infusions of ischemia, the administration volume is 0.5ml/100g.
The Wistar rat with 12% chloral hydrate intraperitoneal injection of anesthesia (360mg/kg), is exposed the atlas transverse foramen behind pillow, aim at transverse foramen with bipolar coagulation and fulgerize and solidify the bilateral vertebral artery.Make a kerf at cervical region then and expose bilateral carotid arteries, after the separation, put on sew up wound with No. 1 silk thread.In postoperative 24 hours, when rat regains consciousness, the bilateral carotid arteries folder is closed with the bulldog clamp of band silica gel tube, promptly cause four arterial occlusion GBIs, take out bulldog clamp and can make blood flow logical again, be perfusion phase again.This experiment ischemia is with the filling time is 1 hour again.Observation index is electroencephalogram extinction time behind the ischemia, irritates back electroencephalogram recovery time and righting reflex recovery time.Irritate and finish, broken end is got brain immediately, on electronic balance, claims weight in wet base, brain is placed dry in the constant temperature oven to constant weight (claim every day once, until the difference of double weight less than 1%), obtains the brain moisture content of each group.
Expression that all data are all used
, statistical analysis is checked with t.
1.4 result of the test
1.4.1 Heart pill of Musk pours into brain electricity and the behavioristics's influence of rat again to GBI
Result of the test is seen table 1.Can find out from table 1; Compare with the feminine gender group; Heart pill of Musk various dose group all can make GBI pour into behind the ischemia of rat that the electroencephalogram extinction time prolongs again and perfusion back electroencephalogram recovery time and righting reflex are obviously shortened recovery time, and therapeutic effect and dosage are proportionate.Though wherein Heart pill of Musk low dose group each item index is compared with the feminine gender group and made moderate progress, do not show significant difference (P＞0.05); Electroencephalogram extinction time behind the dose groups ischemia in the Heart pill of Musk, irritate back electroencephalogram recovery time, righting reflex again and compare with the feminine gender group recovery time and all to have significant difference (P＜0.05); Electroencephalogram extinction time behind the Heart pill of Musk high dose group ischemia, irritate back electroencephalogram recovery time, righting reflex is compared with the feminine gender group recovery time all has utmost point significant difference (P＜0.01) again.And electroencephalogram extinction time behind the positive drug nimodipine ischemia, irritate the back electroencephalogram again and compare with the feminine gender group recovery time and all to have significant difference (P＜0.05), righting reflex is compared with the feminine gender group recovery time all then has utmost point significant difference (P＜0.01).
Table 1 Heart pill of Musk pours into brain electricity and the behavioristics's influence of rat again to GBI
*P＜0.05,
*Compare with negative control group P＜0.01
1.4.2 Heart pill of Musk pours into the influence of the cerebral tissue moisture content of rat again to GBI
Result of the test is seen table 2.Can find out that from table 2 the cerebral edema situation that Heart pill of Musk various dose group all can make GBI pour into rat again improves, the brain moisture content of wherein middle dosage and high dose group is lower than negative group (P＜0.05) significantly; Positive drug nimodipine group is compared with the feminine gender group also can obviously reduce cerebral tissue moisture content (P＜0.05).
Table 2 Heart pill of Musk pours into the influence of the brain moisture content of rat again to GBI
*P＜0.05,
*Compare with negative control group P＜0.01;
Embodiment 2 Heart pill of Musk cause the therapeutical effect of focal cerebral ischemia in rats to line bolt method
2.1 test material
2.1.1 confession test agent
Title: Heart pill of Musk; Source: Hehuang Pharmaceutical Co., Ltd., Shanghai; Lot number: G070103; Specification: 42 balls/bottle/box, the heavy 22.5mg of every ball; Character: the glossy watered pill of pitchy
Preparation: get certain ball number in mortar, add 0.5%CMC-Na solution and be ground to the desired concn suspension.
2.1.2 positive control sample
Title: nimodipine raw material; Source: Zhengzhou Rui Kang pharmaceutical factory; Lot number: 20060106; Character: light yellow crystalline powder
Preparation: precision weighing is placed in the mortar, adds 0.5%CMC-Na solution and is ground to the desired concn suspension.
2.1.3 negative control sample
Title: sodium carboxymethyl cellulose (CMC-Na); Source: Chemical Reagent Co., Ltd., Sinopharm Group; Lot number: F20060608; Character: white fiber sprills
Preparation: add distilled water behind the precision weighing and be mixed with concentration 0.5% solution.
2.1.4 experimental animal
Strain: SD rat; Sex: male; Body weight: 250～300 grams; Source: Shanghai Si Laike laboratory animal responsibility company limited; The animal quality certification: SCXK (Shanghai) 2003-0003
Raise: animal feeding in positive pressure purification ventilation Animal House, 23 ± 2 ℃ of room temperatures, humidity 40～70%, artificial lighting's simulation changes ad lib and drinking-water round the clock.
2.1.5 other reagent
Red tetrazolium (TTC), Shanghai chemical reagents corporation of Chinese Medicine group, lot number: F20050620.Take by weighing 1.200g red tetrazolium and 0.456g K2HPO3 and add the distilled water dissolving, and be settled to 100ml, keep in Dark Place.
Diameter 0.26mm nylon wire, Japan produces.
2.2 test method
Establish 5 groups altogether, negative control group (0.5%CMC-Na 5ml/kg), Heart pill of Musk low dose group (6mg/kg), middle dose groups (12mg/kg), high dose group (24mg/kg) and positive controls (nimodipine 5mg/kg).Administration when pouring into again, the administration volume is 0.5ml/100g.
With rat with 12% chloral hydrate intraperitoneal injection of anesthesia (360mg/kg) after, lie on the back and be fixed on the operating-table.Room temperature maintains about 25 ℃.Cut the right side skin of neck, separation, ligation right carotid, external carotid artery and bifurcated artery thereof.Separate right side internal carotid artery (ICA), branch's arteria pterygopalatina to visible its cranium in bubbling place, this branch of root ligation.Be equipped with line, far-end placement bulldog clamp at the ICA near-end; Common carotid artery crotch otch; Inserting diameter is nylon wire 17～20mm of 0.26mm, and the bolt line gets into ICA, passes middle cerebral artery (MCA) initiating terminal to the anterior cerebral artery near-end, all blood flow sources of blocking-up MCA.Tighten line fully, after 2 hours, extract nylon wire, make its blood flow logical again, ligation is equipped with line and skin suture, administration when pouring into again, and the rat of will performing the operation divides cage to put back to Animal House.
Postoperative 24h carries out behavioristics's scoring with single blind method, and methods of marking is: about 1 chi of Mus tail built on stilts is carried in (1), observes the forelimb situation.Normal rat two forelimbs stretch to ground symmetrically.If left side shoulder inward turning is arranged, to receive phenomenon in the left fore and send out the survivor, scoring is 4 minutes, otherwise is 0 minute.(2) check the resistance that opposing promotes with pushing away a left side (or right) shoulder on the sliding floor of animal horizontalization respectively to side shifting.Normal rat bilateral resistance is obvious and symmetrical.If push away right the shoulder when moving to the left, find the resistance descender, according to the difference of decline degree, scoring is 1～3 minute.(3) animal two forelimbs are put on the wire netting, observed the muscular tension of two forelimbs.Normal rat two forelimb tension force are obvious and symmetrical.And left fore tension force descender takes place, be chosen as 0～3 fen according to the weight of decline degree.According to above standard marking, full marks 10 minutes.Scoring finishes, and broken end is got brain.Crownly be divided into 5 with brain is average, be put in the TTC solution 37 ℃ of incubation 10～15min dyeing.Infarcted region is not painted, and normal cerebral tissue dyes redness.Difference full brain weight of weighing and downright bad part weight behind the digital photographing are calculated the percentage rate that necrotic area weight accounts for full brain weight.The statistical analysis of all data is checked with t.
2.3 result of the test
Result of the test is seen table 3.Can see, positive drug with receive the reagent thing can significantly improve behavioristics's defective that line bolt method causes the focal cerebral ischemia in rats model to mark, reduce the brain necrosis percentage rate.Heart pill of Musk is proportional to the improvement effect and the dosage of cerebral ischemia.The middle and high dose groups of Heart pill of Musk relatively has utmost point significant difference (P＜0.01) with negative group.The positive drug nimodipine more also has utmost point significant difference (P＜0.01) with negative group.
Table 3 Heart pill of Musk causes the therapeutical effect of focal cerebral ischemia in rats to line bolt method
*P＜0.05,
*Compare with negative control group P＜0.01
Embodiment 3 Heart pill of Musk cause the therapeutical effect of focal cerebral ischemia in rats damage to electrocoagulation
3.1 test material
3.1.1 confession test agent
Title: Heart pill of Musk; Source: Hehuang Pharmaceutical Co., Ltd., Shanghai; Lot number: G070103
Specification: 42 balls/bottle/box, the heavy 22.5mg of every ball; Character: the glossy watered pill of pitchy
Preparation: get certain ball number in mortar, add 0.5%CMC-Na solution and be ground to the desired concn suspension.
3.1.2 positive control sample
Title: nimodipine raw material; Source: Zhengzhou Rui Kang pharmaceutical factory; Lot number: 20060106; Character: light yellow crystalline powder
Preparation: precision weighing is placed in the mortar, adds 0.5%CMC-Na solution and is ground to the desired concn suspension.
3.1.3 negative control sample
Title: sodium carboxymethyl cellulose (CMC-Na); Source: Chemical Reagent Co., Ltd., Sinopharm Group; Lot number: F20060608; Character: white fiber sprills
Preparation: add distilled water behind the precision weighing and be mixed with concentration 0.5% solution.
3.1.4 experimental animal
Strain: Wistar rat; Sex: male; Body weight: 250～300 grams; Source: Shanghai Si Laike laboratory animal responsibility company limited; The animal quality certification: SCXK (Shanghai) 2003-0003
Raise: animal feeding in positive pressure purification ventilation Animal House, 23 ± 2 ℃ of room temperatures, humidity 40～70%, artificial lighting's simulation changes ad lib and drinking-water round the clock.
3.1.5 test apparatus
SW-30 radio frequency bipolar coagulator, detecting instrument factory of Shanghai Detecting Technology Inst..
307-6 table electric dental engine car, Shanghai Dental Medical Apparatus and Instrument Factory.
The SXP-1B operating microscope, Shanghai medical optical instrument factory.
Sartorius BS 110S electronic balance, Beijing Sai Duolisi balance company limited.
3.1.6 other reagent
Red tetrazolium (TTC), Shanghai chemical reagents corporation of Chinese Medicine group, lot number: F20050620.Take by weighing 1.200g red tetrazolium and 0.456g K
2HPO
3, add the distilled water dissolving and be settled to 100ml, keep in Dark Place.
3.2 test method
Establish 5 groups altogether, negative control group (0.5%CMC-Na 5ml/kg), Heart pill of Musk low dose group (6mg/kg), middle dose groups (12mg/kg), high dose group (24mg/kg) and positive controls (nimodipine 5mg/kg).Administration immediately after operation, the administration volume is 0.5ml/100g.
Carry out right side near-end middle cerebral artery electric coagulation; Animal is with 12% chloral hydrate intraperitoneal injection of anesthesia (360mg/kg); Lateral position is fixed on the operating-table, cuts the about 2cm of skin along the middle point vertical of right external auditory canal and right eye outer canthus line in line, and the temporalis center line cuts off temporalis and masseter successively in the operating microscope lower edge then; These muscle are separated to both sides, expose the jugal bridge. note the protective surface nerve and the parotid gland during operation.Remove zygomatic arch with rongeur, and cut off fascia, thereby expose the temporo precoila along skull.With little stretching device that the distance support between zygomatic arch and the mandibular bone is big, the major part of exposure squamosal bone. the about 2mm in the front lower place of before cheekbone and squamosal bone, uniting then place holes, and opens the microcephalia window of an about 2mm diameter.At this moment, see through the just visible straight and few ramose little blood vessel of cerebral dura mater, be middle cerebral artery (MCA).It is almost vertically passed by tractus olfactorius and upwards goes.Puncture cerebral dura mater at microscopically with fine needle, pia mater encephali and arachnoidea tissue around the separating blood vessel make it free.Gently provoke middle cerebral artery with the segmentation pin at tractus olfactorius and middle cerebral artery intersection then, electricity burns the interior 1mm of tractus olfactorius with fixed attention to the middle cerebral artery between the inferior cerebral vein.When electricity coagulates,, middle cerebral artery is provoked as far as possible, make the interior oligemia of blood vessel for avoiding electricity hemorrhage due to coagulating not exclusively.In addition, for the protection surrounding tissue is avoided burn, with wet cotton balls protection.Behind the blocking-up middle cerebral artery, dab on the cranium window with fritter muscular tissue, reach anastalsis, postoperative steams again raises.Above process is all carried out under the constant situation of room temperature, is beneficial to estimate the cerebral ischemia degree.
Postoperative carried out behavioristics's scoring in 24 hours, and single blind method is adopted in scoring, and methods of marking is: about 1 chi of Mus tail built on stilts is carried in (1), observes the forelimb situation.Normal rat two forelimbs stretch to ground symmetrically.If left side shoulder inward turning is arranged, to receive phenomenon in the left fore and send out the survivor, scoring is 4 minutes, otherwise is 0 minute.(2) check the resistance that opposing promotes with pushing away a left side (or right) shoulder on the sliding floor of animal horizontalization respectively to side shifting.Normal rat bilateral resistance is obvious and symmetrical.If push away right the shoulder when moving to the left, find the resistance descender, according to the difference of decline degree, marking is the 1-3 branch.(3) animal two forelimbs are put on the wire netting, observed the muscular tension of two forelimbs.Normal rat two forelimb tension force are obvious and symmetrical.And left fore tension force descender takes place, be chosen as the 0-3 branch according to the weight of decline degree.According to above standard marking, full marks 10 minutes.Scoring finishes, and broken end is got brain.Crownly be divided into 5 with brain is average, be put in the TTC solution 37 ℃ of incubation 10～15min dyeing.Infarcted region is not painted, and normal cerebral tissue dyes redness.Difference full brain weight of weighing and downright bad part weight behind the digital photographing are calculated the percentage rate that necrotic area weight accounts for full brain weight.The statistical analysis of all data is checked with t.
3.3 result of the test
Result of the test is seen table 4.Can see, positive drug with receive the reagent thing can significantly improve behavioristics's defective that line bolt method causes the focal cerebral ischemia in rats model to mark, reduce the brain necrosis percentage rate.Receive the reagent thing proportional to the improvement effect and the dosage of cerebral ischemia, wherein Heart pill of Musk low dose group and negative group more only behavioristics's defective mark significant difference (P＜0.05) arranged; Middle dose groups compares two indexs with negative group all has significant difference (P＜0.05); High dose group compares two indexs with negative group all has utmost point significant difference (P＜0.01).The positive drug nimodipine more also has utmost point significant difference (P＜0.01) with negative group.
Table 4 Heart pill of Musk causes the therapeutical effect of focal cerebral ischemia in rats to electrocoagulation
*P＜0.05,
*Compare with negative control group P＜0.01
Embodiment 4 Heart pill of Musk are to the research of anesthetized dog periphery and cerebral blood flow influence
4.1 test material
4.1.1 given the test agent
Title: Heart pill of Musk; Source: Hehuang Pharmaceutical Co., Ltd., Shanghai; Lot number: G070103;
Specification: 42 balls/bottle/box, the heavy 22.5mg of every ball; Character: the glossy watered pill of pitchy
Preparation: get certain ball number in mortar, add an amount of 0.5%CMC-Na solution and be mixed with that concentration is respectively 2,4, the suspension of 8mg/ml
4.1.2 positive control sample
Title: nimodipine; Source: Zhengzhou Rui Kang pharmaceutical factory; Lot number: 20060106; Character: these article are buff powder
Preparation: grind with 0.5%CMC-Na solution, being made into concentration is the 1.5mg/ml suspension
4.1.3 other medicine
Pentobarbital sodium, content＞95.0%, China Medicine (Group) Shanghai Chemical Reagent Co.,, lot number: F20030816.
Heparin sodium, 140U/mg, China Medicine (Group) Shanghai Chemical Reagent Co.,, lot number: F20020930.
Normal saline: Anhui BBCA Pharmaceuticals Co., Ltd. inaction pharmaceutical factory, lot number: 06062256.
4.1.4 animal
Strain: hybrid dog; Sex: male and female half and half; Body weight: 10.0 ± 0.8kg; Source: Shanghai Institute of Pharmaceutical Industry's Animal House;
4.1.5 key instrument
Seimens-Elama Minogograf-82 type eight is led physiograph
The MFV-2100 electromagnetic flowmeter, Japanese photoelectricity
GPS-2 type high frequency electro surgical unit, Wujin, Jiangsu radio factory
4.2 dosage setting
Rat anti cerebral ischemia drug effect dosage is 6,12 and 24mg/kg, is converted to the basic, normal, high dosage of dog administration and is respectively 2,4 and 8mg/kg.
4.3 test method:
Dog is anaesthetized with 3% pentobarbital sodium 30mg/kg intravenous injection.The animal dorsal position is fixed on the operating-table, and the groin place separates femoral vein in the right side, inserts conduit and makes transfusion usefulness; Separate right common femoral artery, intubate connects pressure transducer, measures the periphery blood pressure; Separate the left side femoral artery, measure the peripheral arterial blood flow; Separate the crotch of right carotid artery up to external carotid artery and internal carotid artery, the ligation external carotid artery, internal carotid artery is continued to employ, and the electromagnetic flowmeter probe is hooked in measures blood flow on the common carotid artery, as cerebral blood flow; Cut off the about 5cm of animal abdominal part from ventrimeson, find duodenum, and make pocket, intubate is in order to administration.Medicine is from duodenal administration, and volume is 1ml/kg, and administration time is 1min.Observed after the administration 3 hours, respectively before administration with administration after 5,10,15,30 and 60,90,120,180 minutes record animal electrocardiograms and peripheral arterial and carotid artery flow amount and blood pressure.Negative control group in kind gives 0.5%CMC-Na, and volume is 1ml/kg.Put to death dog in 180 minutes after the administration, get brain and weigh.Multiply by 2 representative full cerebral blood flows (CBF) with the right carotid blood flow.The available following formula of cerebral vascular resistance (R) calculates:
R=MAP (kPa)/[CBF (ml/min) 100g brain].
Test data measures from record.The MAP computing formula is 1mmHg=0.1333KPa.
Experimental data is represented with mean+SD
.Experimental result statistics is carried out t with the changing value of each time point after the administration before with administration and negative control group with the changing value of time point and is checked
4.4 result of the test
The Heart pill of Musk duodenal administration is seen table 5～table 11 to the influence of blood flow and cerebral vascular resistance in anesthetized dog heart rate, blood pressure, periphery and the neck, Fig. 1～Fig. 4.
The heart rate of negative control group anesthetized dog, blood pressure all change less than tangible in 3 hours after administration, maintain a metastable level.As time goes on periphery and internal carotid artery flow decrease, and the cerebral vascular resistance of calculating also increases in time to some extent, and this is changed to the animal experiment time and longly causes spontaneous variation, and is irrelevant with medicine.
Compare with negative control group, Heart pill of Musk 2～8mg/kg duodenal administration does not have obvious influence (P＞0.05) to anesthetized dog internal carotid artery flow, peripheral arterial flow; Heart pill of Musk 2～4mg/kg does not have tangible influence to the arteriotony of anesthetized dog, and 8mg/kg dose groups administration 60～120min after-contraction pressure, mean pressure decrease, but do not have significance (P＞0.05) with the negative control group comparing difference.The anesthetized dog heart rate decreases after each dose groups administration of Heart pill of Musk 2～8mg/kg, but does not relatively have significant difference (P＞0.05) with negative control group.Compare with negative control group, the anesthetized dog cerebral vascular resistance does not have obviously change (P＞0.05) yet after each dose groups administration of Heart pill of Musk 2～8mg/kg.
Nimodipine 1.5mg/kg can make the peripheral arterial flow obviously increase, when 5min and blank control group significant difference (P＜0.05) is relatively arranged; The internal carotid artery flow after administration 10,15,30, during 60min and blank control group significant difference (P＜0.05) is relatively arranged; The arteriotony persistence is reduced; Make heart rate highly significant property reduction (P＜0.01) 15,30, during 60min; Make the reduction of cerebral vascular resistance highly significant property.
4.5 conclusion
Pedis Canitis blood flow experimental result shows, compares Heart pill of Musk 2～8mg/kg administration with the feminine gender group dog internal carotid artery flow, peripheral arterial blood flow and cerebral vascular resistance are not had obvious influence.Heart pill of Musk 2～4mg/kg does not have tangible influence to the arteriotony of anesthetized dog, and 8mg/kg dose groups administration 60～120min after-contraction pressure, mean pressure decrease, but do not have significance with the negative control group comparing difference.The anesthetized dog heart rate decreases after each dose groups administration of Heart pill of Musk 2～8mg/kg, but does not relatively have significant difference with negative control group.
5.1 test material
5.1.1 confession test agent
Title: Heart pill of Musk; Source: Hehuang Pharmaceutical Co., Ltd., Shanghai; Lot number: G070103
Specification: 42 balls/bottle/box, the heavy 22.5mg of every ball; Character: the glossy watered pill of pitchy
Preparation: get certain ball number in mortar, add 0.5%CMC-Na solution and be ground to the desired concn suspension.
5.1.2 control sample
Title: Radix Salviae Miltiorrhizae Injection; Source: Zhengda Qingchunbao Pharmaceutical Co., Ltd; Lot number: 0701022
Specification: 10ml; Character: weak yellow liquid
5.1.3 negative control sample
Sample title: normal saline; Source: Anhui BBCA Pharmaceuticals Co., Ltd. inaction pharmaceutical factory; Lot number: 06062256
5.1.4 experimental animal
Strain: SD rat; Sex: male; Body weight: 280～350g; Source: Shanghai Si Laike laboratory animal responsibility company limited; The animal quality certification: SCXK (Shanghai) 2003-0003
Raise: animal feeding in positive pressure purification ventilation Animal House, 23 ± 2 ℃ of room temperatures, humidity 40～70%, artificial lighting's simulation changes ad lib and drinking-water round the clock.
5.1.5 experimental apparatus
307-6 table electric dental engine car (Shanghai Dental Medical Apparatus and Instrument Factory's production)
SXP-1B operating microscope (production of Shanghai medical optical instrument factory)
SQF-E anatomic microscope (Shanghai Wanke Instrument Co., Ltd.)
5.2 test method
Get 48 of healthy male SD rats; Be divided into 6 groups; Every group 8; Be respectively normal control (sham-operation) group, negative control group (normal saline 2ml/kg), positive drug Radix Salviae Miltiorrhizae Injection group (2ml/kg), Heart pill of Musk low dose group (6mg/kg), middle dose groups (12mg/kg) and high dose group (24mg/kg), sample is injected preceding 30 minutes immediately through the administration of rat oral administration gavage in macromolecule right rotary glycoside, and the administration volume is 2ml/kg.
Rat with 12% chloral hydrate intraperitoneal anesthesia (350mg/kg), is made the skull windowing, cut off cerebral dura mater and expose the Interhemispheric E Ding of side district, observe the pia mater encephali microcirculation respectively at 30 minutes anatomic microscopes behind operation back and the oral administration.After observing the pia mater encephali microcirculation, from macromolecule right rotary glycoside (the molecular weight 500,000) normal saline solution of sublingual vein injection 10%, dosage 15ml/kg observed the pia mater encephali microcirculation change in back 5 minutes in injection.Observation index is following:
1) fluidised form: erythrocytic fluidised form can be divided into 4 grades: 0 grade, and linearity; The I level, the dotted line shape; The II level, granular; The III level, stasis shape (cutout).
2) blood capillary site counting: get area and be about the FX (this zone surrounds the border by blood vessel) about 1 square millimeter, calculate the number of hits of blood capillary and border (blood vessel) in this zone.Do not count with the crossing blood capillary in border.
3) color: observe color, divide scarlet, dark red, light red etc.
4) variation around the blood capillary: mainly observe to have or not around the blood capillary and ooze out and bleeding.
5.3 statistical procedures
The site enumeration data is expression with
, and statistical analysis is checked with t.Other qualitative response data is with the non parametric tests of a plurality of independent samples.
5.4 result of the test
Result of the test is seen table 12,13.
1) meninges microcirculation change of flow state: after negative control group was given macromolecule right rotary glycoside, meninges microcirculation site counting significantly reduced, and compared significant difference P＜0.01 before the modeling, test each treated animal injection macromolecule right rotary glycoside after, the blood fluidised form has abnormal change.The blood fluidised form becomes dotted line shape, granular by normal band shape, wire, even becomes stasis shape (cutout), and is the most obvious with negative control group blood stasis symptom.Heart pill of Musk also can improve the blood stasis symptom that the macromolecule right rotary glycoside intravenous injection causes rat in dose dependent ground, shows as that site counting increases, the stasis of blood stream state makes moderate progress, but compares difference nonsignificance (P＞0.05) with the feminine gender group.The positive drug Radix Salviae Miltiorrhizae Injection has improvement in various degree to the blood fluidised form due to the macromolecule right rotary glycoside; Showing as the hemocyte aggregation extent alleviates to some extent; Become granular like the blood fluidised form by the stasis shape; Or by granular band shape or the wire of becoming, or become wire by the dotted line shape, comparing difference with the feminine gender group has highly significant meaning (P＜0.01).
2) color changes: matched group and each treated animal of experiment are behind the injection macromolecule right rotary glycoside, and color changes with comparing originally not have obviously.
3) variation around the blood capillary: test each treated animal behind injection macromolecule right rotary glycoside and sample, with compared blood capillary originally around do not see and ooze out with hemorrhage.
4) capillary network changes before and after the intravenous drug: the positive drug Radix Salviae Miltiorrhizae Injection can obviously increase the site counting (comparing p＜0.05 with matched group) of pia mater encephali microcirculatory vascular; Though each dose groups of Heart pill of Musk can increase rat's pial blood capillary site counting in dose dependent ground, compares difference nonsignificance (p＞0.05) with the feminine gender group.
Table 12 Heart pill of Musk various dose group is to the influence (
n=8) of meninges blood capillary site counting
*P＜0.05,
*Compare with negative group p＜0.01
Table 13 Heart pill of Musk various dose group is to the influence of brain microcirculation fluidised form
5.5 conclusion
The result shows positive drug Radix Salviae Miltiorrhizae Injection group; After administration, the blood fluidised form has improvement in various degree, shows as the hemocyte aggregation extent and alleviates to some extent; Become granular like the blood fluidised form by the stasis shape; Or by granular band shape or the wire of becoming, or become wire by the dotted line shape, and meninges blood capillary site counting obviously increases (P＜0.05).Heart pill of Musk also can improve the blood stasis symptom that the macromolecule right rotary glycoside intravenous injection causes rat in dose dependent ground, shows as that site counting increases, the stasis of blood stream state makes moderate progress, but compares difference not statistically signigicant (P＞0.05) with the feminine gender group; There is not significant change around each experimental group animal brain microcirculatory vascular color and the blood vessel.Results suggest Heart pill of Musk treating cerebral ischemia, maybe part with to improve the brain microcirculation relevant.
Embodiment 6 Heart pill of Musk are to the influence of hemorheology of rat
6.1 test material
6.1.1 confession test agent
Title: Heart pill of Musk; Source: Hehuang Pharmaceutical Co., Ltd., Shanghai; Lot number: G070103
Specification: 42 balls/bottle/box, the heavy 22.5mg of every ball; Character: the glossy watered pill of pitchy
Preparation: get certain ball number in mortar, add 0.5%CMC-Na solution and be ground to the desired concn suspension
6.1.2 control sample:
Title: Radix Salviae Miltiorrhizae Injection; Source: Zhengda Qingchunbao Pharmaceutical Co., Ltd; Lot number: 0701022
Specification: 10ml; Character: weak yellow liquid
6.1.3 experimental animal
Strain: SD rat; Sex: male; Body weight: 250～270 grams; Source: Shanghai Si Laike laboratory animal responsibility company limited; The animal quality certification: SCXK (Shanghai) 2003-0003
Raise: animal feeding in positive pressure purification ventilation Animal House, 23 ± 2 ℃ of room temperatures, humidity 40～70%, artificial lighting's simulation changes ad lib and drinking-water round the clock.
6.1.4 test apparatus
NXE-1B type cone and plate viscometer, Chengdu Instruement Factory; Type B cone-plate (1.565 °), measuring cup 1.2ml cuts speed D=3.845N (1/s).
The LH586-1A thermostatic water bath, music theory machinery plant of Shanghai City section.
6.2 test method
50 of SD rats are divided into 5 groups, negative control group (0.5%CMC-Na 5ml/kg), Heart pill of Musk low dose group (6mg/kg), middle dose groups (12mg/kg), high dose group (24mg/kg) and positive controls (Radix Salviae Miltiorrhizae Injection 2ml/kg).Positive drug 15min tail vein injection administration before blood sampling, administration volume 2ml/kg; Other each group is 30min gastric infusion before blood sampling all, administration volume 5ml/kg.
Animal with 12% chloral hydrate intraperitoneal injection of anesthesia (360mg/kg) after, it is fixing to lie on the back.Cut open the belly,, add heparin sodium 100IU anticoagulant, get blood 1.3ml, add the sample cup of cone and plate viscometer from ventral aorta blood sampling 5ml, all the other centrifugal blood separated plasmas, the blood supply slurry viscosity is measured.Blood viscosity is measured and is adopted height to cut (115S
-1) and the low (11.5S that cuts
-1) two conditions, and from high tangential low shearization; Plasma viscosity is measured and is adopted height to cut (115S
-1).Measure temperature and be 37 ℃.
6.3 result of the test
Result of the test is seen table 14,15.Can see that the positive drug Radix Salviae Miltiorrhizae Injection all can the utmost point significantly reduce the viscosity (P＜0.01) of rat whole blood with low when cutting at Gao Qie, and plasma viscosity is not had obvious influence.Heart pill of Musk also can reduce WBV, and the WBV of high dose group animal is starkly lower than negative control group (P＜0.05), but each dose groups does not all have obvious influence (P＞0.05 is compared with the feminine gender group) to plasma viscosity.
Table 14 Heart pill of Musk is to the influence of rat blood viscosity
Compare with the feminine gender group:
*P＜0.05,
*P＜0.01
Table 15 Heart pill of Musk is to the influence of rat plasma viscosity
Compare with the feminine gender group:
*P＜0.05,
*P＜0.01.
Claims (9)
1. Heart pill of Musk treats and/or prevents the application in the medicine of mammal transient ischemic attack in preparation.
2. application according to claim 1 is characterized in that, said Heart pill of Musk is formed by Moschus, Radix Ginseng extract, artificial Calculus Bovis, Cortex Cinnamomi, Styrax, Venenum Bufonis and Borneolum Syntheticum seven flavor medicine material or extract combination.
3. application according to claim 1 and 2 is characterized in that, said mammal behaviour, rat and Canis familiaris L. preferably are the people.
4. according to each described application in the claim 1 to 3; It is characterized in that transience ischemia that said transient ischemic attack is the local prominent cerebral ischemia that causes with fixed attention of middle cerebral artery electricity, line bolt method causes or bilateral vertebral artery obstruction add the bilateral common carotid arteries folder and close the GBI due to opening again.
5. according to each described application in the claim 1 to 4, it is characterized in that the consumption of said Heart pill of Musk is 1.125～24mg/kg.
6. according to each described application in the claim 1 to 5, it is characterized in that when said mammal is a man-hour, the consumption of said Heart pill of Musk is 1.125～2.25mg/kg.
7. according to each described application in the claim 1 to 6, it is characterized in that when said mammal was rat, the consumption of said Heart pill of Musk was 6～24mg/kg, more preferably 12～24mg/kg.
8. according to each described application in the claim 1 to 7, it is characterized in that when said mammal was Canis familiaris L., the consumption of said Heart pill of Musk was 2～8mg/kg, is preferably 8mg/kg.
9. according to each described application in the claim 1 to 8, it is characterized in that said medicine is an oral formulations, is preferably pill.
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| CN114522190A (en) * | 2020-11-20 | 2022-05-24 | 上海和黄药业有限公司 | Pharmaceutical composition for resisting myocardial ischemia injury and preparation method and application thereof |
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Cited By (3)
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| CN105726464A (en) * | 2016-03-23 | 2016-07-06 | 上海和黄药业有限公司 | Preparation method of test sample of musk Baoxinwan slow release gel for pharmacological research |
| CN105726464B (en) * | 2016-03-23 | 2019-10-22 | 上海和黄药业有限公司 | A kind of slow-releasing gel used preparation method of test article for pharmacological research of Shexiang Baoxin Pills |
| CN114522190A (en) * | 2020-11-20 | 2022-05-24 | 上海和黄药业有限公司 | Pharmaceutical composition for resisting myocardial ischemia injury and preparation method and application thereof |
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