CN1857534A - Medicine composition for treating cardiac and cerebral vascular diseases - Google Patents
Medicine composition for treating cardiac and cerebral vascular diseases Download PDFInfo
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- CN1857534A CN1857534A CNA2006100205098A CN200610020509A CN1857534A CN 1857534 A CN1857534 A CN 1857534A CN A2006100205098 A CNA2006100205098 A CN A2006100205098A CN 200610020509 A CN200610020509 A CN 200610020509A CN 1857534 A CN1857534 A CN 1857534A
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Abstract
The medicine composition for treating cardiac and cerebral vascular diseases has ligustilide and volatile grassleaved sweetflag rhizome oil in the weight ratio of 1 to 0.5-20 as effective medicinal components and contains also borneol and musk and pharmaceutically acceptable supplementary material. Test proves the synergistic effect between ligustilide and volatile grassleaved sweetflag rhizome oil as well as of borneol and musk in resisting cerebral ischemia reperfusion injury and resisting anoxia.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for cardiovascular and cerebrovascular diseases, particularly is the pharmaceutical composition of medicinal active ingredient with the effective ingredient in the natural drug.
Background technology
Cardiovascular and cerebrovascular disease is a kind of common and multiple sexually transmitted disease (STD), especially with the sickness rate height of mid-aged population, and serious harm people's healthy and quality of life.Traditional single medicinal material and corresponding compound medicine have certain prevention and therapeutical effect to cardiovascular and cerebrovascular disease.As Rhizoma Chuanxiong injection, main effective ingredient is a Rhizoma Chuanxiong volatile oil, ligustilide content wherein the highest (Wang Shuqi, " Chinese patent medicine research " 1981,10:31; Lai Fusheng etc., " shanghai Medicine " 1995,18 (3): 157), clinical and zoopery proves that Rhizoma Chuanxiong injection can suppress platelet activation, improves the blood microcirculation, reduce vascular resistance, and ischemic diseases is had obvious curative effects (the shady silk floss of official etc., " PLA's medical journal " 1979,4:98).Multiple phthalide analog compound in the Rhizoma Chuanxiong volatile oil be proved to be to play in the Rhizoma Chuanxiong cardiovascular and cerebrovascular vessel effect main effective ingredient (Natio T, et al., " Nat Med " 1995,49:288).Rhizoma Chuanxiong volatile oil has microcirculation improvement, the effect of cerebral blood flow increasing amount, can make the blood capillary spasmolytic, increase the open number of blood capillary, accelerate blood flow rate, make accumulative erythrocyte depolymerization, after ligustilide in the Rhizoma Chuanxiong volatile oil decomposed, its pharmacological action then obviously descended even disappears, and shows that ligustilide is main effective ingredient (the stone coolie etc. in its volatile oil, " Chinese J Pharmacol Toxicol " 1995,9 (2): 157; Zhang Yong etc., " the Hebei traditional Chinese medical science " 2003,25 (6): 471).197) and 20%-50% (Lin Yanzhi etc., " CHINA JOURNAL OF CHINESE MATERIA MEDICA " 2004,29 (2): 154) weight content of ligustilide in Rhizoma Chuanxiong medical material and volatile oil is about 1.5% respectively, and (rolling waits West China Journal of Pharmaceutical Sciences 2004,19 (3) really:.
Rhizoma Acori Graminei is the dry rhizome of acorus gramineus araceae plant (Acorus tatarinowii Schott), has the removing dampness appetizing, the eliminating phlegm of having one's ideas straightened out, and the refreshment Fructus Alpiniae Oxyphyllae, Chinese Pharmacopoeia record volatile oil content wherein is greater than 1.0% (ml/g).Rhizoma Acori Graminei volatile oil can significantly suppress by the inductive cranial nerve cell apoptosis of ischemia-reperfusion, main effective ingredient beta-Asarone wherein can improve cerebral edema, improve mice blood brain permeability and hypoxia-bearing capability, obviously suppress rat brain cortex and hippocampal neurons apoptosis, suppress (Wu Hongbin etc. such as BAX gene expression, " Chinese medicine academic periodical " 2004,22 (1): 127).
Borneolum Syntheticum, promptly borneolum syntheticum contains Borneolum Syntheticum (C
10H
18O) greater than 55.0%, have the refreshment of having one's ideas straightened out, the effect of clearing away heat to alleviate pain is usually used in the calentura coma, faints from fear apoplexy syncope due to accumulation of phlegm, the treatment of attacked by pestiferous factors stupor etc.Moschus is the rare medicinal herbs simply that records in the Chinese Pharmacopoeia, has the refreshment of having one's ideas straightened out, and the effect of promoting blood circulation to restore menstrual flow is usually used in the calentura coma, the apoplexy syncope due to accumulation of phlegm, and the treatment of attacked by pestiferous factors stupor etc., main effective ingredient is a muscone, at present widely used is the artificial Moschus.Bibliographical information, Moschus, Borneolum Syntheticum can see through blood brain barrier rapidly and directly act on the central nervous system, antagonism ischemic cerebral lesion, the effect with convulsion and cerebral edema; Borneolum Syntheticum can also increase the permeability of blood brain barrier, improves concentration (Liu Yamin etc., " new Chinese medicine and the clinical pharmacology " 2002,13 (4): 23) of medicine in brain.
Cardiovascular and cerebrovascular disease is the disease of a class complication system, the pathogenic factor complexity, and the influence factor is numerous, and the medicine of single active ingredient or single target spot effect is difficult to obtain satisfied curative effect.Traditional Chinese compound medicine is many at present is used as medicine with the medical material compatibility, and the volume and the dose of pharmaceutical preparation are big, and effective ingredient is indeterminate, and it absorbs with bioavailability also undesirable, has influenced the performance of curative effect of medication.In addition, the quality of medicinal material instability easily causes the drug quality instability, also makes not high to the controllability of drug quality.
Share in the treatment apoplexy sequela brain injury due to anoxia, the ischemia, the existing report of the research of cerebrovascular disease such as alzheimer disease to be extracted into grouping by different armaticity medical material volatile oil.Related to " refreshment nasal drop " medicine of forming by Rhizoma Acori Graminei, Moschus, Borneolum Syntheticum as Ke Xuehong etc. at " the HPLC method is measured the content of beta-Asarone, α-asaricin in the refreshment nasal drop " (" new Chinese medicine and clinical pharmacology " 2002,13 (6)).Jiang Honglan etc. have reported the research of the Borneolum Syntheticum/Rhizoma Acori Graminei volatile oil of different proportion composition to the protective effect of neurocyte hypoxic damage at " the Rhizoma Acori Graminei Borneolum Syntheticum is to the protective effect of neurocyte hypoxic damage " (" Traditional Chinese Medicine University Of Guangzhou's journal " 2003,20 (1)).Liu Yamin etc. in " Moschus, Borneolum Syntheticum pour into the influence of rat cerebral tissue's amino acid neurotransmitter again to global brain ischemia " (" new Chinese medicine and clinical pharmacology " 2002,13 (4)), research and inquirement drugs of causing resuscitation by administering aromatic drugs treatment ischemic cerebrovascular mechanism.
Summary of the invention
At above-mentioned situation, the present invention is according to the theory of Chinese medicine, select the ligustilide blood circulation promoting and blood stasis dispelling for use, promoting the circulation of QI to relieve pain are monarch drug, have one's ideas straightened out with the Rhizoma Acori Graminei volatile oil circulation of qi promoting, Fructus Alpiniae Oxyphyllae is a ministerial drug, the two gathers promoting flow of QI and blood altogether, the effect that blood stasis dispelling is had one's ideas straightened out, and can also further be aided with the sensible switching of Borneolum Syntheticum, and/or the Moschus refreshment of having one's ideas straightened out, be adjuvant, further strengthen the curative effect of medicine, not only have even more ideal and satisfied regulating qi to disperse stagnation thereby reach, the have one's ideas straightened out pharmaceutical composition of refreshment and nootropic effect, and the effective ingredient of this pharmaceutical composition is clear and definite, be convenient to be processed into various more superior pharmaceutical preparatioies, and can significantly reduce the treatment consumption, the convenient use.
The present invention treats the pharmaceutical composition of cardiovascular and cerebrovascular disease, basic effective medicinal ingredient consists of ligustilide and Rhizoma Acori Graminei volatile oil, can also contain Borneolum Syntheticum and Moschus two effective ingredient simultaneously more on this basis, form jointly with the auxiliary adding ingredient of acceptable in the medicine.The weight portion ratio of the ligustilide/Rhizoma Acori Graminei volatile oil in said effective medicinal ingredient is 1/0.5～20, and further preferred proportion is 1/5～10; The weight portion ratio of Borneolum Syntheticum is 0～300% of a Rhizoma Acori Graminei volatile oil weight, and further the preferred proportion scope is 100～200%; The weight portion ratio of Moschus is a Rhizoma Acori Graminei volatile oil weight 0～100%, and further the preferred proportion scope is 10～50%.
In effective medicinal ingredient of above-mentioned said pharmaceutical composition, the ligustilide composition allows to use the Rhizoma Chuanxiong volatile oil composition of the ligustilide that contains said significant proportion amount to replace.
Ligustilide (ligustilide) or permission as the effective medicinal ingredient of aforementioned pharmaceutical compositions of the present invention are used as the Rhizoma Chuanxiong volatile oil of replacing, and effective medicinal ingredient such as Rhizoma Acori Graminei volatile oil, can also can extract or preparation available from commercially available commodity raw material by the method for at present existing bibliographical information.For example; ligustilide can obtain (Li Shaobai etc. through chemical improvement and/or after modifying by the full chemosynthesis mode of existing report or by other related compound; " SCI " 1995; 16 (9): 1420); also can adopt by extracting in the suitable natural medicinal raw material that contains this composition, the latter's extracting mode usually can be more easy and commonly used.The said natural medicinal raw material of this composition that contains is except that the Rhizoma Chuanxiong that can directly adopt, also comprise other multiple natural medicinal raw materials such as the Chinese medicine angelica that equally also contains the ligustilide composition, Rhizoma Ligustici, through extract with separate after obtain (Ma Jianlong etc.: " medicine evaluation " 2005,2 (3): 214).
The common adoptable method of the extraction of Rhizoma Chuanxiong volatile oil has conventional straight run distillation or vapor distillation mode, perhaps adopts modes such as supercritical CO 2 extraction.These methods are extracted the volatile oil that obtains and are shown by analysis, its main component is identical, be ligustilide, cnidiumm lactone (cnidium lactone), butylidene phthalide, 3-n-butylphthalide, neocindilide etc., wherein the weight content of ligustilide generally can be greater than 20%.Especially more complete with the chemical constituent of supercritical CO 2 extraction volatile oil in these methods, yield height (former virtue forever etc., " Chinese Pharmaceutical Journal " 2000,35 (2): 84; Hong Ying etc., " Chinese Pharmaceutical " 2003,12 (6): 31).Rhizoma Acori Graminei volatile oil also can adopt the conventional way of distillation to extract or supercritical CO
2Extraction, the volatile oil main component of gained is beta-Asarone, α-asaricin, γ-asaricin, methyleugenol, cis, trans-methylisoeugenol etc., wherein the weight content of beta-Asarone generally can be greater than 30% (Tang Daoquan etc., " time precious traditional Chinese medical science traditional Chinese medicines " 2001,12 (4): 34; Dai Jian etc., " fine chemistry industry " 2005,22 (5): 359).
When employing obtains the ligustilide composition by natural medicinal raw material extracting mode, effective medicinal ingredient as aforementioned pharmaceutical compositions of the present invention, except that the ligustilide of the single respective pure form that can adopt correlation method to carry out to obtain behind the purification, allow to adopt in the ligustilide that contains above-mentioned said significant proportion amount, also contain the mixture of the cnidiumm lactone (cnidium lactone), butylphthalide, butylidene phthalide and other phthalide analog compound and/or other volatile oil component that mainly are present in its extract.Test shows, in aforementioned pharmaceutical compositions of the present invention, adopts and replaces with the Rhizoma Chuanxiong volatile oil extract that contains said significant proportion amount ligustilide, generally tangible interference or adverse effect can not arranged to the drug action of effective ingredient.
Be appreciated that thus, said active drug composition in the application's aforementioned pharmaceutical compositions, except that the composition form that can adopt its single neat compounds, according to its source, mode and/or different preparation and different needs such as process and integrated cost consideration thereof, can allow to contain other unavoidable impurity and/or can not cause and disturb and/or the composition of adverse effect the drug action of said effective ingredient.
Respectively with ligustilide or Rhizoma Chuanxiong volatile oil and the Rhizoma Acori Graminei volatile oil manner of formulation, another preparation method of pharmaceutical composition of the present invention is to mix medicinal material coarse powder through supercritical carbon dioxide extraction with Rhizoma Chuanxiong and Rhizoma Acori Graminei except that above-mentioned.Result of the test shows that Rhizoma Chuanxiong supercritical carbon dioxide extraction yield is about 3%, and ligustilide content wherein is about 25%, and the supercritical carbon dioxide extraction yield of Rhizoma Acori Graminei volatile oil is about 3%.Therefore, be that 4/1～4/10 mixing medicinal material coarse powder can obtain pharmaceutical composition of the present invention through supercritical carbon dioxide extraction with Rhizoma Chuanxiong/Rhizoma Acori Graminei medical material weight ratio.Concrete grammar is: Rhizoma Chuanxiong and Rhizoma Acori Graminei were pulverized 20 mesh sieves, adopt supercritical carbon dioxide cyclic countercurrent extraction, separation, extracting pressure 8～40Mpa, 30～60 ℃ of temperature, per hour the circulate weight proportion of consumption of Rhizoma Chuanxiong and Rhizoma Acori Graminei material consumption and carbon dioxide is 1: 5～1: 30,1～6 hour extraction time; Carry out extracting operation under these conditions, the carbon dioxide that is rich in Rhizoma Chuanxiong and Rhizoma Acori Graminei volatile oil that obtains is introduced separator by extractor and is carried out decompression separation, promptly gets Rhizoma Chuanxiong volatile oil and stone Chang volatile oil, and average yield is about 3%.
With two above-mentioned basic effectively medicinal ingredient ligustilide and Rhizoma Acori Graminei volatile oil, and effective ingredient such as Borneolum Syntheticum that further can contain simultaneously and/or Moschus, handle by corresponding pharmaceutical methods and processes with acceptable auxiliary adding ingredient in the medicine, promptly may be made in the pharmaceutical preparation of corresponding oral type, injection-type or other available form.For example, with can received disintegrating agent in oral formulations, after auxiliary interpolation composition that excipient, lubricant, binding agent, filler etc. are commonly used mixes, handle by corresponding common process method, promptly may be made in the oral drugs of the solid preparation forms such as slow releasing agent, controlled release agent of tablet, drop pill, capsule or appropriate format; Mix with surfactant, pH regulator agent, diluent, stabilizing agent, thickening agents etc. such as the solubilizing agent of using always, cosolvent, emulsifying agent, wetting agent, handle by corresponding common process method, promptly may be made in corresponding pharmaceutical preparation such as Emulsion, spray, nasal drop, aerosol.Press in the injectable drug preparation and to allow the appropriate solvent that uses and after additives cooperate and corresponding technological operation handles, can be prepared into the injection agent medicine of muscle such as corresponding Emulsion or powder pin or vein form.
The specific embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
The specific embodiment
Embodiment 1
Obtain the pure product of single ligustilide by the Rhizoma Chuanxiong volatile oil separation and purification respectively, obtain Rhizoma Acori Graminei volatile oil through vapor distillation by the Rhizoma Acori Graminei medical material.Get ligustilide 2g, Rhizoma Acori Graminei volatile oil 10g (wherein containing beta-Asarone 39.6%), add injection soybean oil 120g, be preheated to 55 ℃ as oil phase, standby.Other gets injection soybean phospholipid 12g, adds injection water 500ml and disperses, and adds glycerol for injection 25g again, stirs and makes dissolving, be heated to 55 ℃, and continue to stir, slowly add oil phase simultaneously, high speed homogenization made colostrum in 6 minutes, and colostrum is crossed high pressure dispersing emulsification machine circulation 4 times, promptly got submicron emulsion.Under the stirring at low speed submicron emulsion is added the injection water to 1000ml, filtration, packing, sterilization promptly gets the emulsion-type injection.
Embodiment 2
Obtain Rhizoma Chuanxiong volatile oil by the Rhizoma Chuanxiong medical material through the vapor distillation mode respectively; By the Rhizoma Acori Graminei medical material through supercritical CO
2Extraction obtains Rhizoma Acori Graminei volatile oil.Get Rhizoma Chuanxiong volatile oil 6g (containing ligustilide 35.1%), Rhizoma Acori Graminei volatile oil 20g (wherein containing beta-Asarone 53.1%), join in the PEG-6000 fused solution, stirring and evenly mixing is made 5000 drop pill in the drop pill machine, be described pill-type medicine.
Embodiment 3
Get ligustilide 15g, Rhizoma Acori Graminei volatile oil 15g, add soybean oil 40g, standby as oil phase.It is an amount of to get Ovum Gallus domesticus Flavus lecithin 3g, glycerol 12g, tragacanth 5g, ethyl hydroxybenzoate 0.5g and edible essence, adding distil water 250ml stirs and makes dissolving, is heated to 70 ℃, and continue to stir, slowly add oil phase simultaneously, high speed homogenization made colostrum in 8 minutes, and colostrum is crossed high pressure dispersing emulsification machine circulation 6 times, adding distil water is to 500ml under stirring at low speed, filtration, packing are put in the special-purpose collunarium bottle or in the spray bottle, promptly get nasal drop and spray.
Embodiment 4
Get artificial Moschus 20g, micronization adds by the Rhizoma Chuanxiong medical material through supercritical CO
2The Rhizoma Chuanxiong volatile oil 10g that the extraction mode obtains (wherein containing ligustilide 25.6%), Rhizoma Acori Graminei volatile oil 40g, Borneolum Syntheticum 80g and soybean oil 1050g, it is standby that the emulsifying homogenizing is made medicinal liquid.Got it filled in 3: 1.2: 3 by volume with gelatin, G ﹠ W, make the capsule material after, above-mentioned standby medicinal liquid and capsule material are pressed into 4000 of soft capsules on the soft capsule press that conventional formulation uses, be described capsule.
Embodiment 5
With Rhizoma Chuanxiong/Rhizoma Acori Graminei weight ratio is that 2: 1 crude drug raw material pulverizing classification is sieved, and gets 20～80 order coarse powder 100kg, supercritical fluid CO
2The circulation counter-current extraction with separate extracting pressure 20MPa, 45 ℃ of extraction temperature, extractant CO
21000 kilograms of consumptions/time, 2 hours extraction time, separator is resolved pressure 10Mpa, and 40 ℃ of resolution temperatures obtain Rhizoma Chuanxiong and Rhizoma Acori Graminei volatile oil 3.1kg.Got it filled in 3: 1.2: 3 by volume with gelatin, G ﹠ W, make the capsule material after, above-mentioned volatile oil and capsule material are pressed into soft capsule on the soft capsule press that conventional formulation uses, the 0.3g/ grain is described capsule.
On the basis of said extracted method,, can prepare the Rhizoma Chuanxiong and the Rhizoma Acori Graminei volatile oil extract of different proportion by selecting the relevant parameters condition.
Trial drug to the above-mentioned form pharmaceutical composition of the present invention has carried out following relevant pharmacodynamics test.
One, to the therapeutical effect of bolt collimation method focal brain ischemia-reperfusion injury in rats model
1, medicine preparation: ligustilide (the single pure product that obtain by separation and purification in the Rhizoma Chuanxiong volatile oil), Rhizoma Acori Graminei volatile oil (through the volatile oil that vapor distillation obtains, containing beta-Asarone 39.6%) by the Rhizoma Acori Graminei medical material.It is used the 4%Tween-80 mixing, and the reuse pure water is mixed with the trial drug of concentration form as shown in table 1.
2, test method: the SD rat, male and female are used with, and body weight 250-300g is divided into sham operated rats (I), model group (II) at random, gives trial drug group (III～XIII), 30 every group of different proportion of composing form ligustilide/Rhizoma Acori Graminei volatile oil.Each trial drug group is irritated ligustilide/Rhizoma Acori Graminei volatile oil suspension 10mlkg that stomach gives corresponding proportion respectively by table 1 mode
-1D
-1, sham operated rats and model group are irritated the pure water 10mlkg that stomach gives 4% Tween 80
-1D
-1, give 7 days continuously, underwent surgery as follows in 2 hours after the last administration.
With 10% chloral hydrate 3ml/kg intraperitoneal injection of anesthesia, the neck median incision separates and ligation right carotid proximal part, external carotid artery and bifurcated artery thereof with rat.Separate the right side internal carotid artery, separate wing jaw tremulous pulse downwards along internal carotid artery, this branch of root ligation.Be equipped with line, far-end placement bulldog clamp at the internal carotid artery near-end, common carotid artery crotch otch inserts the 4-0 nylon wire, and its degree of depth is 17～20mm, and the bolt line enters internal carotid artery, goes into cranium to anterior cerebral artery, all blood flows sources of blocking-up middle cerebral artery.Remove bulldog clamp, tighten line fully, stay the long the end of a thread of 1cm outward, skin suture.Ischemia is perfusion again after 2 hours, need not anaesthetize and cut skin once more, lift gently institute's the end of a thread that stays to resistance is arranged time prompting nylon wire head end to the common carotid artery incision, make blood flow logical again.Sham operated rats is except that plug wire not, and all the other steps are the same.
After the survival Mus pours into 24 again, observe rat behavior and change, carry out behavior scoring.The five-grade marking system standards of grading with reference to Zea Longa:
0 minute, normal, impassivity damage symptom;
1 minute, can not full extension offside fore paw;
2 minutes, turn-take laterally;
3 minutes, topple over to offside;
4 minutes, can not spontaneously walk loss of consciousness.
Broken end is got the experimental mouse brain fast then, and a part is the left and right cerebral hemisphere weight in wet base of weighing respectively, puts in 160 ℃ of baking boxs to claim dry weight after 24 hours, calculates brain water content as follows:
Brain water content (%)=(weight in wet base-dry weight)/weight in wet base * 100%;
Another part downcuts the crown brain sheet of thick about 2mm on the anterior commissure plane, place 2%TTC solution at once, hatches 30 minutes for 37 ℃.Infarct presents white, and non-infarct presents redness.Digital camera is taken record, and (Nanjing Mei Yi scientific ﹠ technical corporation) measures brain sheet cumulative volume and infarct volume with Medbrain2.0 software, and calculates the percentage ratio (%) that infarct accounts for whole cerebral tissue; Some is made tectology and observes again: cerebral tissue after fixing, the crown brain that cuts, conventional dehydration, the paraffin embedding film-making, HE dyeing, light microscopic is checked.
3, observation index and observing time: observe the variation of rat behavior, cerebral infarct volume, tectology.Observing time is for pouring into 24 hours again.
4, result of the test:
(1) to the influence of behavior: all no abnormal behavior of sham operated rats rat, neural behavior scoring is 0; The nerve injury symptom that the model group rat occurs can not full extension, the offside fore paw is turn-taked laterally or topple over to offside, behavior scoring is 1.74 ± 0.71.Trial drug V～X group all can significantly reduce the rat neural behavior scoring, with model group relatively there were significant differences (P＜0.05, P＜0.01), the single ligustilide that is better than giving same dose becomes grouping (III, IV group) and single Rhizoma Acori Graminei volatile oil become to divide into groups (XI～XIII organizes), and is as shown in table 1.
Table 1 pair rat ischemia poured into the influence of 24 hours neurological's scoring, cerebral hemisphere water content and cerebral infarct volume in 2 hours again
| Group | Drug level (mg/ml) | Drug dose (mg/kg) | Behavior scoring | Right hemisphere water content (%) | Infarct volume accounts for whole cerebral tissue percentage ratio (%) | |
| The I sham operated rats | - | - | 0±0 | 80.5±0.81 | 0±0 | |
| The II model group | - | - | 1.74±0.71 ## | 84.3±1.12 ## | 26.6±6.3 ## | |
| III 1/0 | 0.1/0 | 1/0 | 1.26±0.65 | 83.9±1.05 | 22.4±6.5 | |
| IV 2/0 | 0.2/0 | 2/0 | 1.08±0.59 | 83.3±0.90 | 20.7±5.0 | |
| Trial drug group ★ | V 1/0.5 | 0.2/0.1 | 2/1 | 0.87±0.63 * | 83.0±0.84 * | 17.2±5.2 ** |
| VI 1/2 | 0.2/0.4 | 2/4 | 0.80±0.61 * | 82.7±0.91 ** | 16.9±5.7 ** | |
| VII 1/5 | 0.2/1.0 | 2/10 | 0.64±0.50 ** | 82.0±0.75 *** | 13.1±4.9 *** | |
| VIII 1 ▲/5 | 0.2 ▲/1.0 | 2 ▲/10 | 0.60±0.48 ** | 81.6±0.71 *** | 12.5±4.3 *** | |
| IX 1/10 | 0.1/1.0 | 1/10 | 0.69±0.57 ** | 82.5±0.83 ** | 15.0±6.1 ** | |
| X 1/20 | 0.1/2.0 | 1/20 | 0.65±0.52 ** | 82.1±0.78 ** | 14.3±5.4 ** | |
| XI 0/20 | 0/2.0 | 0/20 | 0.82±0.56 * | 82.9±0.84 * | 16.8±5.6 ** | |
| XII 0/10 | 0/1.0 | 0/10 | 1.05±0.63 | 83.4±0.80 | 19.2±6.0 * | |
| XIII 0/4 | 0/0.4 | 0/4 | 1.13±0.68 | 83.7±0.76 | 21.6±6.2 | |
Annotate: ★ is ligustilide/Rhizoma Acori Graminei volatile oil,
▲For containing the Rhizoma Chuanxiong volatile oil of significant proportion amount ligustilide;
Compare with sham operated rats:
=P＜0.01; Compare with model group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
(2) to the influence of brain water content: model group ischemia-reperfusion one side (right hemisphere) brain water content highly significant is higher than the group of doing evil through another person (P＜0.01).Trial drug V～X group brain water content all significantly is lower than model group, with model group relatively there were significant differences (P＜0.05, P＜0.01, P＜0.001), be better than the ligustilide (III, IV group) and the Rhizoma Acori Graminei volatile oil (XI～XIII group) of the one-component form of same dose, as shown in table 1.
(3) to the influence of cerebral infarct volume: the sham operated rats cerebral tissue does not have infraction, and model group ischemia side cerebral tissue has the infraction phenomenon, and the percentage ratio that infarct accounts for whole brain tissue is 26.6 ± 6.3%.Trial drug V～X group all can significantly be dwindled ischemia side cerebral tissue infarct volume, with model group relatively there were significant differences (P＜0.01, P＜0.001), be better than the ligustilide (III, IV group) and the Rhizoma Acori Graminei volatile oil (XI～XIII group) of same dose one-component form, as shown in table 1.
(4) to the influence of tectology: sham operated rats both sides cerebral tissue is normal, and model group, the non-ischemia side of trial drug group cerebral tissue are all normal.For ischemia side brain hemisphere: cerebral tissue hemorrhagic necrosis and the serious edema of cerebral tissue, focal necrosis appear in model group; Trial drug V～X group all can be dwindled the hemorrhagic necrosis kitchen range, is better than the ligustilide (III, IV group) and the Rhizoma Acori Graminei volatile oil (XI～XIII group) of same dose one-component form.
Above-mentioned result of the test shows, trial drug of the present invention with ligustilide and Rhizoma Acori Graminei volatile oil two basic effectively medicinal ingredients compositions, can obviously dwindle the cerebral tissue hemorrhagic necrosis kitchen range that cerebral ischemia reperfusion injury causes, the damage that alleviates neurocyte and nerve fiber, and the ligustilide and the Rhizoma Acori Graminei volatile oil that are better than same dose one-component form, show that it has obvious role in synergism, wherein preferred ratio ligustilide/Rhizoma Acori Graminei volatile oil is 1/5～10 (VII group～IX group).In addition, the result of table 1 is also clear to be shown,, can not produce the drug action of pharmaceutical composition of the present invention and to disturb or adverse effect as the active drug composition with the Rhizoma Chuanxiong volatile oil that contains significant proportion amount ligustilide.
Two, to the influence of mice hypoxia-bearing capability
1, medicine preparation: trial drug is with 4% Tween-80 mixing, and the reuse pure water is mixed with desired concn (table 2).
2, experimental technique:
Get 80 of ICR mices, body weight is 18-22g, is divided into model group (I) at random and gives trial drug group (II～IX), 10 every group, the male and female half and half of said medicine.In preceding 6 days of experiment, II～IX group was irritated stomach by table 2 and is given trial drug suspension 10mlkg
-1D
-1, the I group is irritated the pure water 10mlkg that stomach gives 4% Tween 80
-1D
-1, after the last administration in the 7th day 30 minutes, mice is placed the airtight wide mouthed bottle of the 60ml that the 25g sodica calx is housed, the death time of record mice.
3, observation index and observing time: observe the time that mice survives under anaerobic environment.
The influence of table 2 pair mice hypoxia-bearing capability
| Group | Drug level (mg/ml) | Drug dose (mg/kg) | Time-to-live (min) | |
| The I model group | - | - | 12.9±2.7 | |
| The trial drug group | II a/b | 0.2/2.0 | 2/20 | 16.4±2.1 * |
| III a ▲/b | 0.2 ▲/2.0 | 2 ▲/20 | 17.0±2.5 * | |
| IV a/b/c | 0.2/2.0/2.0 | 2/20/40 | 18.3±2.6 *** | |
| V a/b/d | 0.2/2.0/1.0 | 2/20/10 | 19.1±3.0 *** | |
| VI a | 0.2 | 2 | 14.5±2.4 | |
| VII b | 2.0 | 20 | 14.8±2.2 | |
| VIII c | 2.0 | 40 | 13.3±2.5 | |
| IX d | 1.0 | 10 | 15.1±2.0 | |
Annotate: a is a ligustilide, and b is a Rhizoma Acori Graminei volatile oil, and c is a Borneolum Syntheticum, and d is the artificial Moschus,
▲For containing the Rhizoma Chuanxiong volatile oil of significant proportion amount ligustilide; Compare with model group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
The result of table 2 further shows, trial drug group of the present invention (II～V group) but the equal time-to-live of significant prolongation mice under anaerobic condition, with model group relatively there were significant differences (P＜0.05, P＜0.01, P＜0.001), and be better than ligustilide, Rhizoma Acori Graminei volatile oil, Borneolum Syntheticum and the Moschus of the independent type of service of same dose, have obvious role in synergism.The result of table 2 is clear equally to be shown,, can not produce the drug action of pharmaceutical composition of the present invention and to disturb or adverse effect as the active drug composition with the Rhizoma Chuanxiong volatile oil extract that contains significant proportion amount ligustilide composition.
Above-mentioned result of the test shows, the effect of the pharmaceutical composition of the effective medicinal ingredient composition form of the present invention aspect anti-cerebral ischemia reperfusion injury and oxygen lack resistant function, all obviously be better than the wherein effectively independent effect of medicinal ingredient, have remarkable role in synergy, can have gratifying DEVELOPMENT PROSPECT and value.
Claims (6)
1. treat the pharmaceutical composition of cardiovascular and cerebrovascular disease, it is characterized in that basic effectively medicinal ingredient is ligustilide and Rhizoma Acori Graminei volatile oil, and Borneolum Syntheticum that can also contain and Moschus, form jointly with the auxiliary adding ingredient of acceptable in the medicine, the weight portion ratio of ligustilide/Rhizoma Acori Graminei volatile oil is 1/0.5～20 in said effective medicinal ingredient, the weight portion ratio of Borneolum Syntheticum is 0～300% of a Rhizoma Acori Graminei volatile oil weight, and the weight portion ratio of Moschus is a Rhizoma Acori Graminei volatile oil weight 0～100%.
2. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease as claimed in claim 1, the weight portion ratio that it is characterized in that said active drug composition ligustilide/Rhizoma Acori Graminei volatile oil is 1/5～10.
3. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease as claimed in claim 1 is characterized in that the ligustilide in the said active drug composition is the Rhizoma Chuanxiong volatile oil that contains the ligustilide of said significant proportion amount.
4. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease as claimed in claim 1 is characterized in that the weight of Borneolum Syntheticum in the said active drug composition is preferably 100～200% of Rhizoma Acori Graminei volatile oil weight.
5. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease as claimed in claim 1 is characterized in that the weight of Moschus in the said active drug composition is preferably 10～50% of Rhizoma Acori Graminei volatile oil weight.
6. as the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of one of claim 1 to 5, it is characterized in that at least a in oral agents, injection, nasal drop, spray or the aerosol.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106138135A (en) * | 2016-08-18 | 2016-11-23 | 四川省中医药科学院 | Medicine for treatment of vascular cognitive disorder and preparation method thereof |
| CN110123925A (en) * | 2019-06-27 | 2019-08-16 | 河南中医药大学 | It is a kind of to treat hydrocephalic nasal nanometer emulsion in-situ gel and preparation method thereof |
| CN113398105A (en) * | 2021-07-29 | 2021-09-17 | 宫念樵 | Application of methyl eugenol in preparation of medicine for relieving liver ischemia reperfusion injury |
| CN113425706A (en) * | 2021-08-12 | 2021-09-24 | 宫念樵 | Application of methyl eugenol in preparation of medicine for relieving renal ischemia reperfusion injury |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1302775C (en) * | 2003-11-25 | 2007-03-07 | 中国人民解放军第二军医大学 | Use of ligustilide for prevention and treatment of atherosclerosis |
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2006
- 2006-03-17 CN CNB2006100205098A patent/CN100431575C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106138135A (en) * | 2016-08-18 | 2016-11-23 | 四川省中医药科学院 | Medicine for treatment of vascular cognitive disorder and preparation method thereof |
| CN110123925A (en) * | 2019-06-27 | 2019-08-16 | 河南中医药大学 | It is a kind of to treat hydrocephalic nasal nanometer emulsion in-situ gel and preparation method thereof |
| CN113398105A (en) * | 2021-07-29 | 2021-09-17 | 宫念樵 | Application of methyl eugenol in preparation of medicine for relieving liver ischemia reperfusion injury |
| CN113425706A (en) * | 2021-08-12 | 2021-09-24 | 宫念樵 | Application of methyl eugenol in preparation of medicine for relieving renal ischemia reperfusion injury |
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