CN102908572B - Application of Ruyizhenbao pill/tablet to treatment of vascular dementia - Google Patents
Application of Ruyizhenbao pill/tablet to treatment of vascular dementia Download PDFInfo
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Abstract
The invention provides application of a Ruyizhenbao pill/tablet to the treatment of vascular dementia, wherein the Tibetan drug is prepared by the following raw materials: nacre, agilawood, travertine, lapis micae aureus, carthamus tinctorius, crab, clove, pitted fructus terminaliae billericae, myristica fragrans, cardamun, phyllanthus emblica, amomum tsao-ko, ajowan, sandalwood, semen nigellae, lignum dalbergiae odoriferae, piper longum, pitted myrobalan, galangal, liquorice cream, cinnamon, olibanum, costustoot, semen cassiae, cornu bubali or cornu bubali concentrated powder, ambrette, lagotis brachystachya, radix inulae racemosae, muskone, calculus bovis factitius or in-vitro cultured calculus bovis.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to the new purposes of Tibetan medicine jewellery ball/sheet as one wishes.
Background technology
Vascular dementia (vascular dementias, VD), is called again multi-infarct dementia, is the second largest cause of disease that causes senile dementia, accounts for 10%～50% in dementia.VD is a syndrome, rather than a single disease, and different vascular pathologicals changes all can cause VD symptom, comprise large and small arterial disease, diffusivity ischemic white matter lesion, the come off thromboembolism of embolus of heart, hemodynamic change, hemorrhage, hematologic agent and hereditary etc.The pathophysiological mechanism relevant with VD comprises the infringement of focal ischemia's property, white matter lesion, other factor, functional factor relevant with ischemia.In a word, be long-term hypertension, arteriosclerosis, the multiple infarctions of lacunar infarction or other reasons occurs repeatedly, cause the ventricles of the brain to expand, cortical atrophy, destroys corresponding conductive beam, dull-witted under the cortex engendering.
At present, the diagnostic criteria of vascular dementia is to adopt neuropathy association of the U.S. " neurodiagnosis and statistic handbook " the 4th edition (DSM-IV), be specially: (1) many-sided cognitive defect occurs, show as following the two: memory impairment (can not learn new data and maybe can not recall acquired data); Has one of following cognitive disorder at least: aphasia, apraxia are (although motor function is no problem, but can not perform an action), agnosia (although sensory function is no problem, can not be familiar with or recognition object), carry out the obstacle (plan, organize, arrange order, abstract etc.) of managerial function; (2) above cognitive defect causes social activity or occupational function defect, and before can finding that these functions are obviously not so good as; (3) there is limitation nervous system signs and symptom (for example: deep tendon reflex is hyperfunction, stretch plantar reflex, pseudobulbar paralysis, gait disorder, a certain limbs weakness); Or there is the laboratory of prompting cerebrovascular disease for example, also can think the cause of disease of this obstacle according to (, relating to many infractions of cortex and white matter); (4) these defects are not due to due to delirium.
Vascular dementia is a kind of multi-factor disease, is the unique dull-witted type that can prevent and treat now, is applicable to starting the cognitive symptom of Drug therapy once VD diagnosis is established.Clinical conventional medicine comprises cerebral circulation promoter, acts on medicine, Neuroprotective Agents and the herbal treatment of neurotransmitter, and wherein, herbal treatment mostly is determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs.
Cerebral circulation promoter comprises: Dihydroergotoxine (Hydergine, dihydroergotoxine, hydergine, the brain that relaxes is peaceful), can directly act on DA and 5-HT receptor, reduce cerebral vascular resistance, increase cerebral blood flow and the utilization rate of brain to oxygen, improve synapse neurotransmission function; Aspirin (Aspirin), platelet aggregation inhibitor, is widely used in the control of cardiovascular and cerebrovascular disease; Nicergoline (Nicergoine, nicergoline) there is the blood vessel dilating effect of a receptor retardance, increase cerebral blood flow, strengthen the utilization of metabolism, increase blood oxygen and the glucose of brain cell, in addition, still have promote dopamine metabolism, promote the synthetic of brain protein, the effects such as anticoagulant and antithrombotic; Nafronyl (Naftidrofuryl, Clarantin, brain is strengthened), it is 5-HT receptor antagonist, reduce the neuronal necrosis due to ischemia by anti-5-HT, easily see through directly expansion of cerebral vascular and peripheral blood vessel of blood brain barrier, increase erythrocytic morphotropism and reduce blood denseness and can promote cellular metabolism, cell hypoxia is also had to protective effect; Pentoxifylline (Pentoxifylline), there is expansion brain and peripheral vascular effect, also may play a role by affecting erythrocytic morphotropism, platelet adhesion and Platelet, clinical in various brain vessel blood obstacle diseases; Vinpocetine (Vinpocetine), can increase cerebral blood flow, improves brain oxygen supply, reduce blood viscosity, and cerebrovascular is had to higher selection.
The medicine that acts on neurotransmitter comprises: donepezil (Donepezil, aricept): the acetyl gallbladder acyl that reversibly acetylcholine esterase inhibition (AchE) causes is hydrolyzed and the acetyl choline content of increase acceptor site, donepezil may also have other mechanism, comprises the direct effect of disposal, neurotransmitter receptor or Ca2+ passage to peptide; Huperzine A-Zhulin Antun (huperzine): its main component is a kind of alkaloid (huperzine A) extracting from natural plants Herba Lycopodii serrati, belong to reversibility cholinesterase inhibitor, easily see through blood brain barrier, have the effect that promotes that memory represents and hypermnesis keep.
Neuroprotective Agents comprises: memantine (Memantine): brain hypoxic-ischemic can cause presynaptic excitatory amino acid to discharge and picked-up minimizing again, excessive EAA can activate postsynaptic EAA receptor (being mainly nmda receptor and ampa receptor), increase the weight of neuronal damage, memantine, as the non-nmda receptor antagonist of striving property unexpectedly, can alleviate the nerve injury in cerebrum ischemia anoxia process; Nimodipine (Nimodipine): be calcium channel blocker, can effectively regulate intracellular Ca2+ level, suppress the neural cell injury that calcium overload causes, promote the regeneration of injured neurons.
The jewellery ball of complying with one's wishes is traditional Tibetan medicine, and Cheng Fang, in 13rd century of Christian era, is loaded in the blue or green heavily fortified point of Tibetan medicine and pharmacology scholar core and praises in shown " secret formula Margarita string " book.Its prescription, according to Tibetanmedicine principle, is selected natural, precious, the rare Tibetan medicine material that is grown in roof of the world special ecological environment, and refining the forming that combine with traditional handicraft with modern scientific method.Mainly by Concha Margaritifera, Lignum Aquilariae Resinatum, Tufa, Lapis Micae Aureus, Flos Carthami, Eriocheir sinensis, Flos Caryophylli, Fructus Terminaliae Billericae (enucleation), Semen Myristicae, Fructus Amomi Rotundus, Fructus Phyllanthi, Fructus Tsaoko, Cuminum celery, Lignum Santali Albi, Semen Nigellae, Lignum Dalbergiae Odoriferae, Fructus Piperis Longi, Fructus Chebulae, Rhizoma Alpiniae Officinarum, GANGCAO GAO, Cortex Cinnamomi, Olibanum, the Radix Aucklandiae, Semen Cassiae, Cornu Bubali, Semen seu folium abelmoschi moschati, Lagotis brachystachya Maxim., Radix Inulae, artificial Moschus, bezoar pearl mother, Lignum Aquilariae Resinatum, 30 kinds of medical material compositions such as Radix Glycyrrhizae, its function cures mainly as heat clearing away, consciousness-restoring and orifice-opening, channels sootheing and network vessel quickening, for distemper, outmoded heat symptom-complex, aortic arch syndrome, numb limbs and tense tendons, paralysis, facial hemiparalysis, obnubilation, limbs are stiff, articular instability.
The jewellery sheet of complying with one's wishes is the improvement dosage form of jewellery ball as one wishes, with reference to the preparation standard of the jewellery ball of complying with one's wishes, provides in the mode of tablet, conveniently takes.There is no at present the report about the jewellery ball of complying with one's wishes/sheet treatment vascular dementia or relevant disease.
Summary of the invention
The object of the present invention is to provide the novel medical use of Tibetan medicine, the application of jewellery ball/sheet in treatment vascular dementia (Vascular Dementia, VD) that comply with one's wishes be provided.Described Tibetan medicine is made up of following raw material:
Concha Margaritifera 22.69 weight portions, Lignum Aquilariae Resinatum 22.69 weight portions, Tufa 22.69 weight portions, Lapis Micae Aureus 6.81 weight portions, Flos Carthami 22.69 weight portions, Eriocheir sinensis 11.34 weight portions, Flos Caryophylli 9.07 weight portions, Fructus Terminaliae Billericae 22.69 weight portions of enucleation, Semen Myristicae 9.07 weight portions, Fructus Amomi Rotundus 9.07 weight portions, Fructus Phyllanthi 29.49 weight portions, Fructus Tsaoko 6.81 weight portions, Cuminum celery 9.07 weight portions, Lignum Santali Albi 18.15 weight portions, Semen Nigellae 9.07 weight portions, Lignum Dalbergiae Odoriferae 74.86 weight portions, Fructus Piperis Longi 6.81 weight portions, Fructus Chebulae's 29.49 weight portions of enucleation, Rhizoma Alpiniae Officinarum 18.15 weight portions, GANGCAO GAO 9.07 weight portions, Cortex Cinnamomi 11.34 weight portions, Olibanum 13.61 weight portions, the Radix Aucklandiae 18.15 weight portions, Semen Cassiae 13.61 weight portions, Cornu Bubali or Pulvis Cornus Bubali Concentratus 9.07 weight portions, Semen seu folium abelmoschi moschati 11.34 weight portions, Lagotis brachystachya Maxim. 34.03 weight portions, Radix Inulae 18.15 weight portions, artificial Moschus's 0.45 weight portion, artificial Calculus Bovis or In vitro cultured Calculus Bovis 0.45 weight portion.
Tibetan medicine of the present invention can provide with any suitable peroral dosage form of taking, for example pill, capsule, tablet, powder and granule, preferred dosage form is pill or tablet, jewellery ball/the sheet of complying with one's wishes can be traditional jewellery ball as one wishes, can be also the improved jewellery sheet as one wishes providing with tablet form.
By the rat model (VD rat) of suffering from vascular dementia being used to the jewellery sheet as one wishes of high, medium and low dosage, by Animal Behavior Science test, mediator assay experiment and rat brain blood flow observe and prove, the jewellery sheet of complying with one's wishes can improve significantly the ability of learning and memory of VD rat space and conditioning stimulus and improve the coordination ability of VD rat; Mediator NE, DA, 5-HT, ASP in brain are had to extraordinary protective effect, GABA in serum is also had to protective effect; Can significantly increase VD rat brain blood flow, thereby improve the brain injury causing because of cerebral blood supply insufficiency.Therefore the jewellery ball/sheet of complying with one's wishes can be used for treating vascular dementia clinically.
The specific embodiment
Below by the description to preferred embodiments of the present invention, describe in detail but do not limit the present invention.
1, experiment material
1.1 test samples: the jewellery sheet of complying with one's wishes is provided by Gansu Qizheng Tibetan Medicine Co., Ltd.
Prescription and preparation method:
Get following composition by weight: Concha Margaritifera 22.69g, Lignum Aquilariae Resinatum 22.69g, Tufa 22.69g, Lapis Micae Aureus 6.81g, Flos Carthami 22.69g, Eriocheir sinensis 11.34g, Flos Caryophylli 9.07g, the Fructus Terminaliae Billericae 22.69g of enucleation, Semen Myristicae 9.07g, Fructus Amomi Rotundus 9.07g, Fructus Phyllanthi 29.49g, Fructus Tsaoko 6.81g, Cuminum celery 9.07g, Lignum Santali Albi 18.15g, Semen Nigellae 9.07g, Lignum Dalbergiae Odoriferae 74.86g, Fructus Piperis Longi 6.81g, the Fructus Chebulae 29.49g of enucleation, Rhizoma Alpiniae Officinarum 18.15g, GANGCAO GAO 9.07g, Cortex Cinnamomi 11.34g, Olibanum 13.61g, Radix Aucklandiae 18.15g, Semen Cassiae 13.61g, Cornu Bubali or Pulvis Cornus Bubali Concentratus 9.07g, Semen seu folium abelmoschi moschati 11.34g, Lagotis brachystachya Maxim. 34.03g, Radix Inulae 18.15g, artificial Moschus 0.45g, artificial Calculus Bovis or In vitro cultured Calculus Bovis 0.45g,
Other composition except artificial Calculus Bovis or In vitro cultured Calculus Bovis, Cornu Bubali or Pulvis Cornus Bubali Concentratus, artificial Moschus, GANGCAO GAO is ground into fine powder or micronizing; add artificial Calculus Bovis or In vitro cultured Calculus Bovis, Cornu Bubali fine powder or Pulvis Cornus Bubali Concentratus, artificial Moschus; sieve; mix; adding suitable quantity of water by GANGCAO GAO granulates, is dried; tabletting, coating, to obtain final product.
Character: this product is Film coated tablets, removes after film-coat aobvious brown to rufous; Feeble QI perfume (or spice), bitter in the mouth, sweet.
Specification: every heavy 0.5g.
Lot number: 20101113.
1.2 positive control medicines
1.2.1 donepezil hydrochloride sheet (aricept), defends material (China) pharmaceutcal corporation, Ltd and manufactures, lot number: 110110A,
Date of manufacture: in January, 2011, valid until in December, 2013, specification: 5mg/ sheet.Preservation condition: room temperature.
1.2.2 Dihydroergotoxine Mesylate (hydergine), Tianjin Huajin Pharmaceutical Co., Ltd., lot number: 9M862T,
Date of manufacture: in December, 2009, valid until in November, 2012, specification: 1mg/ sheet.Preservation condition: room temperature.
1.3 reagent
1.3.1 pentobarbital sodium: China Medicine (Group) Shanghai Chemical Reagent Co.,, lot number: 100808.
1.3.2 normal saline: Qidu Pharmaceutical Co., Ltd., Shandong Prov., lot number: 20041208.
1.3.3 potassium dihydrogen phosphate: Tianjin chemical reagent three factories, lot number: 20041208.
1.3.4 methanol: Tianjin Concord Technology Co., Ltd., lot number: 20111209.
1.3.5 sodium acetate: Tianjin chemical reagent three factories, lot number: 20090926.
1.3.6 sodium borate:, Tianjin chemical reagent three factories, lot number: 20100120.
1.3.7 3-mercaptoethanol: Beijing ancient cooking vessel state biotechnology, lot number: 20111203.
1.3.8 aspartic acid: Yuan Ye bio tech ltd, Shanghai, lot number: 20110503.
1.3.9r-aminobutyric acid: Yuan Ye bio tech ltd, Shanghai, lot number: 20110503.
1.3.10 norepinephrine: Chinese food drug assay institute, lot number: 100169-201103.
1.3.11 dopamine: Augsburg, C13082000, lot number: 00714.
1.3.125-hydroxytryptamine: Sigma, H9523, lot number: 1001156278.
1.3.13 metoprolol: AstraZeneca pharmaceutical Co. Ltd, lot number: 1108091.
1.3.14 penicillin sodium: HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory, lot number: 101214706,80 ten thousand units/0.5g/ prop up.
1.4 instrument and consumptive material
1.4.1MG-3 type labyrinth stimulator, Yuanyang County, Henan Province Zhenhua Educational Instrument Factory.
1.4.2PB-203 type electronic balance, METTLER-TOLEDO GROUP produces.
1.4.31200series high performance liquid chromatograph, Agilent Technologies co.
1.4.413300 type refrigerated centrifuge, Thermo science co.
1.4.5G & G T2000 type electronic balance, two outstanding fraternal (group) company limiteies of the U.S..
1.5 laboratory animal
1.5.1SD rat
250 SPF level male rats, by Beijing Vital River Experimental Animals Technology Co., Ltd. (production licence number: SCXK (capital) 2006-0009), the animal quality quality certification number: 0247353.
2. determining of route of administration, method, dosage, frequency and medication time limit
Route of administration: oral.
Administering mode: gavage.
Administration volume: rat: 10ml/kg.
Dosage design considerations:
Jewellery sheet as one wishes: an oral 4-5 sheet, 2 times on the one, every heavy 0.5g.People is with 70kg weighing machine, and rat body surface dose,equivalent is 0.419g/kg, and according to blood stasis experimental result, 1.6g/kg just has significant function of promoting blood circulation to disperse blood clots, therefore effect experiment dosage is:
Rat: 1.6g crude drug/kg, 0.8g crude drug/kg, 0.4g crude drug/kg.
Donepezil: quantity, every daily dose is 5mg/ people, and it is 0.419mg/kg that 5mg/ people/sky is equivalent to rat body surface dose,equivalent, and dosage setting is: rat: 0.4mg/kg.
Dihydroergotoxine Mesylate: quantity, every day, maximal dose was 6mg/ people, and it is 0.502mg/kg that 6mg/ people/sky is equivalent to rat body surface dose,equivalent, and dosage setting is: rat: 0.5mg/kg.
3. method for preparation of drug and administration concentration
3.1 jewellery sheets as one wishes
Get 64 of jewellery sheets as one wishes, add after a small amount of deionized water grinding evenly, deionized water is settled to 200ml, is high dose medicinal liquid, and concentration is 0.16g/ml.With deionized water by high dose medicinal liquid proportional diluted, (0.08g/ml), low (0.04g/ml) dosage medicinal liquid in preparation.
3.2 donepezil
Get 2 of donepezil sheets (5mg/ sheet), add after a small amount of deionized water grinding evenly, deionized water is settled to 250ml, and dosage is 0.04mg/ml.
3.3 Dihydroergotoxine Mesylate
Get 13 of Dihydroergotoxine Mesylate sheets (1mg/ sheet), add after a small amount of deionized water grinding evenly, deionized water is settled to 260ml, and dosage is 0.5mg/ml.
4. date processing and analysis
Adopt SPSS11.0One-Way ANOVA (one factor analysis of variance) to carry out after variance analysis data, employing t check is compared between organizing.
The making of [embodiment 1] VD rat model and laboratory animal grouping
250 adult healthy male SD rats, first through MG-3 type Y type labyrinth, the rat (eliminating 31 rats) that superseded reaction is too blunt or responsive especially to electricity irritation.20 rats of random choose, as sham operated rats, remain 199 rats and adopt the permanent ligation method of improvement bilateral common carotid arteries to make VD animal model.The preoperative 12h fasting of rat, rat is weighed, gavage gives metoprolol (0.5mg/kg), half an hour, pneumoretroperitoneum was injected 1% pentobarbital sodium (4.5ml/kg) anesthesia, preoperative eye socket blood-letting 3ml, rat lies on the back fixing, preserved skin, sterilization, cervical region median incision, after blunt separation sternohyoid and sternocleidomastoid, just can see carotid arterial pulse, blunt separation bilateral common carotid arteries, No. 0 toe-in is pricked its proximal part far away, and cut off from centre, sew up the incision, putting back to insulation in cage raises, inject 1% penicillin sodium 4ml/kg (dosage is 6.4 ten thousand units/kg) postoperative and next day, postoperative gavage gives metoprolol (0.5mg/kg) once a day, give continuously 1 week, strengthen VD rat cerebral ischemia effect (in operation process dead 28).Rats in sham-operated group is sewed up the incision after separating common carotid artery.
After operation finishes, rat recovers to detect after 2 days whether success of modeling, and 171 operation rats carry out Y Y-maze test, and screening principle is that correct number of times is greater than above eliminating 10 times.Wherein qualified rat is 122, is divided at random 6 groups, and except 22 of model group, all the other respectively organize 20 every group, respectively organize rat gastric infusion in morning every day once, successive administration 3 weeks, and model group and sham operated rats give same volume deionized water.10 rats of every group of random choose are cooked behavioristics's experiment, after last administration finishes, inject 1% sodium pentobarbital (4.5ml/kg) anesthetized rat and carry out cerebral blood flow detection, detect and finish rear direct broken end and get brain and carry out monoamine transmitters and amino acids mediator index in brain and detect.All the other each group rats, abdominal aortic blood immediately after administration finishes, centrifuging and taking supernatant carries out amino acids mediator index in serum and detects, gets brain and carry out histopathology detection.
The experiment of [embodiment 2] behavioristics
1 impact of jewellery sheet as one wishes on VD learning and memory in rats
Its Memory result is tested in each group rat application Y-Shaped labyrinth of MG-3 type.Y labyrinth is made up of three identical arms, is called I arm, II arm, III arm.At the bottom of labyrinth, lay diameter 0.2cm, long 14cm, the electric grid of spacing 1cm, the stimulation of can switching on.15W signal lights is respectively equipped with on three arm tops, and light, as the signal of electric shock, distinguishes that with trained rat light stimulates and the ability of clearing bearing.When experiment, wherein have the lamp of the one arm end to send light, now this arm bottom electrical grid no current is by being place of safety, and the lamp of another two arms does not work, and bottom electrical Netcom electricity is non-security district.Place of safety and non-security district randomly changing.Before experiment, first rat is put into labyrinth, make it freely movable, adapt to 5min, training Day rat shock by electricity in starting area to be caused it and escapes to place of safety, and light continues 10s, the rest 5s that then turns off the light, and beginning next operation, tests altogether 15 times.Be that test day operates with training Day next day, records correct response number of times in 15 tests and carry out statistical analysis.Experiment is carried out under dark, quiet environment.Regulation rat directly escapes from starting area to be called " correct response " to the reaction of place of safety after being shocked by electricity, otherwise is " wrong reaction ".The results are shown in Table 1.
Result demonstration, with sham operated rats comparison, the minimizing of the correct number of times highly significant of animal pattern before administration, shows VD modelling success.The minimizing of administration 2 weeks and 3 weeks equal highly significants of the correct number of times of model group of administration, the ability of learning and memory of VD rat significantly declines, wherein 2 weeks P < 0.001 of administration, 3 weeks significances of administration are P < 0.01.With model group comparison, administration 2 weeks, (significance is respectively P < 0.01 to the correct number of times of increase of donepezil, the equal energy of the jewellery sheet high dose highly significant of complying with one's wishes, P < 0.001), administration 3 weeks, donepezil, high, the middle dosage of jewellery sheet of complying with one's wishes also all can increase correct number of times (significance is respectively P < 0.05, P < 0.01, P < 0.05) significantly.Hydergine group indices there are no significant difference.Experimental result shows that jewellery sheet as one wishes can improve the ability of learning and memory of VD rat space and conditioning stimulus significantly.
The impact of table 1 jewellery sheet as one wishes on VD rat Y maze experiment
*p and sham operated rats ratio,
*p < 0.01,
* *p < 0.001; #P and model group ratio, #P < 0.05, ##P < 0.01, ###P < 0.001
Y-maze experiment result shows, administration 2 weeks, and the correct number of times of electricity irritation reaction is escaped in the increase of the jewellery sheet high dose group energy highly significant of complying with one's wishes, administration 3 weeks, high, the middle dosage of jewellery sheet of complying with one's wishes also all can improve correct number of times significantly.Experiment shows, the jewellery sheet of complying with one's wishes can improve the ability of learning and memory of VD rat space and conditioning stimulus.
2 jewellery sheets as one wishes are held the impact of rope time on VD rat
Administration 3 weeks, holds rope experiment, the coordination ability of test experience rat to each group of rat.The nylon rope horizontal direction that is 5mm by a diameter ties up to overhead 1m place, pads sponge cushion on vertical lower ground.Two experimental rat fore paws are placed on nylon rope, then loose one's grip, the record time t of rat between dropping that loose one's grip.
The results are shown in Table 2.
Result demonstration, with sham operated rats comparison, model group rat is held the reduction of rope time highly significant.With model group comparison, donepezil group, the high, medium and low dosage of jewellery sheet group of complying with one's wishes all can extend significantly and hold the rope time.Experimental result shows that jewellery sheet as one wishes can extend significantly VD rat and hold the rope time, significantly improves the VD rat coordination ability.
Table 2 jewellery sheet as one wishes is held the impact of rope time on VD rat
*p and sham operated rats ratio,
*p < 0.01; #P and model group ratio, #P < 0.05,
Hold rope experimental result and show, the high, medium and low dosage group of jewellery sheet that complies with one's wishes is held the rope time to VD rat all significant prolongation, and the jewellery sheet that shows to comply with one's wishes can significantly improve VD rat motor harmony.
The experiment of [embodiment 3] mediator assay
1 impact of jewellery sheet as one wishes on monoamine transmitters in VD rat brain
The preparation of brain homogenate sample:
Experiment finishes rear rat directly breaks end, and separates rat whole brain (retaining brain and diencephalon) on ice platform, weighs.Add the ratio of 1ml 5% perchloric acid to add perchloric acid in 0.1g brain (weight in wet base), put into glass homogenate tube, homogenate under ice bath.Homogenate is collected in 1.5ml centrifuge tube, and in 12000r/min ,-4 ℃ of centrifugal 20min, get supernatant sample detection.
Chromatographic condition:
Chromatographic column: ZORBAX Eclipse Plus-C
18, 150 × 4.6mm, 5 μ m.
Mobile phase is the KH of 0.1mol/L
2pO
4buffer-methanol (volume ratio 9: 1).Flow velocity is 0.7ml/min, and sampling volume is 20ul, and column temperature is 35 ℃, and the excitation wavelength of fluorescence detector is 254nm, and emission wavelength is 338nm.
The range of linearity:
Adopt external standard method, measure with the titer sample introduction of variable concentrations, take peak area Y as vertical coordinate, sample introduction concentration X is abscissa mapping, calculates equation of linear regression, in table 3.
Table 3NE, the equation of linear regression of DA and 5-HT
The demonstration of table 4 result, with sham operated rats comparison, the minimizing (significance is P < 0.001) of model group rat brain interior three kinds of monoamine transmitters NE, DA, the equal highly significant of 5-HT content.With model group comparison, donepezil, hydergine all can suppress the minimizing (significance is P < 0.001) of three kinds of monoamine transmitterses significantly.The high, medium and low dosage of jewellery sheet group of complying with one's wishes all can suppress three kinds of monoamine transmitterses in brain and reduce (wherein DA high dose group significance P < 0.05, all the other significances are P < 0.001).Experimental result shows that jewellery sheet as one wishes has extraordinary protective effect to three kinds of monoamine transmitters NE, DA, 5-HT in brain.
The impact of table 4 jewellery sheet as one wishes on three kinds of monoamine transmitter contents in VD rat brain
*p and sham operated rats ratio,
* *p < 0.001; #P and model group ratio, #P < 0.05, ###P < 0.001
Remarks: 2 of model group rats deaths before experiment, 2 samples of sham operated rats loss in 2 of donepezil group rats deaths, mediator mensuration process.
2 impacts of jewellery sheet as one wishes on amino acids mediator in VD rat brain
The preparation of brain homogenate sample:
Rat directly breaks end, and separates rat whole brain (retaining brain and diencephalon) on ice platform, weighs.Add the ratio of 1ml 5% perchloric acid to add perchloric acid in 0.1g brain (weight in wet base), put into glass homogenate tube, homogenate under ice bath.Homogenate is collected in 1.5ml centrifuge tube, and in 12000r/min ,-4 ℃ of centrifugal 20min, get supernatant sample detection.
Chromatographic condition:
Chromatographic column: ZORBAX Eclipse Plus-C
18, 150 × 4.6mm, 5 μ m.
Mobile phase: 1) water: 0.05M sodium acetate solution, adjusting the pH value of solution with acetic acid is 6.7.
2) organic facies: 97.5% methanol and 2.5% oxolane mixed solution.
Each mobile phase is all used G before using
6sintered filter funnel filters.
Flow velocity: 1.0ml/min.
Fluorescopy detector wavelength set: excitation wavelength: 340nm, emission wavelength: 450nm.
The preparation of derivatization reagent:
9mg OPA is dissolved in the methanol of 167 μ l, then adds the sodium borate of 1.5ml 0.4M and the 3-mercaptoethanol of 7 μ l, mix homogeneously, this solution keeps in Dark Place at 4 ℃, and reprovision is once weekly.
Detect:
Accurately draw sample 20 μ l, add 40 μ l derivatization reagents to carry out injection liquid phase system after pre-column derivatization, adopt geopressure gradient eluting, relevant aminoacid is separated, detect with fluorescence detector.
The range of linearity:
Adopt external standard method, measure with the titer sample introduction of variable concentrations, take peak area Y as vertical coordinate, sample introduction concentration X is abscissa mapping, calculates equation of linear regression.
The equation of linear regression of table 5ASP and GABA
Result (in table 6) demonstration, with sham operated rats comparison, in model group rat brain, ASP mediator content reduces (significance is P < 0.05) significantly, and GABA changes without significance.With model group comparison, donepezil can significantly suppress the minimizing (significance is P < 0.05) of ASP, and hydergine affects without significance ASP.High, the middle dosage of jewellery sheet group of complying with one's wishes all can suppress significantly ASP and reduce (significance is respectively P < 0.05, P < 0.001), and low dosage ASP also has certain rising.Experimental result shows that jewellery sheet as one wishes has significant protective effect to ASP mediator in brain.
The impact of table 6 jewellery sheet as one wishes on 2 seed amino acid class mediator content in VD rat brain
*p and sham operated rats ratio,
*p < 0.05; #P and model group ratio, #P < 0.05, ##P < 0.01, ###P < 0.001
Remarks: 2 of model group rats deaths before experiment, 2 samples of sham operated rats loss in 2 of donepezil group rats deaths, mediator mensuration process.
3 impacts of jewellery sheet as one wishes on amino acids mediator in VD rat blood serum
The preparation of blood serum sample:
Experiment finishes rear rat aorta and gets blood 2ml, and in 3000r/min, centrifugal 10min, gets supernatant.Get supernatant 100ul, add 5% perchloric acid in 1: 1 ratio, in 1.5ml centrifuge tube, shake 2min, leave standstill 2min, in 12000r/min ,-4 ℃ of centrifugal 20min, get supernatant sample detection.
Chromatographic condition:
Chromatographic column: ZORBAX Eclipse Plus-C
18, 200 × 4.6mm.
Mobile phase: 1) water: 0.05M sodium acetate solution, adjusting the pH value of solution with acetic acid is 6.7.
2) organic facies: 97.5% methanol and 2.5% oxolane mixed solution.
Each mobile phase is all used G before using
6sintered filter funnel filters.
Flow velocity: 1.0ml/min.
Fluorescopy detector wavelength set: excitation wavelength: 340nm, emission wavelength: 450nm.
The preparation of derivatization reagent:
9mg OPA is dissolved in the methanol of 167 μ l, then adds the sodium borate of 1.5ml 0.4M and the 3-mercaptoethanol of 7 μ l, mix homogeneously, this solution keeps in Dark Place at 4 ℃, and reprovision is once weekly.Detect:
Accurately draw dialysis solution 20 μ l, add 40 μ l derivatization reagents to carry out injection liquid phase system after pre-column derivatization, adopt geopressure gradient eluting, relevant aminoacid is separated, detect with fluorescence detector.
The range of linearity:
Adopt external standard method, measure with the titer sample introduction of variable concentrations, take peak area Y as vertical coordinate, sample introduction concentration X is abscissa mapping, calculates equation of linear regression.
The equation of linear regression of table 7ASP and GABA
Result (in table 8) demonstration, with sham operated rats comparison, in model group rat peripheral blood, mediator GABA content reduces (significance is P < 0.05) significantly, and ASP content changes without significance.With model group comparison, donepezil, hydergine are on GABA there are no significant impact.The high, medium and low dosage of jewellery sheet of complying with one's wishes all can suppress significantly GABA mediator and reduce (significance is respectively P < 0.01, P < 0.01, P < 0.05).Experimental result shows that jewellery sheet as one wishes has protective effect to GABA mediator in serum.
The impact of table 8 jewellery sheet as one wishes on 2 seed amino acid class mediator content in VD rat peripheral blood
*p and sham operated rats ratio,
*p < 0.05; #P and model group ratio, #P < 0.05, ##P < 0.01
Remarks: dead 2 of rats in sham-operated group, 4 of model group rats deaths, 2 of donepezil group rats deaths before experiment.In serum, in amino acid neurotransmitters mensuration process, in No. 4 samples of model group, No. 3 samples of jewellery sheet high dose group of complying with one's wishes, the jewellery sheet of complying with one's wishes, in 1,5, No. 7 sample treatment processes of dosage group, lose.
Cerebral tissue mediator content results shows; the high, medium and low dosage of jewellery sheet group of complying with one's wishes all can suppress NE, DA in brain, 3 kinds of monoamine transmitterses of 5-HT reduce; high, the middle dosage of jewellery sheet group of complying with one's wishes all can suppress ASP mediator significantly to be reduced; in serum, mediator content results shows; the high, medium and low dosage of jewellery sheet group of complying with one's wishes all can suppress GABA mediator significantly to be reduced; experimental result shows; NE, DA, 5-HT, ASP mediator in brain are had to extraordinary protective effect, GABA mediator in serum is also had to protective effect.
The impact of [embodiment 4] jewellery sheet as one wishes on VD rat brain blood flow
After experiment finishes, respectively organize rat and carry out doppler ultrasound detection, detect the hemodynamic variation of rat brain.Testing result (in table 9) shows, with sham operated rats ratio, cerebral blood flow peak systolic velocity, blood flow speed at the end of vasodilation, the equal highly significant of mean blood flow velocity lower than sham operated rats, reflection cerebral blood perfusion and blood supply wretched insufficiency, with model group ratio, the rising of cerebral blood flow peak systolic velocity, blood flow speed at the end of vasodilation, the equal highly significant of mean blood flow velocity in donepezil group, the jewellery sheet group that complies with one's wishes, experimental result shows, the jewellery sheet energy significance of complying with one's wishes increases rat brain blood flow, thereby improves the brain injury that blood supply insufficiency causes.
The impact of table 9 jewellery sheet as one wishes on VD rat brain blood flow
*p and sham operated rats ratio,
*p < 0.01; #P and model group ratio, #P < 0.05, ##P < 0.01, ###P < 0.001
Remarks: 2 of donepezil group rats deaths before cerebral hematoncometry experiment
Cerebral blood flow test experience result shows, the rising of the high, medium and low dosage of jewellery sheet as one wishes to cerebral blood flow peak systolic velocity, blood flow speed at the end of vasodilation, the equal energy of mean blood flow velocity highly significant.Experimental result shows, thereby the jewellery sheet of complying with one's wishes can improve the brain injury that cerebral blood supply insufficiency causes by increasing VD rat brain blood flow.
Above detailed description of the present invention does not limit the present invention, and those skilled in the art can make according to the present invention various changes and distortion, only otherwise depart from spirit of the present invention, all should belong to appended claims limited range of the present invention.
Claims (4)
1. the purposes of Tibetan medicine in preparation treatment vascular dementia medicine, described Tibetan medicine is made up of following raw material:
Concha Margaritifera 22.69 weight portions, Lignum Aquilariae Resinatum 22.69 weight portions, Tufa 22.69 weight portions, Lapis Micae Aureus 6.81 weight portions, Flos Carthami 22.69 weight portions, Eriocheir sinensis 11.34 weight portions, Flos Caryophylli 9.07 weight portions, Fructus Terminaliae Billericae 22.69 weight portions of enucleation, Semen Myristicae 9.07 weight portions, Fructus Amomi Rotundus 9.07 weight portions, Fructus Phyllanthi 29.49 weight portions, Fructus Tsaoko 6.81 weight portions, Cuminum celery 9.07 weight portions, Lignum Santali Albi 18.15 weight portions, Semen Nigellae 9.07 weight portions, Lignum Dalbergiae Odoriferae 74.86 weight portions, Fructus Piperis Longi 6.81 weight portions, Fructus Chebulae's 29.49 weight portions of enucleation, Rhizoma Alpiniae Officinarum 18.15 weight portions, GANGCAO GAO 9.07 weight portions, Cortex Cinnamomi 11.34 weight portions, Olibanum 13.61 weight portions, the Radix Aucklandiae 18.15 weight portions, Semen Cassiae 13.61 weight portions, Cornu Bubali or Pulvis Cornus Bubali Concentratus 9.07 weight portions, Semen seu folium abelmoschi moschati 11.34 weight portions, Lagotis brachystachya Maxim. 34.03 weight portions, Radix Inulae 18.15 weight portions, artificial Moschus's 0.45 weight portion, artificial Calculus Bovis or In vitro cultured Calculus Bovis 0.45 weight portion.
2. purposes claimed in claim 1, wherein said Tibetan medicine is any peroral dosage form that is selected from pill, capsule, tablet, powder and granule.
3. purposes claimed in claim 2, wherein said Tibetan medicine is the jewellery ball of complying with one's wishes.
4. purposes claimed in claim 2, wherein said Tibetan medicine is the jewellery sheet of complying with one's wishes.
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| Title |
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| 中华人民共和国药典委员会.如意珍宝丸.《中华人民共和国***药品标准-藏药》.1995,第317页. * |
| 哈斯巴根,等.蒙药治疗老年性痴呆的体会.《中国民族医药杂志》.1999,第5卷第21-22页. * |
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