CN1309408C - Medicine for treating parkinson's disease and Parkinson's syndrome and its prepn - Google Patents
Medicine for treating parkinson's disease and Parkinson's syndrome and its prepn Download PDFInfo
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- CN1309408C CN1309408C CNB2005100327921A CN200510032792A CN1309408C CN 1309408 C CN1309408 C CN 1309408C CN B2005100327921 A CNB2005100327921 A CN B2005100327921A CN 200510032792 A CN200510032792 A CN 200510032792A CN 1309408 C CN1309408 C CN 1309408C
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Abstract
The present invention discloses a medicine for effectively treating Parkinson's disease and Parkinson's syndrome and a preparation method thereof. The medicine is prepared from white peony alba, uncaria, tall gastrodis tuber, puncturevine caltrop fruit, sea-ear shell, prepared fleeceflower root, nacre, oyster shell, red sage root and prepared liauorice root. The preparation method comprises the following steps that (a) ethanol with the concentration of 10 to 90% is added into the uncaria, the tall gastrodis tuber, the prepared fleeceflower root and the red sage root to be extracted for multiple times in a refluxing mode, and the ethanol extracting solutions are merged and filtered; (b) the ethanol in the filtrate is recovered and concentrated until the relative density is from 1.0 to 13; (c) water is added into the medicine dregs, the white peony alba, the puncturevine caltrop fruit, the sea-ear shell, the nacre, the oyster shell and the prepared liauorice root to be decocted for multiple times, the water decoction solution is filtered, and the filtrate and the alcohol extracting concentrated solution are merged and concentrated until the relative density is from 1.1 to 1.4; (d) a proper amount of auxiliary material is added into the solution to prepare the medicine. The present invention has the advantages of unique prescription and preparation method, and obvious treatment effect.
Description
Technical field
The present invention relates to a kind of medicine for the treatment of parkinson disease and parkinsonism and preparation method thereof, belong to the field of Chinese medicines.
Background technology
Parkinson disease and parkinsonism (Parkinson, PD) be common clinical, particularly along with aged tendency of population, the ratio and the absolute number of aging population increase gradually, just increase sharply as the parkinson disease of old degeneration encephalopathy and its sickness rate of parkinsonism and prevalence.Parkinson disease (PD) are to be the degenerative disease of the central nervous system of main clinical manifestation with carrying out property dyskinesia, tremble, stiff and hypokinesia is its topmost clinical manifestation.
At present, the Chinese patent medicine that does not still have treatment parkinson disease and parkinsonism on the market.The treatment of parkinson disease and parkinsonism mainly is Drug therapy and operative treatment two big classes, operative therapy is owing to have strict indication (Idiopathic Parkinson's part patient), about 70% relapse rate, technical difficulty big, factor such as have postoperative complication, cost an arm and a leg, therefore, only only limit to a small amount of patient of large hospital, can not popularize, and the still main dependence Drug therapy of a large amount of patients is main.Present Drug therapy mainly is that Western medicine is main, and medicine commonly used is divided into the Dopaminergics preparation, and is peaceful etc. as levodopa, madopar, breath, this is the Parkinsonian main medicine of treatment, in addition, also has dopamine-receptor stimulant, as Ergolactin, Celance etc., anticholinergic agents is as trihexyphenidyl etc., in addition, increase the medicine that dopamine discharges in addition, as amantadine, suppress the medicine of dopamine degraded, as Selegiline etc.Present medicine mainly is to improve symptom, can not delay the development of the state of an illness, and, much discover,, use too early though the Dopaminergics alternative medicine is evident in efficacy, or prolonged application, or large usage quantity, may promote on the contrary self dopaminergic nerve cell atrophy and produce the afunction of dopamine, carrying out property of the state of an illness is increased the weight of, therefore, generally do not advocate to use in early days the Dopaminergics preparation now, do not advocate to widely apply yet.And propose the medication consideration of " doing the effect of not demanding perfection little by little without a break ", or promote " therapy holiday " etc.The curative effect of general Dopaminergics preparation is tending towards after 5～10 years disappearing in medication, and body absorbs no longer validly and utilizes dopamine, occurs the situation that no medicine can be cured at last.In addition, treat Parkinsonian medicine majority and have more side effect, untoward reaction such as hallucination, unusual fluctuation disease, hypotension, stomach discomfort, serious heart failure, arrhythmia, psychosis, the dyskinesia appear in patient's majority of prolonged application, and specific questions such as " on-off phenomenon ", " agent end phenomenon ", " dosage peak hyperkinetic syndrome " can also appear in prolonged application, and simultaneously a lot of complication such as coronary heart disease, hypotension, diabetes, glaucoma, gastropathy etc. have all limited the application of Western medicine because of untoward reaction.Often curative effect is relatively poor to parkinsonism to cling to the amine alternative medicine in addition, even it is invalid, so, actively seek other and treat way safely and effectively, improve patient's life quality, especially early stage light-duty patient can replace the medicine that has no adverse reaction again of crust amine preparation and patient with severe symptoms to improve crust amine preparation curative effect, increase its curative effect lasting time, alleviate the efficacy enhancing and toxicity reducing of its untoward reaction, and the medicine that improves patient's life quality is the emphasis of modern parkinson disease drug research and exploitation.
Summary of the invention
The object of the present invention is to provide a kind of the summary for many years on the empirical basis of clinical treatment parkinson disease, by the further investigation of the characteristics of clinical symptoms, syndrome and the body constitution of parkinson disease clinical patients and etiology and pathogenesis being made the medicine of treatment parkinson disease and parkinsonism.
Another object of the present invention has provided the preparation method of this Chinese medicine composition.
The medicament selection Radix Paeoniae Alba of the present invention, Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, Fructus Tribuli, Concha Haliotidis, Radix Polygoni Multiflori Preparata, Concha Margaritifera, Concha Ostreae, Radix Salviae Miltiorrhizae, Radix Glycyrrhizae Preparata make up, these drug regimens are made each efficacy of drugs generation effect, thus the symptom that can treat the Parkinsonian effectively.Wherein select for use the Radix Paeoniae Alba to be because the Radix Paeoniae Alba has suppressing liver-YANG, yin fluid astringing nourishes blood, the easing the affected liver relieving convulsion with compatibilities such as Rhizoma Gastrodiae, Ramulus Uncariae Cum Uncis, can play suppressing the hyperactive liver and subsiding YANG, relieving spasm by subduing liver-wind, be used for hyperactivity of YANG due to deficiency of YIN, moving in the ailment said due to cold or exposure, limbs or head tremble, shake, excessive rising of liver-YANG such as dizzy, headache, irritated irritability, syndrome of liver wind stirring up internally; Select for use Ramulus Uncariae Cum Uncis to be because Ramulus Uncariae Cum Uncis has the endogenous wind stopping relieving convulsion, the merit of calming liver and clearing heat is share with the Radix Paeoniae Alba and to be strengthened Radix Paeoniae Alba suppressing the hyperactive liver to relieve the wind syndrome and alleviate limbs muscle arteries and veins contracture, the effect of ineffective and limb tremor slow in one's movements; Select for use Rhizoma Gastrodiae to be because Rhizoma Gastrodiae has the endogenous wind stopping relieving convulsion, suppressing the hyperactive liver and subsiding YANG, the merit of dispelling wind and removing obstruction in the collateral.Share the effect of can strengthen suppressing liver-YANG, the convulsion of relaxing only being quivered with the Radix Paeoniae Alba; Select for use Fructus Tribuli to be because Fructus Tribuli to have a suppressing the hyperactive liver soothing the liver, the merit of dispelling pathogenic wind for improving eyesight is share with the Radix Paeoniae Alba, Rhizoma Gastrodiae etc., can assist and strengthen the Radix Paeoniae Alba, Ramulus Uncariae Cum Uncis suppressing the hyperactive liver and subsiding YANG, the effect of endogenous wind stopping relieving convulsion; Select for use Concha Haliotidis to be because Concha Haliotidis has and lets out liver-fire clearly, the merit of tranquillizing and subduing liver-yang owing to have the effect of salty-cold nourishing hepatic yin, is share with the Radix Paeoniae Alba simultaneously, and the cloudy blood that can strengthen the nourishing liver of the Radix Paeoniae Alba is alleviated the effect of spasm of muscles and vessels; Select for use Radix Polygoni Multiflori Preparata to be because Radix Polygoni Multiflori Preparata has the cloudy blood of liver and kidney tonifying, the merit of loosening bowel to relieve constipation.Share with the Radix Paeoniae Alba, the cloudy blood that can strengthen the nourishing liver of the Radix Paeoniae Alba is alleviated the effect of spasm of muscles and vessels.Simultaneously, Radix Polygoni Multiflori also has the merit of loosening bowel to relieve constipation, and the constipation that Parkinsonian's majority is associated with has better action; Select for use Concha Margaritifera to be because Concha Margaritifera has suppressing the hyperactive liver and subsiding YANG, liver heat removing and eyesight improving, tranquilizing effect share with the Radix Paeoniae Alba, can strengthen the suppressing liver-YANG of the Radix Paeoniae Alba, the yin fluid astringing that nourishes blood, the effect of easing the affected liver relieving convulsion.With important city medicine suppressing the hyperactive liver and subsiding YANG drug combinations such as Concha Haliotidis, adjuvant drug Concha Ostreaes, can strengthen suppressing the hyperactive liver and subsiding YANG, the effect of only quivering in the important city.Share with Ramulus Uncariae Cum Uncis, can strengthen the merit of Ramulus Uncariae Cum Uncis suppressing liver-YANG; Selecting Concha Ostreae for use is because have suppressing the hyperactive liver and subsiding YANG, and the effect of tranquillization with heavy prescription is share with Concha Haliotidis, Concha Margaritifera, is applicable to deficiecny of liver-YIN, cards such as trembling due to the excessive rising of liver-YANG, dizzy, headache, irritated irritability.Concha Ostreae matter Beijing South Maxpower Technology Co. Ltd town has the merit of calming the nerves simultaneously, is applicable to irritability, palpitation with fear palpitation with a distress feeling, cards such as insomnia and dreamful sleep; Select for use Radix Salviae Miltiorrhizae to be because Radix Salviae Miltiorrhizae has promoting blood circulation and stopping pain, the effect of relieving restlessness clears away heart-fire, the Radix Salviae Miltiorrhizae nourishing blood and promoting blood circulation can be strengthened the effect of Radix Paeoniae Alba nourishing the blood and yin in addition, Radix Salviae Miltiorrhizae is cooler in the nature, is apt to into heart channel, and the relieving restlessness that can clear away heart-fire is calmed the nerves, share with Concha Haliotidis, Concha Margaritifera, the Concha Ostreae in important city, for Parkinsonian's irritability, the palpitation with fear palpitation with a distress feeling, cards such as insomnia and dreamful sleep have therapeutical effect preferably; Select for use Radix Glycyrrhizae Preparata to be because Radix Glycyrrhizae Preparata has the QI invigorating invigorating middle warmer, relieving spasm to stop pain, the effect of the mediation property of medicine, Radix Glycyrrhizae Preparata sweet in the mouth, share with the Radix Paeoniae Alba, sour and sweet drugs can transforme into YIN, the anxious pain relieving of gentle muscular atonia can be strengthened the yin fluid astringing that nourishes blood of the Radix Paeoniae Alba, the easing the affected liver relieving convulsion is alleviated spasm of muscles and vessels, and then increases the limbs motility.Simultaneously because the Radix Glycyrrhizae Preparata sweet in the mouth is flat, the property that must neutralize, can relax the rigidity of Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, all medicines of Fructus Tribuli, make its effect soft and lasting, be unlikely acting on strong and impairing the liver, share with the product in matter such as Concha Haliotidis, Concha Margaritifera, Concha Ostreae Jie's class important city heavily, can alleviate stimulation, slow down the property of diving and fall in its important city, Gu the hepatoprotective stomach to stomach, therefore the effect of existing adjuvant drug has the effect of messenger drug again.The all medicines in comprehensive full side, this product has suppressing the hyperactive liver and subsiding YANG, and yin fluid astringing nourishes blood, relieving spasm by subduing liver-wind, tranquilizing by nourishing the heart, the merit that easypro convulsion is only quivered, all medicines are made a concerted effort, played nourishing the liver and kidney, suppressing the hyperactive liver and subsiding YANG, the effect of endogenous wind stopping relieving convulsion is just in time with the pathogenesis hepatic and renal YIN deficiency, the excessive rising of liver-YANG of this product, the liver-wind stirring up internally basically identical reaches the symptom and the life quality that improve parkinson, parkinsonism patient.
Medicine of the present invention is made by following component: (consumption is a weight portion)
The Radix Paeoniae Alba 73.73～2.99 Ramulus Uncariae Cum Uncis 73.73～2.99 Rhizoma Gastrodiaes 44.16～1.79
Fructus Tribuli 74.72～3.03 Concha Haliotidis 73.73～2.99 Radix Polygoni Multiflori 53.09～2.15
Concha Margaritifera 73.73～2.99 Concha Ostreaes 73.73～2.99 Radix Salviae Miltiorrhizaes 53.09～2.15
Radix Glycyrrhizae Preparata 22.23～0.90.
Formula optimization weight (part) ratio range of preparation medicine of the present invention is:
The Radix Paeoniae Alba 47.88～2.99 Ramulus Uncariae Cum Uncis 47.88～2.99 Rhizoma Gastrodiaes 28.68～1.79
Fructus Tribuli 48.52～3.03 Concha Haliotidis 47.88～2.99 Radix Polygoni Multiflori Preparatas 34.48～2.15
Concha Margaritifera 47.88～2.99 Concha Ostreaes 47.88～2.99 Radix Salviae Miltiorrhizaes 34.48～2.15
Radix Glycyrrhizae Preparata 14.44～0.90.
The optimum weight of medicine of the present invention (part) proportioning is:
The Radix Paeoniae Alba 11.97 Ramulus Uncariae Cum Uncis 11.97 Rhizoma Gastrodiaes 7.17
Fructus Tribuli 12.13 Concha Haliotidis 11.97 Radix Polygoni Multiflori Preparatas 8.62
Concha Margaritifera 11.97 Concha Ostreaes 11.97 Radix Salviae Miltiorrhizaes 8.62
Radix Glycyrrhizae Preparata 3.61.
Medicine of the present invention can adopt the conventional method of Chinese medicine preparation to be prepared into the medicine for oral administration of any routine.
The preparation method of above-mentioned each component being made medicine of the present invention is:
A) Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae are added 10～90% ethanol, extract repeatedly, each 0.5～3.0 hour, merge ethanol extract, filtration;
B) filtrate recycling ethanol and be concentrated into relative density and be 1.0～1.3, standby;
C) medicinal residues and the Radix Paeoniae Alba, Fructus Tribuli, Concha Haliotidis, Concha Margaritifera, Concha Ostreae, Radix Glycyrrhizae Preparata decoct with water repeatedly, and each 0.5～3.0 hour, decocting liquid filtered, merging filtrate and alcohol extraction concentrated solution, and being concentrated into relative density is 1.1～1.4;
D) add an amount of adjuvant, make medicament.
Adjuvant can be dextrin, Aspartane.
Medicine of the present invention has the effect of suppressing the hyperactive liver and subsiding YANG, relieving spasm by subduing liver-wind.Be used for the treatment of because of excessive rising of liver-YANG, parkinson disease that liver-wind stirring up internally causes and parkinsonism, disease is seen limbs chatter, stiff, dumb, slow in one's movements, constipation, stiff, the moving difficulty of facial expression, dizzy, headache, irritated irritability, numb limbs and tense tendons, insomnia, dreaminess, cardiopalmus, red tongue, diseases such as stringy pulse.
Description of drawings
Fig. 1 is that the HPLC standard substance detect collection of illustrative plates.
Fig. 2 is a HPLC striatum sample detection collection of illustrative plates.
Fig. 3 causes parkinson disease original mold type rat substantia nigra place tyrosine hydroxylase immunohistochemical staining collection of illustrative plates.
Fig. 4 is the technology path figure of medicine of the present invention to the pharmacological action of unilateral nigra striatum path damage rat model.
Fig. 5 is the pharmacological action sketch map of drug particles of the present invention to medicine muscular tremor model mice.
Fig. 6 is drug particles of the present invention causes PD original mold type mice to MPTP a pharmacological action sketch map.
The specific embodiment
Below routine by experiment beneficial effect of further setting forth medicine of the present invention, these experimental examples are the pharmacodynamics test of medicine of the present invention:
[experimental example I] medicine of the present invention is to the pharmacological action of unilateral nigra striatum path damage rat model
This experimental example is investigated medicine of the present invention, and damage causes the influence of DOPAMINE CONTENT IN RABBIT and black substance place neuronal quantity in parkinson disease original mold type motor function in rats, rat layer lipid peroxide level, the striatum to unilateral nigra striatum path.
Experiment material:
1, animal: the SD rat, male, body weight 200 ± 20g
2, reagent and instrument
Reagent: 6-OHDA (6-hydroxydapamine, 6-OHDA), perfluoroetane sulfonic acid sodium salt (octylsulfate sodium salt, OSA), dopamine (Dopamine, DA), dihydroxyphenyl acetic acid (dihydroxyphenylacetic acid, DOPAC), dihydroxy benzenes methylamine (3,4-dihydroxybenzylamine, DHBA), 4-hydroxy-3-methoxy-.alpha.-toluic acid. (homovanillic acid, HVA), thiobarbituricacid (Thiobarbituric acid, TBA), ethylenediaminetetraacetic acid (ethylenediaminetetra-acetic acid, EDTA), perchloric acid, methanol, phenol, the Tyrosine hydroxylase antibodies.
Instrument: SN-2N type animal brain stereotaxic instrument, 8453 type ultraviolet-uisible spectrophotometers, high performance liquid chromatograph, 460 electrochemical detectors, carbon 18 reversed phase chromatographic column, T21 type High speed refrigerated centrifuge, Image-pro plus image acquisition and analytical system.
Experimental technique:
1, the foundation of the directed damage of striatum 6-OHDA rat model:
Set up the P of Rats D model of the directed damage of 6-OHDA striatum with reference to the method for Yukio lchitani etc.: 6-OHDA is dissolved in 0.9% normal saline and (contains 0.1% ascorbic acid).Rat is with 10% chloral hydrate anesthesia, the brain solid positioner location, flat cranium head position, the right side is strong side, 4 injections are carried out in the left side, 4 are respectively: (AP) 0.5-1.0mm before the bregma, other (ML) 3.0mm that opens of center line, from the skull surface degree of depth (DV) 5.5mm and 4.5mm each a bit, and flat bregma, other (ML) 3.0mm that opens of center line, from the skull surface degree of depth (DV) 5.5mm and 4.5mm each a bit, every some injection 6-OHDA 2 μ l (3 μ g/ μ l).Matched group (sham-operation) injection equivalent normal saline.
2, the screening of the detection of rat circling behavior and model mouse:
Experimental technique with reference to Gao Wen etc.: 2 weeks of postoperative rise each group laboratory animal lumbar injection apomorphine hydrochloride (0.25mg/kg), and observe its behavioristics and change, after 3 minutes, opening entry rat number of revolutions, METHOD FOR CONTINUOUS DETERMINATION 40 minutes.
At modeling 4 all laggard row filters: traditional parkinson disease sample rat model preparation method is the orientation damage of the 6-OHDA of black substance place, select rotating cycle＞6 circles/minute rat as qualified rat model, but the content of dopamine (DA) seriously descends in the rat brain at this moment, reduce more than 95% more, for ease of observing the drug effect effect, we have selected the moderate damage modeling mode of the directed damage in 6-OHDA striatum place, select constant to being good for sideway swivel and rotating cycle＞rat of/40 minutes of 40 circles as qualified model mouse, select arbitrary time sham-operation rat Mus in contrast that does not all produce circling behavior of measuring, all the other are then eliminated.
When 2 weeks of medication and 6 weeks, measure the inductive circling behavior of respectively organizing rat of apomorphine respectively, minute 40 minutes.Calculate rotating cycle rate of descent after every rat medication.Computational methods: rotating cycle * 100% before rate of descent=(rotating cycle after the preceding rotating cycle-medication of medication)/medication.
3, grouping and administration:
Will be through screening qualified rat random packet.Sham operated rats: distilled water (10ml/kg) continuous irrigation 7 weeks of stomach; Model group: distilled water (10ml/kg) continuous irrigation 7 weeks of stomach; Drug component of the present invention does not give granule 1g/kg, 2g/kg, 7 weeks of 4g/kg continuous irrigation stomach; Madopar group (positive control drug group): give madopar 50mg/kg/ day (twice on the one) to gavage for 7 weeks continuously.
4, cerebral tissue lipid peroxidation product malonaldehyde (MDA) is measured:
Cerebral tissue is weighed, and adds 0.2M pH7.4 phosphate buffer with 1: 8 ratio and carries out homogenate, and the centrifugal 10min of 3000rpm gets supernatant 0.5ml.Add 1/24mol/L H
2SO
44ml, 10% phosphotungstic acid 0.5ml stir, and room temperature was placed 5 minutes, and centrifugal 10 minutes of 3000rpm abandons supernatant, controls 1min.Add 1/24mol/LH
2SO
42ml, 10% phosphotungstic acid 0.3ml stir, and room temperature was placed 5 minutes, and centrifugal 10 minutes of 3000rpm abandons supernatant, controls 1 minute.According to the form below adds reagent.
| Measure pipe | Standard pipe | Blank pipe | |
| Homogenate precipitate tetraethoxypropane (5nmol/ml) normal saline (ml) 0.05mol/L HCl (ml) TBA solution 6.7mg/ml (ml) | Have-0.5 11 | - 0.5 - 1 1 | - - 0.5 1 1 |
| The mixing of jumping a queue is put boiling water bath 1h postcooling, and the centrifugal 5min of 2000rpm gets supernatant, and 532nm surveys the OD value | |||
Calculate concentration of malondialdehyde: concentration of malondialdehyde=f/F * 5nmol/ml (F: standard solution OD, f: sample (OD)
5, high performance liquid chromatography is to the mensuration of cerebral tissue monoamine neurotransmitter and metabolite thereof:
The standard substance preparation: each standard substance all is dissolved in the mobile phase, and concentration is 0.1mg/ml, is diluted to 10ng/ml during use respectively, sample size 10 μ l.
Chromatographic condition: Waters company carbon eighteen incompatible medicaments phase chromatographic column, eluent: 80mM sodium hydrogen phosphate, 60mM citric acid, 0.22mM disodiumedetate, 0.5mM octyl sulfate sodium salt, 20% methanol.Transferring pH is 4.3, and flow 1.0ml/min is used in degassing back after filtration.Electrochemical detector running voltage 0.7v measures 37 ℃ of temperature.Standard substance have good linear relationship between concentration and peak area, r
2＞0.99.
Sample pretreatment: the method with reference to people such as Zhang Linkui is carried out The pretreatment: (every 100ml contains L-cysteine 5mg to add 0.1M perchloric acid according to the ratio of 1: 10 (w/v) in striatum, interior mark DHBA concentration is 200ng/ml) preparation homogenate, putting High speed refrigerated centrifuge 12000 changes, temperature be 4 ℃ centrifugal 20 minutes.Get the content of supernatant 10 μ l mensuration dopamine wherein with its metabolite.
6, the immunohistochemical staining of substantia nigra place Tyrosine hydroxylase
Perfusion is fixing, draws materials: with 10% chloral hydrate intraperitoneal injection of anesthesia animal, animal is fixed on the platform, open breast, cut off left ventricle, insert the perfusion syringe needle to aortic root by the apex of the heart, and cut off the right auricle, pour into warm saline fast, depletion of blood in ventricle, liver bleaches, the perfusion fixative of reuse pre-cooling pours into fixing, and is stiff until the animal whole body, again after flood irrigation 10-20 minute, take out cerebral tissue and put into the back fixative, treat to use after tissue sinks.
Immunohistochemical staining: cerebral tissue is taken out from the fixative of back, wash with tap water, repair piece, place isopentane, put into liquid nitrogen quick-freezing 10-15 paper money, tissue is cut to the thick tissue slice of 40 μ m through coronal section, tissue is put into PBS liquid wash, 5 minutes/time * 3 times, tissue 3%H
2O
2Incubated at room 10 minutes, to remove endogenous peroxidase activity, PBS washing liquid thorough washing, 5 minutes/time * 3 times, use sheep blood serum incubated at room 30 minutes with the 5-10% sealing, with the minimizing non-specific adsorption, the sucking-off sheep blood serum, (the TH incubated at room changes 4 ℃ over to and hatched 48 hours after 2 hours to add the Tyrosine hydroxylase antibodies that dilutes at 1: 5000.PBS washing liquid thorough washing, 5 minutes/time * 3 times, adding biotin labeled Mus two, anti-(dilution factor is 1: 300, insulation is 30 minutes in 37 ℃ of water baths, PBS washing liquid thorough washing, 5 minutes/time * 3 times, add three anti-(dilution factor is 1: 200) of horseradish peroxidase-labeled, insulation is 60 minutes in 37 ℃ of water baths, PBS washing liquid thorough washing, 5 minutes/time * 3 times, the DAB colour developing, mirror is the control dye levels down, the gradient ethanol dehydration, dimethylbenzene is transparent, the neutral gum mounting.Setting up of negative control: replace one anti-ly to carry out immunohistochemical staining with the normal rabbit serum of washing liquid and non-immunity respectively, all the other steps are the same.Positive reaction is assembled for the histiocyte structure is brown yellow granule.
Immunohistochemical staining result's image analysis: 3 rats underwent SABC sections of every group of picked at random, place 10 * 10 microscopicallies to observe each animal black substance positive cell section, with Image-pro plus software collection image and analysis, record positive cell number, area and average gray.
Experimental result:
1. medicine of the present invention is to the influence of rat model circling behavior
For one-sided nigrostriatum path damage model, the black substance of homonymy-striatum path destroys, intrastriatal neuron loses the domination of dopaminergic nerve, its dopamine receptor is in a kind of super quick state, after giving ectogenic dopamine-receptor stimulant such as apomorphine, the reaction of animal injury side can't keep balance with regard to being better than strong side, and to strong sideway swivel, and the frequency of rotation is roughly consistent with the extent of damage of dopaminergic neuron in the black substance.2 week and 6 weeks before this research administration, after the administration, respectively rat has been carried out circling behavior mensuration, for eliminating of the influence of animal individual difference to experimental result, we carry out after the administration calculating of self number of revolutions rate of descent respectively to every rat, model group and other are respectively organized rate of descent (%) do the t check.Experiment is found: the model group rat obviously increases than the matched group rotating cycle, and each dosage group of medicine of the present invention all obviously reduces the rat number of revolutions, and medicine 1g/kg wherein of the present invention compares difference tool significance (table 1) with 2g/kg dosage group with model group.
Table 1. medicine of the present invention is to the influence of 6-OHDA rat circling behavior
| Group | Number of elements | Before the medication | 2 weeks of medication | 6 weeks of medication | ||
| Circle/40min | Circle/40min | Rate of descent % | Circle/40min | 6 all rate of descent % | ||
| Sham operated rats model group madopar medicine 1g/kg of the present invention medicine 2g/kg of the present invention medicine 4g/kg of the present invention | 10 10 10 10 10 9 | 0.0±0.0 96.2±88.1 136.9±92.0 105.5±97.9 122.3±71.6 138.1±68.6 | 0.0±0.0 90.4±102.5 111.7±94.0 68.8±102.6 79.8±49.2 101.0±70.5 | / 25.2±36.9 29.1±24.9 49.0±40.5 37.2±38.1 33.4±29.4 | 0.0±0.0 87.5±132.6 67.8±82.8 54.4±87.5 54.8±42.1 80.1±74.8 | / 27.6±30.3 67.5±30.9 ** 56.9±42.2 * 54.9±26.2 50.3±30.5 |
Rate of descent (%) is done the t check, compare with model group
*P＜0.05,
*P＜0.01
2) drug particles of the present invention is to the influence of rat model cortex lipid peroxide
After 7 weeks of administration,, get cortex and measure lipid peroxidation metabolite malonaldehyde (MDA) content the rat sacrificed by decapitation.The result shows: the model group rat is compared with the normal control group, and the content of cortex MDA obviously raises, and drug particles medication group of the present invention then can significantly reduce the level (table 2) of MDA.
The influence of table 2 medicine of the present invention to 6-OHDA rat brain cortex MDA
| Group | N | MDA (nmol/mg albumen) |
| Sham operated rats model group medicine 1g/kg of the present invention medicine 4g/kg of the present invention | 18 12 10 10 | 68.9±13.4 * 77.5±11.5 77.7±6.7 69.4±8.5 * |
Compare with model group,
*P＜0.05
3) drug particles of the present invention is to the influence of rat model brain striatum dopamine neurotransmitter and metabolite content thereof:
After 7 weeks of rat administration, sacrificed by decapitation is got brain striatum, measures the content of monoamine neurotransmitter and metabolite thereof with high performance liquid chromatograph.Detect in the index at this, the computational methods that we adopt are as follows: neurotransmitter content reduction rate=(strong nervus lateralis mediator content-damage side content)/strong nervus lateralis mediator content * 100%.Found that: dopamine (DA), DOPA acid (DOPAC) and 4-hydroxy-3-methoxy-.alpha.-toluic acid. (HVA) content reduction rate increase the weight of than matched group is obvious in the model group rat damage side striatum.After using drug particles of the present invention, can obviously dwindle damage side and the difference (seeing also Fig. 1, Fig. 2, table 3) of not damaging nervus lateralis mediator content
Table 3 drug particles of the present invention is to the influence of dopamine and metabolite content reduction rate thereof in the 6-OHDA rat model striatum
| Group | N | DA reduction rate (%) | DOPAC reduction rate (%) | HVA reduction rate (%) |
| Sham operated rats model group madopar 50mg/kg medicine 1g/kg of the present invention medicine 2g/kg of the present invention medicine 4g/kg of the present invention | 6 7 8 6 9 6 | 42.7±27.8 ** 83.1±8.1 68.0±17.5 69.6±13.2 * 74.1±8.3 * 72.7±20.6 | 22.4±27.6 ** 77.0±5.9 61.3±13.9 ** 62.7±12.6 * 69.9±8.4 * 61.0±16.9 * | 21.4±20.1 ** 68.7±13.9 59.2±14.5 56.0±3.7 * 65.6±6.5 67.9±16.9 |
Neurotransmitter content reduction rate=(strong nervus lateralis mediator content-damage side content)/strong nervus lateralis mediator content * 100% is compared with model group
*P＜0.05,
*P＜0.01
4) drug particles of the present invention is to the influence of rat model black substance place Tyrosine hydroxylase stained positive cell:
In this index, we carry out self contrast with the cell number of every treated animal left and right sides black substance place's Tyrosine hydroxylase (TH) stained positive, calculate the rate of descent of damage side TH positive cell number and cell area, the rate of descent of finding the model group rat damage side black substance TH of place positive cell is used the TH positive cell rate rebound significantly (table 4) that drug particles of the present invention can make reduction apparently higher than the normal control group
Table 4, drug particles of the present invention is to the influence of 6-OHDA rat model black substance place Tyrosine hydroxylase stained positive cell
| Group | N | Positive cell number rate of descent % | Positive cell area rate of descent % |
| Sham-operation model group madopar 50mg/kg medicine 1g/kg of the present invention medicine 2g/kg of the present invention medicine 4g/kg of the present invention | 3 3 3 3 3 3 | 32.32±15.61 ** 87.32±4.21 62.37±19.93 ** 36.15±12.00 ** 37.54±6.62 ** 64.10±11.99 ** | 26.35±15.32 ** 80.83±8.92 58.90±22.20 ** 35.04±13.03 ** 38.28±5.16 ** 68.95±14.44 ** |
Positive cell number rate of descent=(strong side-damage side TH positive cell number)/strong side TH positive cell number * 100%
Positive cell area rate of descent=(strong side-damage side TH positive cell area)/strong side TH positive cell area * 100%
Compare with model group,
*P＜0.05,
*P＜0.01
Experiment shows; drug particles of the present invention can reduce the infringement of neurotoxic substance 6-OHDA (6-OHDA) to dopaminergic neuron in the black substance; it is had good protective action, obviously promote the content of interior dopamine of animal damage striatum and metabolite thereof.
[experimental example 2] drug particles of the present invention is to the pharmacological action of medicine muscular tremor model mice
This experimental example has been selected two kinds of medicine muscular tremor models for use: arecoline trembles and the oxygenate tremorine trembles.
Record animal incubation period of occurring trembling and trembling the lasting time is to observe drug particles of the present invention to the tremble influence of behavior of medicine.
Experiment material
1, animal: the ICR mice, male, cleaning level, body weight 18 ± 2g.
2, reagent: 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. (Oxotremorin), arecoline (Arecoline).
Experimental technique:
1, animal grouping and administration situation
The mice random packet, normal control group mice gives distilled water continuous irrigation stomach (0.3ml/ is only) 3 weeks in that to give 0.9% normal saline single intraperitoneal injection (0.3ml/ only) preceding; The model group mice gives arecoline (25mg/kg) or the preceding distilled water continuous irrigation stomach of 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. (0.15mg/kg) single intraperitoneal injection (0.3ml/ only) 3 weeks; Behind the medicine preliminary experiment, we to medicine group granule medication group mice of the present invention modeling before 3 weeks of continuous irrigation stomach, drug particles dosage of the present invention is respectively 1g/kg, 2g/kg, 4g/kg; Madopar group (positive control drug group) mice preceding 1 day in modeling, madopar 65mg/kg irritates stomach.
2, arecoline muscular tremor mice behavior evaluation: adopt the ICR mice that grows up, arecoline 25mg/kg lumbar injection, write down every mice from giving behind the arecoline to producing the obvious visible muscular tremor required time of naked eyes for trembling incubation period, after the generation of trembling to the required time that disappears for trembling the persistent period.
3, the 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. mice behavior evaluation that trembles: adopt the ICR mice that grows up, 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. 0.15mg/kg lumbar injection, write down every mice from giving after the 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. to producing the obvious visible muscular tremor required time of naked eyes for trembling incubation period, after the generation of trembling to the required time that disappears for trembling the persistent period.
Experimental result:
1, drug particles of the present invention causes the tremble influence of behavior of mice to arecoline:
The result shows: the model group mice occurs significantly trembling, behaviors such as sialorrhea, restlessness after giving the arecoline lumbar injection, and its lasting time of trembling is apparently higher than matched group.Drug particles administration group mice of the present invention is trembled, symptom such as sialorrhea, restlessness alleviates than model group behind the lumbar injection arecoline, and the persistent period of trembling significantly shortens (table 5) than model group.
Table 5 drug particles of the present invention causes the tremble influence of time of mice to arecoline
| Group | N | Persistent period (second) |
| Matched group model group madopar (65mg/kg) drug particles 1g/kg of the present invention drug particles 2g/kg of the present invention drug particles 4g/kg of the present invention | 15 15 15 15 15 15 | 0.0±0.0 ** 430.5±55.1 397.3±39.3 * 395.8±46.9 * 370.6±37.9 ** 406.8±46.9 |
Compare with model group,
*P＜0.05,
*P＜0.01
2, drug particles of the present invention causes the tremble influence of behavior of mice to 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne.:
The result shows: the model group mice behavior of significantly trembling occurs after giving the 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. lumbar injection, its lasting time of trembling is apparently higher than matched group.Drug particles administration group mice of the present invention is trembled, symptom such as sialorrhea, restlessness alleviates than model group after the lumbar injection 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne., and the persistent period of trembling significantly shortens (table 6) than model group.
Table 6 drug particles of the present invention causes the tremble influence of time of mice to 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne.
| Group | N | Persistent period (second) |
| Matched group model group madopar (65mg/kg) drug particles 1g/kg of the present invention drug particles 2g/kg of the present invention drug particles 4g/kg of the present invention | 15 15 15 15 15 15 | 0.0±0.0 ** 38.9±7.6 32.1±4.1 ** 39.5±3.9 * 34.4±5.9 * 32.8±6.4 * |
Compare with model group,
*P＜0.05,
*P＜0.01
Parkinson patient's clinical manifestation the most intuitively be muscular tremor, stiff and the motion can not.Arecoline and 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne. are the m receptor agonist, can cause the violent contraction of muscle, can simulate the performance of trembling of this disease, so this model also is an a kind of necessary animal model of estimating the sick drug effect of anti-handkerchief gold.Medicine of the present invention can significantly shorten animal and tremble the persistent period.
[experimental example 3] drug particles of the present invention causes the pharmacological action of PD original mold type mice to MPTP
Experiment material:
1, animal: C57BL mouse, female, hero half and half, cleaning level, body weight 18 ± 2g.
2, reagent and instrument: 1-methyl-4-phenyl-1,2,3, the 6-tetrahydropyridine (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP).
Instrument: CS-2 type mice autonomic activities program instrument.
Experimental technique:
1, MPTP causes the foundation of parkinsonian mouse model: MPTP and directly is dissolved in 0.9% physiological saline solution, and regulating its final concentration is 2mg/ml.The continuous lumbar injection MPTP20mg/kg of model group animal, modeling is 8 days altogether.
2, grouping and administration: C57BL mouse random packet.The normal control group: distilled water is irritated stomach after 3 weeks, the isodose normal saline of lumbar injection and model group 8 days.Model group: distilled water is irritated stomach after 3 weeks, the continuous lumbar injection of MPTP20mg/kg, and modeling is 8 days altogether.Drug particles medication group of the present invention is giving drug particles of the present invention after 3 weeks, lumbar injection MPTP20mg/kg, and modeling is 8 days altogether.Drug particles of the present invention is after giving for 3 weeks, and lumbar injection MPTP20mg/kg is total to modeling 8 days.The dosage of drug particles of the present invention is respectively 1g/kg, 2g/kg, 4g/kg; Madopar group (positive control drug group) began to give madopar 65mg/kg the same day for modeling.
3, mice pole-climbing experiment:
With reference to Nobutaka Arai; The experimental technique of Kazuaki Misugi is revised slightly, concrete assay method is as follows: the experiment apparatus is long 0.5 meter of self-control stainless steel, diameter 1cm (twining with adhesive plaster on it) top is the wooden ball of a diameter 2.5cm, animal gives MPTP the previous day, carry out the pole-climbing training earlier, climb at the bottom of the bar every training 4 times in the guiding animal 10 seconds by masthead.During formal mensuration, at first measure the pole-climbing time of using the preceding mice of MPTP, after giving MPTP, in 1-2 hour, animal is carried out the mensuration of pole-climbing time for the second time.Concrete assay method is as follows: hold mouse tail, its head is placed masthead portion (place ball on be as the criterion with mouse hind leg) downwards, allow it climb down naturally, the record mice is the platform required time at the bottom of standing in masthead to two forelimb contact levers.Measure 120 seconds time limits, Mus can not be held bar, complete natural downslide person, and writing down its pole-climbing time is 120 seconds.Calculating is respectively organized mice and is given MPTP the difference (the pole-climbing time is shorter than when being untreated after giving MPTP, and its data record is 0) of front and back pole-climbing time.The METHOD FOR CONTINUOUS DETERMINATION modeling is respectively organized mice and is handled front and back pole-climbing time difference in 8 days.
4, the spontaneous activity in mice numeration is measured:
With reference to method of reporting such as Li Bin, use the CS-2 type mice autonomic activities program instrument of developing behind Chinese Academy of Medical Sciences's drug research and measure the spontaneous activity in mice number of times, after computer enters the mensuration program, mice is put into active box (height: 13cm, diameter: 25cm), at every turn measure 4 mices simultaneously, in each active box one, automatically write down the mice active situation by computer, measure the movable number of times in every Mus 5 minutes, carry out statistical procedures.
5, high performance liquid chromatography is to the mensuration of cerebral tissue monoamine neurotransmitter and metabolite thereof:
The standard substance preparation: each standard substance all is dissolved in the mobile phase, and concentration is 0.1mg/ml, during use, is diluted to 10ng/ml respectively, sample size 10 μ l.
Chromatographic condition: Waters company carbon eighteen incompatible medicaments phase chromatographic column, eluent: 80mM sodium hydrogen phosphate, 60mM citric acid, 0.22mM disodiumedetate, 0.5mM octyl sulfate sodium salt, 20% methanol.Transferring pH is 4.3, and flow 1.0ml/min is used in degassing back after filtration.Electrochemical Detection running voltage 0.7v measures 37 ℃ of temperature.Standard substance have good linear relationship between concentration and peak area, r
2＞0.99.
Sample pretreatment: the method with reference to people such as Zhang Linkui is carried out The pretreatment: (every 100ml contains L-cysteine 5mg to add 0.1M perchloric acid according to the ratio of 1: 20 (w/v) in striatum, in mark DHBA concentration be 200ng/ml) preparation homogenate, put High speed refrigerated centrifuge 12000 change 4 ℃ centrifugal 20 minutes.Get supernatant 10 μ l measure wherein dopamine and the content of metabolite.
Experimental result:
1, drug particles of the present invention is to the influence of mice pole-climbing time
The pole-climbing time has been reflected the coordination exercise ability of animal.Well then animal pole-climbing time required time is short for harmony, inaccurate coordination, and then the pole-climbing time is long.Found that: the model group mice pole-climbing time is compared significant prolongation with the normal control group, and the drug particles medication group mice pole-climbing time of the present invention obviously shortens (table 7).
Table 7 drug particles of the present invention is to the influence of mice pole-climbing time
| Group | N | Time (second) before time-modeling after the modeling |
| Matched group model group madopar (65mg/kg) drug particles 1g/kg of the present invention drug particles 2g/kg of the present invention drug particles 4g/kg of the present invention | 14 15 15 13 15 14 | 0.32±0.69 ** 9.19±5.09 7.09±3.20 * 5.67±3.18 ** 6.70±3.68 * 5.45±2.64 * |
Compare with model group,
*P＜0.05,
*P＜0.01
2, drug particles of the present invention is to the influence of mice autonomic activities
The autonomic activities number has reflected the voluntary movement ability of animal.The model group mice is compared with the normal control group, and autonomic activities obviously reduces.Drug particles medication group mice autonomic activities of the present invention significantly increases (table 8) than model group.
Table 8 drug particles of the present invention is to the influence of mice autonomic activities
| Group | N | Time (second) before time-modeling after the modeling |
| Contrast model madopar (65mg/kg) drug particles 1g/kg of the present invention drug particles 2g/kg of the present invention drug particles 4g/kg of the present invention | 14 15 15 13 15 14 | 38.6±33.0 ** 12.2±9.2 70.0±34.7 ** 18.7±8.4 * 18.9±11.9 * 20.7±13.2 * |
Compare with model group,
*P＜0.05,
*P＜0.01
3, drug particles of the present invention is to the influence of dopamine and metabolite content thereof in the MPTP model mice brain striatum:
After the mice modeling 14 days, sacrificed by decapitation was got the content of brain striatum with HPLC electrochemical detector determining monoamine neurotransmitter and metabolite thereof.The result shows: the content of dopamine (DA), DOPA acid (DOPAC) and 4-hydroxy-3-methoxy-.alpha.-toluic acid. (HVA) all obviously reduces than matched group in the model group mouse brain striatum, difference tool significance.Each dosage drug particles of the present invention can both be in various degree raising animal pattern brain striatum in the content (table 9) of dopamine.
Table 9. drug particles of the present invention is to the influence (the ng/mg striatum is heavy) of MPTP model mice striatum dopamine and metabolite content thereof
| Group | N | DA | DOPAC | HVA |
| Contrast model madopar (65mg/kg) drug particles 1g/kg of the present invention drug particles 2g/kg of the present invention drug particles 4g/kg of the present invention | 10 10 10 10 10 10 | 7.02±2.54 ** 2.08±1.24 3.54±1.91 * 2.82±1.12 3.60±1.83 * 4.43±2.32 ** | 6.17±1.99 ** 2.76±2.24 4.11±2.43 4.55±1.88 * 5.37±1.78 ** 3.74±1.18 | 2.91±0.57 ** 2.07±0.66 3.17±1.60 * 2.50±0.82 2.76±0.90 * 2.30±0.53 |
Compare with model group,
*P＜0.05,
*P＜0.01
Conclusion:
1, damage causes parkinson disease (PD) rat model for unilateral nigra striatum path, drug particles of the present invention improves significantly to the unusual circling behavior of model mouse, it can also suppress increasing of model mouse cerebral cortex lipid peroxidation product, increase black substance place Tyrosine hydroxylase stained positive neuron number, promote the content of interior dopamine of rat brain striatum and metabolite thereof.
2, for the muscular tremor mouse model due to arecoline and the 1-(2-oxo-1-pyrrolidinyl)-4-(1-pyrrolidinyl)-2-butyne., drug particles of the present invention can obviously reduce the persistent period of trembling.
3, for MPTP lumbar injection PD mouse model, drug particles of the present invention can obviously strengthen mouse movement harmony, shortens its pole-climbing time, strengthens mice autonomic activities ability, promotes the content of interior dopamine of mouse brain striatum and metabolite thereof.
The granule preparation of [embodiment 1] medicine of the present invention
Medicine of the present invention is made by following materials of weight proportions medicine: the Radix Paeoniae Alba 11.97, Ramulus Uncariae Cum Uncis 11.97, Rhizoma Gastrodiae 7.17, Fructus Tribuli 12.13, Concha Haliotidis 11.97, Radix Polygoni Multiflori Preparata 8.62, Concha Margaritifera 11.97, Concha Ostreae 11.97, Radix Salviae Miltiorrhizae 8.62, Radix Glycyrrhizae Preparata 3.61.
It comprises the following steps:
A) Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae are added 4 times and measure 70% ethanol, reflux, extract, 3 times each 1.5 hours, merges ethanol extract, filtration;
B) decompression filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.12, temperature be 60 ℃ standby;
C) medicinal residues and the Radix Paeoniae Alba, Rhizoma Gastrodiae, Fructus Tribuli, Concha Haliotidis, Concha Margaritifera, Concha Ostreae, Radix Glycyrrhizae Preparata add the water of 8 times of amounts, decoct each 1.5 hours 2 times, decocting liquid filters, merge twice filtrate and alcohol extraction concentrated solution, being concentrated into relative density is 1.15～1.17, and temperature is 60 ℃;
D) add an amount of dextrin and Aspartane 3g, make the granule of medicine of the present invention after the spray drying, through sieve, granulate, packing.
The capsule preparation of [embodiment 2] medicine of the present invention
Medicine of the present invention is made by following materials of weight proportions medicine: the Radix Paeoniae Alba 11.97, Ramulus Uncariae Cum Uncis 11.97, Rhizoma Gastrodiae 7.17, Fructus Tribuli 12.13, Concha Haliotidis 11.97, Radix Polygoni Multiflori Preparata 8.62, Concha Margaritifera 11.97, Concha Ostreae 11.97, Radix Salviae Miltiorrhizae 8.62, Radix Glycyrrhizae Preparata 3.61.
It comprises the following steps:
A) Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae are added 4 times and measure 70% ethanol, reflux, extract, 3 times each 1.5 hours, merges ethanol extract, filtration;
B) decompression filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.12, temperature be 60 ℃ standby;
C) medicinal residues and the Radix Paeoniae Alba, Rhizoma Gastrodiae, Fructus Tribuli, Concha Haliotidis, Concha Margaritifera, Concha Ostreae, Radix Glycyrrhizae Preparata add the water of 8 times of amounts, decoct each 1.5 hours 2 times, decocting liquid filters, merge twice filtrate and alcohol extraction concentrated solution, being concentrated into relative density is 1.15～1.17, and temperature is 60 ℃;
D) add an amount of adjuvant, granulate, drying is divided the snap fit capsule of packing into, promptly obtains the capsule of medicine of the present invention.
The preparation tablets of [embodiment 3] medicine of the present invention
This Parkinsonian medicine of curing the disease is made by following materials of weight proportions medicine: the Radix Paeoniae Alba 11.97, Ramulus Uncariae Cum Uncis 11.97, Rhizoma Gastrodiae 7.17, Fructus Tribuli 12.13, Concha Haliotidis 11.97, Radix Polygoni Multiflori Preparata 8.62, Concha Margaritifera 11.97, Concha Ostreae 11.97, Radix Salviae Miltiorrhizae 8.62, Radix Glycyrrhizae Preparata 3.61.
It comprises the following steps:
A) Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae are added 4 times and measure 70% ethanol, reflux, extract, 3 times each 1.5 hours, merges ethanol extract, filtration;
B) decompression filtrate recycling ethanol and to be concentrated into relative density be 1.10～1.12, temperature be 60 ℃ standby;
C) medicinal residues and the Radix Paeoniae Alba, Rhizoma Gastrodiae, Fructus Tribuli, Concha Haliotidis, Concha Margaritifera, Concha Ostreae, Radix Glycyrrhizae Preparata add the water of 8 times of amounts, decoct each 1.5 hours 2 times, decocting liquid filters, merge twice filtrate and alcohol extraction concentrated solution, being concentrated into relative density is 1.15～1.17, and temperature is 60 ℃;
D) add an amount of adjuvant, granulate, drying, compacting in flakes, packing promptly obtains the tablet of medicine of the present invention.
The above only is the preferred embodiment of patent of the present invention, and all equalizations of being done according to patent claimed range of the present invention change and modify, and all should belong to the covering scope of Patent right requirement of the present invention.
Claims (5)
1. a medicine for the treatment of parkinson disease and parkinsonism is characterized in that the crude drug of making active ingredient consists of
The Radix Paeoniae Alba 73.73～2.99 Ramulus Uncariae Cum Uncis 73.73～2.99 Rhizoma Gastrodiaes 44.16～1.79
Fructus Tribuli 74.72～3.03 Concha Haliotidis 73.73～2.99 Radix Polygoni Multiflori Preparatas 53.09～2.15
Concha Margaritifera 73.73～2.99 Concha Ostreaes 73.73～2.99 Radix Salviae Miltiorrhizaes 53.09～2.15
Radix Glycyrrhizae Preparata 22.23～0.90.
2. the medicine of treatment parkinson disease according to claim 1 and parkinsonism, wherein the weight proportion of each raw material is
The Radix Paeoniae Alba 47.88～2.99 Ramulus Uncariae Cum Uncis 47.88～2.99 Rhizoma Gastrodiaes 28.68～1.79
Fructus Tribuli 48.52～3.03 Concha Haliotidis 47.88～2.99 Radix Polygoni Multiflori Preparatas 34.48～2.15
Concha Margaritifera 47.88～2.99 Concha Ostreaes 47.88～2.99 Radix Salviae Miltiorrhizaes 34.48～2.15
Radix Glycyrrhizae Preparata 14.44～0.90.
3. the medicine of treatment parkinson disease according to claim 1 and parkinsonism, wherein the weight proportion of each raw material is
The Radix Paeoniae Alba 11.97 Ramulus Uncariae Cum Uncis 11.97 Rhizoma Gastrodiaes 7.17
Fructus Tribuli 12.13 Concha Haliotidis 11.97 Radix Polygoni Multiflori Preparatas 8.62
Concha Margaritifera 11.97 Concha Ostreaes 11.97 Radix Salviae Miltiorrhizaes 8.62
Radix Glycyrrhizae Preparata 3.61.
4. the preparation method of treatment parkinson disease according to claim 1 and parkinsonism medicine is characterized in that it comprises the following steps:
A) Ramulus Uncariae Cum Uncis, Rhizoma Gastrodiae, Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae are added 10～90% ethanol, reflux, extract, repeatedly each 0.5～3.0 hour, merges ethanol extract, filtration;
B) filtrate recycling ethanol and be concentrated into relative density and be 1.0～1.3, standby;
C) medicinal residues and the Radix Paeoniae Alba, Fructus Tribuli, Concha Haliotidis, Concha Margaritifera, Concha Ostreae, Radix Glycyrrhizae Preparata decoct with water repeatedly, and each 0.5～3.0 hour, decocting liquid filtered, merging filtrate and alcohol extraction concentrated solution, and being concentrated into relative density is 1.1～1.4;
D) add an amount of adjuvant, make medicament.
5. the preparation method of treatment parkinson disease according to claim 4 and parkinsonism medicine is characterized in that: adjuvant is dextrin, Aspartane.
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| 中医药治疗帕金森病进展 谭文澜，山西中医，第20卷第5期 2004 * |
| 舒乐脑心通胶囊治疗高血压106例 佘考东，中医研究中医研究，第15卷第4期 2002 * |
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