CN102018837B - Prescription for treating migraine and preparation method thereof - Google Patents

Prescription for treating migraine and preparation method thereof Download PDF

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CN102018837B
CN102018837B CN2010106063839A CN201010606383A CN102018837B CN 102018837 B CN102018837 B CN 102018837B CN 2010106063839 A CN2010106063839 A CN 2010106063839A CN 201010606383 A CN201010606383 A CN 201010606383A CN 102018837 B CN102018837 B CN 102018837B
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volatile oil
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CN102018837A (en
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田景奎
张琳
荣语媚
陈润泽
应弘梅
戚中杰
徐燕
刘小保
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Zhejiang University ZJU
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Abstract

The invention discloses a traditional Chinese medicine compound preparation for treating migraine and a preparation method thereof. The traditional Chinese medicine compound preparation comprises the following pharmaceutical raw materials: 1-20 parts of Szechuan lovage rhizome, 1-20 parts of dahurian angelica root, 1-20 parts of peppermint, 1-20 parts of oriental waterplantain rhizome, 1-20 parts of fineleaf schizonepeta herb and 1-20 parts of largehead atractylodes rhizome, and the part ratio is weight ratio. Ethanol is adopted for extracting active ingredients of the Szechuan lovage rhizome and the dahurian angelica root; and the steam distillation method is adopted for extracting volatile oil of the peppermint, the oriental waterplantain rhizome, the fineleaf schizonepeta herb and the largehead atractylodes rhizome, and water is further adopted for extracting other active ingredients. Extract solution of the six medicines are concentrated and dried; and the volatile oil is included via beta-cyclodextrin and uniformly mixed with extracts after drying, excipients are added, and a preparation is finally prepared. The medicine has good analgesic effect and can also be antagonistic to shrinkage role of PE (polyethylene) and 5-HT (5-hydroxytryptamine) to blood vessels, improve the diameter of capillary blood vessels, improve the microcirculation and effectively improve the cerebral blood flow of rats, thereby being an effective prescription for treating the migraine and Meniere's syndrome.

Description

Migrainous compound Chinese medicinal preparation of a kind of treatment and preparation method thereof
Technical field
The present invention relates to field of medicaments, relate in particular to migrainous compound Chinese medicinal preparation of a kind of treatment and preparation method thereof.
Background technology
Migraine, dizzy be one of clinical common disease, the clinical onset rate is high, but lacks the efficacious therapy medicine.Like migrainous treatment; Doctor trained in Western medicine adopts non-steroid antiinflammatory drug, analgesic symptomatic treatment more; Part patient adopts Western medicine class selectivity calcium channel blocker such as nimodipine and 5-hydroxy tryptamine (5-HT1B/1D) receptor stimulating agent triptan medicine such as sumatriptan etc. and Ergotamine preparation, and temporary transient analgesic effect is just played in these western medicine headaches, headache recurrence very soon after the drug withdrawal; And this type of drug side effect is bigger, can not be for a long time or excessive use.Menieres disease (dizzy) has the characteristics of outbreak repeatedly; Treatment is main to alleviate the hydrolabyrinth relief of symptoms between stage of attack; Available 20% mannitol intravenous drip can give calmness, emesis treatment for serious vomiting, dizzy, heart-throb person, still not have the medicine that effects a radical cure.
The traditional Chinese medical science, treatment by Chinese herbs migraine, Menieres disease have superiority.The migraine etiology and pathogenesis is very complicated, can be because of decreasing in the wound, and big excessive invasion and attack etc. cause that syndrome is empty or real, or simulataneous insufficiency and excessive, often relate to a plurality of internal organs such as the heart, liver,spleen,kidney, therefore, treating this card should be from integral body, dialectical opinion system; Dizzy many because of internal damage by the excessive seven emotions, or a little less than the deficiency of vital energy blood, due to the internal organs imbalance of YIN and YANG.Each is heavy to some extent for ancient Chinese medicine doctor, and then with dispelling wind to relieve the exterior syndrome, diuretic reduces phlegm in treatment, and cephalocathartic is fixed dizzy to be rule.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, migrainous compound Chinese medicinal preparation of a kind of treatment and preparation method thereof is provided.
The raw material of treating migrainous compound Chinese medicinal preparation consists of: the Rhizoma Alismatis of the Radix Angelicae Dahuricae of the Rhizoma Chuanxiong of 1~20 weight portion, 1~20 weight portion, the Herba Menthae of 1~20 weight portion, 1~20 weight portion, the Herba Schizonepetae of 1~20 weight portion, the Rhizoma Atractylodis Macrocephalae of 1~20 weight portion; Wherein Rhizoma Chuanxiong, the Radix Angelicae Dahuricae are monarch drug, and Herba Schizonepetae, the Rhizoma Atractylodis Macrocephalae are accessory drugs, and Herba Menthae, Rhizoma Alismatis are adjuvant.
The step of method for preparing of treating migrainous compound Chinese medicinal preparation is following:
1) gets the Herba Menthae of 1~20 weight portion, the Rhizoma Alismatis of 1~20 weight portion, the Herba Schizonepetae of 1~20 weight portion, the Rhizoma Atractylodis Macrocephalae of 1~20 weight portion; The water that adds 10~1600 weight portions, heating, vapor distillation extracts volatile oil; 1~10 hour extraction time, obtain volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8: 1ml/g; Water liquid filters, filtrate for later use, medicinal residues add 6-10 times of water reflux, extract, 2~3 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get the Rhizoma Chuanxiong of 1~20 weight portion, the Radix Angelicae Dahuricae coarse powder or the decoction pieces of 1~20 weight portion, add 2~20 times of amount ethanol, concentration of alcohol percent by volume 2-100%, reflux, extract, 1~5 time, 1~5 hour extraction time, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material.
4) the said medicine raw material adds pharmaceutical adjunct, processes capsule, tablet, granules medicine dosage form.
Described pharmaceutical adjunct is starch, sucrose, dextrin, magnesium stearate, aspartame or micropowder silica gel.
This medicine has good analgesic activity; In addition, all right antagonism PE and 5-HT can improve the blood capillary caliber to the contraction of blood vessel; Microcirculation improvement; Can effectively improve the rat brain blood flow, the inductive rat experiment property migraine of nitroglycerin is had the obvious treatment effect, be effective prescription of treatment migraine, Menieres disease.
The specific embodiment
The present invention be mainly used on the treatment wind heat violate, spleen wet rise that expectorant causes various diseases.Invention adopts Rhizoma Chuanxiong, the Radix Angelicae Dahuricae, Herba Menthae, Rhizoma Alismatis, Herba Schizonepetae, the Rhizoma Atractylodis Macrocephalae to form compound recipe, and the hot temperature of Rhizoma Chuanxiong is walked to scurry in the side, and the benefaction head and wind-expelling pain-stopping are for controlling the dizzy key medicine of headache; The Radix Angelicae Dahuricae diffusing wind that induces sweat, understand things pain-stopping, outstanding kind long with the Yangming Channel Jaken that looses, and reach on the fragrance, understand things pain-stopping is used always by controlling YANG MING headache, nasal sinusitis dizziness and acute toothache.Rhizoma Atractylodis Macrocephalae spleen invigorating controlling the water circulation, admittedly hold up Central Region, the Rhizoma Alismatis diuretic removes drink, and turbid to eliminate the phlegm, the two is all accessory drugs, and auxilliary principal agent diuretic eliminates the phlegm, and reaches the purpose of treating both the principal and secondary aspects of a disease.Herba Schizonepetae, the hot ailment said due to cold or exposure of loosing of Herba Menthae is returned lung, liver two warps, kind wind-dispelling heat-dissipating and to help major-minor medicine to control headache dizzy is so be adjuvant.Shared at medicine, main liter looses and dispels the wind, and double diuretic eliminates the phlegm, and long memorial wind is dispelled bitterly altogether, and diuretic ends dizzy effect, reaches the effect of treatment migraine, Menieres disease.
Below in conjunction with embodiment the present invention is described further:
Embodiment 1:
1) get Herba Menthae, Rhizoma Alismatis, each 200 g of Herba Schizonepetae, Rhizoma Atractylodis Macrocephalae 100g, add 10 times of water gagings, heating, vapor distillation extracts volatile oil, 1 hour extraction time, obtains volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8:1 ml/g.Water liquid filters, filtrate for later use, medicinal residues add 6 times of water gaging reflux, extract, 2 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get Rhizoma Chuanxiong, each 400g of the Radix Angelicae Dahuricae, add 2 times of amount ethanol, concentration of alcohol percent by volume 2%, reflux, extract, 1 time, each 1 hour extraction time, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material;
4) the said medicine raw material adds starch, processes capsule, tablet, granules medicine dosage form.
Embodiment 2:
1) get Herba Menthae, Rhizoma Alismatis, Herba Schizonepetae, each 100g of the Rhizoma Atractylodis Macrocephalae, add 1600 times of water gagings, heating, vapor distillation extracts volatile oil, 10 hours extraction times, obtains volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8:1 ml/g.Water liquid filters, filtrate for later use, medicinal residues add 10 times of water gaging reflux, extract, 3 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get Rhizoma Chuanxiong 100g, Radix Angelicae Dahuricae 400g, add 20 times of amount ethanol, concentration of alcohol percent by volume 100%, reflux, extract, 5 times, each 5 hours extraction times, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material;
4) the said medicine raw material adds dextrin, processes capsule, tablet, granules medicine dosage form.
Embodiment 3:
1) get Herba Menthae 200g, Rhizoma Alismatis 100g, Herba Schizonepetae 50g, each 50g of the Rhizoma Atractylodis Macrocephalae, add 100 times of water gagings, heating, vapor distillation extracts volatile oil, 5 hours extraction times, obtains volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8:1 ml/g.Water liquid filters, filtrate for later use, medicinal residues add 7 times of water gaging reflux, extract, 3 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get Rhizoma Chuanxiong 800g, Radix Angelicae Dahuricae 200g, add 10 times of amount ethanol, concentration of alcohol percent by volume 50%, reflux, extract, 2 times, each 2 hours extraction times, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material;
4) the said medicine raw material adds sucrose, processes capsule, tablet, granules medicine dosage form.
Embodiment 4:
1) get Herba Menthae 100g, Rhizoma Alismatis 100g, Herba Schizonepetae 100g, each 100g of the Rhizoma Atractylodis Macrocephalae, add 80 times of water gagings, heating, vapor distillation extracts volatile oil, 6 hours extraction times, obtains volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8:1 ml/g.Water liquid filters, filtrate for later use, medicinal residues add 8 times of water gaging reflux, extract, 2 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get Rhizoma Chuanxiong 100g, Radix Angelicae Dahuricae 100g, add 15 times of amount ethanol, concentration of alcohol percent by volume 60%, reflux, extract, 3 times, each 3 hours extraction times, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material;
4) the said medicine raw material adds aspartame, processes capsule, tablet, granules medicine dosage form.
Embodiment 5:
1) get Herba Menthae 2000g, Rhizoma Alismatis 2000g, Herba Schizonepetae 2000g, each 2000g of the Rhizoma Atractylodis Macrocephalae, add 500 times of water gagings, heating, vapor distillation extracts volatile oil, 7 hours extraction times, obtains volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8:1 ml/g.Water liquid filters, filtrate for later use, medicinal residues add 9 times of water gaging reflux, extract, 3 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get Rhizoma Chuanxiong 2000g, Radix Angelicae Dahuricae 2000g, add 5 times of amount ethanol, concentration of alcohol percent by volume 70%, reflux, extract, 4 times, each 4 hours extraction times, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material;
4) the said medicine raw material adds micropowder silica gel, processes capsule, tablet, granules medicine dosage form.
The effect of this herbal pharmacology:
1. this Chinese medicine has obvious analgesic activity to the mice pain that thermostimulation causes.This Chinese medicine extract 3.75 g/kg, 7.5 g/kg, three dose groups of 15.0 g/kg, analgesia rate of 30 min after administration is respectively-9%, 3%, 53%; The analgesia rate is respectively-1%, 43%, 90% behind 60 min; The analgesia rate is respectively 3%, 27% behind 90 min, and 64%; The analgesia rate is respectively-10% ,-5% ,-7% behind 120 min.60 min after the administration wherein, middle and high dose groups and solvent control group relatively, the raising of analgesia rate has significance meaning (P < 0.001);
2. the stimulation of this Chinese medicine Dichlorodiphenyl Acetate causes the pain mice has obvious analgesic activity.This Chinese medicine extract 3.75 g/kg, 7.5 g/kg, three dose groups analgesias of 15.0 g/kg raising rate is respectively 8%, 37%, 71%; Wherein, middle and high dose groups and solvent control group relatively have significance meaning (P < 0.01);
3. this Chinese medicine does not have obvious influence to isolated rat aortic annulus basis tension force and the inductive vasoconstriction of Arterenol (Hoechst). (PE); Inductive vasoconstriction has tangible antagonism to 5-hydroxy tryptamine (5-HT), and 5 * 10 -7~1 * 10 -3Present the dose dependent relation in the g/ml scope;
4. this Chinese medicine has tangible dilating effect to Mice Auricle blood capillary caliber, and administration is after four days, medicine 3.75 g/kg; 7.5 g/kg; 15.0 g/kg three dose groups blood vessels calibers raising rate is respectively 11%, 14%, 27%, compares with solvent control group, each administration group all has significant difference;
This Chinese medicine extract high dose 15.0 g/kg can antagonism 5-HT cause the cerebrovascular contraction, with the modeling group relatively, significant difference (P < 0.05) is arranged, and medicine 3.75 g/>kg, 7.5 g/kg, three dose groups of 15.0 g/kg present certain dose-dependence;
6. dosage 7.5 g/kg and high dose 15.0 g/kg can effectively treat the inductive rat experiment property migraine of nitroglycerin in this Chinese medicine extract; High, medium and low three dose groups present certain dose-dependence; Time started difficult to tackle and concluding time difficult to tackle and the red situation of ear are similar, with blank control group significant difference (P < 0.01) are arranged more all;
7. conclusion
This Chinese medicine has good analgesic activity; Can improve PE and the 5-HT contraction to blood vessel, can improve the blood capillary caliber, microcirculation improvement can effectively improve the rat brain blood flow; This dosage of drug has the obvious treatment effect greater than 7.5 g/kg to the inductive rat experiment property migraine of nitroglycerin.
Pharmacological experimental method:
Hot plate method is estimated the analgesic activity of this Chinese medicine
Screening ICR female mice, the cleaning level, 50, be divided into 5 groups at random, 10 every group, be respectively solvent control group (distilled water), positive control aspirin group (0.60 g/kg), this Chinese medicine extract 15.0,7.5,3.75 g/kg dose groups.Mice is put in the normal pain response time of measuring each mice on the water-bath hot plate groove, and the pain indicator reaction is: lick metapedes or lift back leg with action later, take out immediately if mice painless response time on hot plate surpasses 60 seconds, calculated by 60 seconds, in order to avoid scald mice.Survey altogether 2 times, each 5 minutes at interval, average.0.5,1,1.5,2,2.5 h carry out the test of mice hot plate method with hot plate behind the gastric infusion.Relatively the difference in each administration group and matched group pain response time is pressed following formula with mean value calculation threshold of pain raising rate.
Estimate the analgesic activity of this Chinese medicine with acetic-acid induced mouse writhing reaction method
The ICR mice, cleaning level, body weight 18~22g; Male and female half and half, 50 of quantity are divided into 5 groups at random; Every group 10, be respectively solvent control group (distilled water), positive control aspirin group (0.60 g/kg), this Chinese medicine extract 15.0,7.5,3.75 g/kg dose groups.1h behind the gastric infusion, the 0.2 ml/10g modeling of lumbar injection 0.6 % glacial acetic acid, that respectively organizes mice behind the record injection glacial acetic acid in 20 min turns round the body number of times.By following formula with the mean value calculation rate of easing pain.
Through to the isolated rat aortic annulus tensile influence estimate this Chinese medicine normal and 5-HT (5-hydroxy tryptamine), PE (PHENYLEPHRINE HYDROCHLORIDE) induced pressor influence
1) preparation of thoracic aortic ring is with stable
With fully blood-letting behind the blunt stunning rat, the aorta that dissociates is rapidly carefully removed thoracic aorta fat and connective tissue on every side, is cut into the long vascular ring of 3~4 mm.Vascular ring is hung in the bath of the K-H liquid that fills preheating (37 ± 0.5 ℃ of constant temperature, and continue to feed 95%O 2+ 5%CO 2Mixed gas), tension variation is transmitted and is recorded in the RM-6240C type multi-path physiology signal acquiring processing system.Vascular ring gives 2.0 g initial tensions again and stablizes 60 min after stablizing 30 min under the 0 g tension force, during per 15 min change K-H liquid once.With 5 * 10 -7The PHENYLEPHRINE HYDROCHLORIDE of mmol/L concentration (PE) stimulates vascular ring, and vascular ring is shunk, and tension force increases points out blood vessel to have active afterflush 3 times about 0.3 g, make vascular ring return to the state before stimulating, and repeats 3 times.
2) to the thoracic aortic ring tensile influence in basis
By 1) a below legal system has active vascular ring, behind tension stability, adds this Chinese medicine extract solution of appropriate amount, makes drug level reach 5 * 10 -7G/mL observes wave form varies.Flush away medicinal liquid behind 20 min washes 3 times with K-H again, stablizes 20min.According to same quadrat method, making this Chinese medicine extraction substrate concentration respectively is 5 * 10 -7G/mL, 1 * 10 -6G/mL, 5 * 10 -6G/mL, 1 * 10 -5G/mL, 5 * 10 -5G/mL, 1 * 10 -4G/mL, 5 * 10 -4G/mL observes the tensile variation of vascular ring.
3) PE is stimulated the tensile influence of thoracic aortic ring in advance
By 1) a below legal system has active vascular ring, and behind tension stability, add PHENYLEPHRINE HYDROCHLORIDE (PE) and make into 5 * 10 -7Mmol/L, treat that its preshrinking reaches stable state after, adopt accumulation dosing method, per 10 min add this Chinese medicine extract solution, make the concentration of this Chinese medicine crude drug in the perfusate reach 5 * 10 respectively -7G/mL, 1 * 10 -5G/mL, 1 * 10 -4G/mL, 1 * 10 -3G/mL observes antiotasis and changes.
4) 5-HT is stimulated the tensile influence of thoracic aortic ring in advance
By 1) a below legal system has active vascular ring, and behind tension stability, add 5-hydroxy tryptamine (5-HT) and make into 6 * 10 -5G/ml, treat that its preshrinking reaches stable state after, adopt accumulation dosing method, every 10min adds this Chinese medicine extract solution, makes the concentration of this Chinese medicine crude drug in the perfusate reach 5 * 10 respectively -7G/mL, 1 * 10 -5G/mL, 1 * 10 -4G/mL, 1 * 10 -3G/mL observes antiotasis and changes.
Microcirculation of mouse auricle is influenced
The ICR mice, cleaning level, 50 of quantity; Body weight 18~22g, male and female half and half are divided into 5 groups at random; Every group 10; Be respectively blank group, positive control nimodipine group (0.60 g/kg), this Chinese medicine extract 15.0,7.5,3.75 g/kg dose groups, each treated animal gastric infusion every day 1 time, continuous 7 d.1h measures auricle blood capillary caliber for twice before administration and after the last administration.During mensuration, mice is through pentobarbital sodium 0.03 g/kg ip anesthesia, and the auricle QUMAO is regulated ear holder height, and auricle is lain on the observation platform, and drips cedar oil on its surface, uses XW-B-3 type microcirculation detector, regulates cold light source to suitably brightness.Under the Optics in Microscope visual field, select outer 1/3rd fine motions of auricle, vein companion row district, observe microcirculation change.
To normal rat and 5-HT cause cerebrovascular shrink rat cerebral blood flow influence experimental technique
The SD rat, the cleaning level, 60 of quantity, body weight 220~240g, male and female half and half are divided into six groups at random.The A group: blank group, duodenum give 0.5%CMC-Na solution 1.0 ml/100g; The B group: model group, duodenum give 0.5%CMC-Na solution 1.0 ml/100g; The C group: positive nimodipine group, duodenum give the positive drug nimodipine 20 mgkg -1The D group: low dose group, duodenum give low dosage 3.75 these Chinese medicine extract of g/kg; The E group: middle dose groups, duodenum give middle this Chinese medicine extract of dosage 7.5g/kg; The F group: high dose group, duodenum give high dose 15.0 these Chinese medicine extract of g/kg.Animal is with 10% chloral hydrate (0.35ml100g -1) anesthesia, dorsal position is fixed, and cuts cervical region center skin, separates LCC (LCA) and jugular vein, separates and the ligation external carotid artery the jugular proximal part of ligation along LCA.Encase internal carotid artery with the round 0.8mm probe of ultrasonic Doppler blood flowmeter.Will be except that the blank group, all the other each groups are 30min after administration all, intravenous injection 20 mgL – 15-HT 0.1ml100g -1, continuous record 90min ICAF amount.
Influence to the experimental Migraine Rats model of nitroglycerin type
1) grouping and modeling:
The SD rat, cleaning level, 60 of quantity; Body weight 220~240g; Male and female half and half are divided into blank group, model group, positive cafergot 2.0 mg/kg group, this Chinese medicine extract low dosage 3.75 g/kg, middle dosage 7.5g/kg, high dose 15.0 g/kg, 10 every group at random.Blank control group: rat skin lower injection normal saline 2 ml/kg; Model group and treatment group rat skin lower injection Nitro-Bid 10mg/kg duplicate experimental Nerve in Migraine Model, and rubescent ears to occur, forelimb is frequently scratched one's head, and climbing the uncomfortable symptom of hints model animal head such as cage increased frequency is the successful index of modeling.Blank control group does not deal with, and 30min irritates stomach distilled water 10ml/kg after the model group modeling, and 30min irritates stomach respectively and gives cafergot and rhizome of chuanxiong root of Dahurian angelica capsule after the modeling of treatment group.
2) observed content and method:
(1) ear is red.The red appearing and subsiding time of ear after the modeling of observation rat.(2) scratch one's head, climb cage.In modeling, per 30 minutes as a time period, adopt the method for persistent period fragmentation count to observe after the rat modeling number of times of scratching one's head, climbing cage in each time period.It is sign that time of occurrence difficult to tackle reaches more than 3 times with rat appearance number of times continuously difficult to tackle, and extinction time is less than 5 times with the number of times difficult to tackle of rat in the time period and asthenia occurs.The tired sign that shows as.
The toxicologic study of this Chinese medicine
1) acute toxicity test
40 of healthy cleaning level ICR mices, male and female half and half, age 4-6 week, body weight ♂ 17.0-19.7g, ♀ 17.0-19.2g, balanced random packet is administration group and ultra-pure water matched group, 20 every group, each 10 of male and female.Single oral (po) gives this Chinese medicine extract 40g/kg dosage (having reached maximum concentration and maximum administration capacity), and administration has after about 15 minutes that climbing appears in 30% mice, hopping response, and 70% mice occurs closing one's eyes, movablely reduces reaction in addition.Wherein climb, hopping response continues to disappear after about 30 minutes, but occur then reducing, close one's eyes with the same activity of 70% mice, tired out, body temperature descends (health is sent out cold during touch) phenomenon, these both mices of reaction all continue about 24 and as a child recovered normally.Administration group mice body weight all increases with the prolongation of test period during the experimental observation, but growth rate is slightly slower than the matched group of corresponding time, and other obvious abnormal response do not occur, do not cause dead mouse yet.After the off-test, dissect mice, observe the internal organs no abnormality seen.
So think; The mice single oral gives the rhizome of chuanxiong root of Dahurian angelica capsule 40g/kg dosage; Its main toxicity is that mice occurs climbing, jumps, movablely reduces, closes one's eyes after the administration, tired out, body temperature decline (health is sent out cold during touch) and body weight gain be slow; But animal dead do not occur, do not see tangible poisoning target organ yet.
2) long term toxicity test
120 of healthy cleaning level SD rats, male and female half and half, age 4-6 age in week; Body weight: ♂ 93-122g, ♀ 82-115g, carry out balanced random packet, be divided into four test group; Be high, medium and low three dose groups of rhizome of chuanxiong root of Dahurian angelica capsule and matched group, 30 every group, female each 15.Per os gave this Chinese medicine extract 8,4,2g/kg in continuous three months; Observe the behavioral activity, sialorrhea, urine, excrement, food ration, body weight change of rat etc. during the administration, in administration 1.5 months (administration mid-term), 3 months (drug withdrawal next day) of administration and 4 weeks of drug withdrawal (convalescent period ends) to SD rat comprehensive inspection of sampling:
Hematological examination: measure RBC number (RBC); Leukocyte count (WBC); Haemachrome concentration (HGB); Red cell volume is than (HCT); Mean corpuscular volume (MCV) (MCV); Mean corpuscular hematochrome content (MCH [HGB/RBC]); Mean corpuscular hemochrome concentration (MCHC [HGB/HCT]); RDW (RDW); Platelet count (PLT); Average platelet volume (MPV); Neutrophil's number (NEUT); Lymphocyte number (LYMPH); Mononuclear cell number (MONO); Oxyphil cell's number (EOS); Basophil number (BASO); Reticulocyte counts (RETIC); Prothrombin time (PT)
Blood biochemical is learned inspection: measure aspartic transaminase (AST), alanine aminotransferase (ALT), alkali phosphatase (ALP), creatine phosphate enzyme (CK), blood urea nitrogen (BUN), creatinine (Crea), total protein (T.P), albumin (ALB), blood glucose (GLU), STB (T.BIL) T-CHOL (T.CHO), total triglyceride (TG), potassium concentration (K +), Na ion concentration (Na +), chlorine ion concentration (Cl -), total calcium (TCa)
System becomes celestial: the taking-up heart, liver, spleen, lung, kidney, adrenal gland, thymus, testis, epididymis, uterus, ovary, brain are weighed after dissecting, and calculate organ coefficient
Histopathologic examination: dirty, the liver of coring, spleen, lungs, kidney, stomach, duodenum, ileum, colon, jejunum, rectum, hypophysis, adrenal gland, pancreas, prostate, thyroid, parathyroid gland, salivary gland, thymus, mammary gland, brain, spinal cord (neck, breast, waist section), breastbone (bone and bone marrow), esophagus, trachea, aorta, sciatic nerve, lymph node, bladder, uterus, ovary, testis, epididymis are done histopathologic examination, and with its variation of pathological image analytical system record.
Continuous three months of SD rat per os respectively gives this Chinese medicine extract 8,4,2g/kg, and the sialorrhea reaction appears in 8g/kg dose groups rat during administration, sialorrhea reaction time of occurrence after each administration at once to the administration in about 30 minutes.Yellow green urine with the medicine color similarity all appears in three dose groups rats during administration, the urine color depth is shallow just to be proportionate with dosage, but sialorrhea reaction and yellow green urine occurs in drug withdrawal convalescent period, shows that these two reactions are that reversibility is reacted.Other tangible toxicities do not occur during whole test, do not cause animal dead yet.Each treated animal body weight all increases with the prolongation of test period.Administration mid-term (administration 1.5 months), drug withdrawal next day (administration 3 months), convalescent period finish (4 weeks of drug withdrawal) each item testing result and show: this Chinese medicine is biochemical to rat blood, hematological indices and Rats Organs and Tissues weight, organ coefficient all do not have obvious influence, and gross examination of skeletal muscle and histopathology are descended to check with mirror through naked eyes and also do not seen obviously because of drug-induced pathomorphology and Histological change.
So think; Continuous three months per os of rat give this Chinese medicine; Main side reaction sialorrhea reaction (only this reaction appears in 8g/kg dose groups rat) occurs during being merely administration; Toxic dose and poisoning target organ show obviously that all it is 8g/kg.d that dosage appears in side reaction, and safety non-toxic dosage is greater than 4g/kg.d (be equivalent to the clinical plan consumption of people 100 times).

Claims (3)

1. the migrainous compound Chinese medicinal preparation of treatment is characterized in that its raw material consists of: the Rhizoma Alismatis of the Radix Angelicae Dahuricae of the Rhizoma Chuanxiong of 1~20 weight portion, 1~20 weight portion, the Herba Menthae of 1~20 weight portion, 1~20 weight portion, the Herba Schizonepetae of 1~20 weight portion, the Rhizoma Atractylodis Macrocephalae of 1~20 weight portion; Wherein Rhizoma Chuanxiong, the Radix Angelicae Dahuricae are monarch drug, and Herba Schizonepetae, the Rhizoma Atractylodis Macrocephalae are accessory drugs, and Herba Menthae, Rhizoma Alismatis are adjuvant.
2. the method for preparing of the migrainous compound Chinese medicinal preparation of treatment as claimed in claim 1 is characterized in that its step is following:
1) gets the Herba Menthae of 1~20 weight portion, the Rhizoma Alismatis of 1~20 weight portion, the Herba Schizonepetae of 1~20 weight portion, the Rhizoma Atractylodis Macrocephalae of 1~20 weight portion; The water that adds 10~1600 weight portions, heating, vapor distillation extracts volatile oil; 1~10 hour extraction time, obtain volatile oil and water liquid; Volatile oil adds beta-schardinger dextrin-stirring, enclose, obtains volatile oil clathrate compound, and the solid-to-liquid ratio of beta-schardinger dextrin-and volatile oil is 8:1 ml/g; Water liquid filters, filtrate for later use, medicinal residues add 6-10 times of water reflux, extract, 2~3 times, filter, gained filtrating merges with the water liquid that extracts behind the volatile oil, concentrate, dry, dry extract A;
2) get the Rhizoma Chuanxiong of 1~20 weight portion, the Radix Angelicae Dahuricae coarse powder or the decoction pieces of 1~20 weight portion, add 2~20 times of amount ethanol, concentration of alcohol percent by volume 2-100%, reflux, extract, 1~5 time, 1~5 hour extraction time, extracting solution is concentrated, dry, gets dry extract B;
3) dry extract A, dry extract B and volatile oil clathrate compound mix, and pulverize, and get medicine material;
4) the said medicine raw material adds pharmaceutical adjunct, processes capsule, tablet, granules medicine dosage form.
3. a kind of method for preparing of treating migrainous compound Chinese medicinal preparation according to claim 2 is characterized in that described pharmaceutical adjunct is starch, sucrose, dextrin, magnesium stearate, aspartame or micropowder silica gel.
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CN100558390C (en) * 2007-05-11 2009-11-11 张燕 A kind of unguentum of external curing arthralgia due to cold-dampnes

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