CN102908572A - 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 the VD symptom, comprise large and small arterial disease, the come off thromboembolism of embolus of diffusivity ischemic white matter lesion, 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, repeatedly the multiple infarctions of lacunar infarction or other reasons occur, cause the ventricles of the brain to enlarge, cortical atrophy destroys corresponding conductive beam, and is dull-witted under the cortex that engenders.
At present, the diagnostic criteria of vascular dementia is to adopt U.S. neuropathy association " neurodiagnosis and statistic handbook " the 4th edition (DSM-IV), be specially: many-sided cognitive defect occurs in (1), show as following the two: memory impairment (can not learn new data and maybe can not recall the data of acquiring); Have one of following cognitive disorder at least: aphasia, apraxia are (although motor function is no problem, but can not execution action), agnosia (although sensory function is no problem, can not be familiar with or recognition object), carry out the obstacle (namely plan, organize, arrange order, abstract etc.) of managerial function; (2) above cognitive defect causes social activity or occupational function defective, and before can finding that these functions obviously are not so good as; (3) there are limitation nervous system signs and symptom (for example: deep tendon reflex is hyperfunction, stretch plantar reflex, pseudobulbar paralysis, gait disorder, a certain limbs be weak); Or the laboratory that the prompting cerebrovascular disease is arranged also can be thought the cause of disease of this obstacle according to (the many infractions that for example, relate to cortex and white matter); (4) these defectives are not due to due to the delirium.
Vascular dementia is a kind of multi-factor disease, is the unique dull-witted type that can prevent and treat now, and the VD diagnosis is in case establish and namely be fit to the cognitive symptom of beginning Drug therapy.Clinical medicine commonly used 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: (hydergine Shu Naoning), can directly act on DA and 5-HT receptor to Dihydroergotoxine for Hydergine, dihydroergotoxine, reduces cerebral vascular resistance, increases cerebral blood flow and brain to the utilization rate of oxygen, improves synapse neurotransmission function; Aspirin (Aspirin), platelet aggregation inhibitor is widely used in the control of cardiovascular and cerebrovascular disease; Nicergoline (Nicergoine, nicergoline) has the blood vessel dilating effect that a receptor blocks, increase cerebral blood flow, strengthen the utilization of metabolism, increase blood oxygen and the glucose of brain cell, in addition, the metabolism that promotes dopamine is still arranged, promote the synthetic of brain protein, the effects such as anticoagulant and antithrombotic; Nafronyl (Naftidrofuryl, Clarantin, brain is strengthened), it is the 5-HT receptor antagonist, reduce neuronal necrosis due to the ischemia by anti-5-HT, easily see through blood brain barrier directly expansion of cerebral vascular and peripheral blood vessel, increase erythrocytic morphotropism and reduction blood denseness and can promote cellular metabolism, cell hypoxia is also had protective effect; Pentoxifylline (Pentoxifylline) has expansion brain and peripheral vascular effect, also may play a role by affecting erythrocytic morphotropism, platelet adhesion and Platelet, and is clinical in various brain vessel blood obstacle diseases; Vinpocetine (Vinpocetine) can increase cerebral blood flow, improve brain oxygen supply, blood viscosity lowering, and cerebrovascular is had higher selection.
The medicine that acts on neurotransmitter comprises: donepezil (Donepezil, aricept): the acetyl gallbladder acyl that reversibility ground 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) that extracts from the natural plants Herba Lycopodii serrati, belong to the reversibility cholinesterase inhibitor, easily see through blood brain barrier, the effect that promotes that memory represents and hypermnesis keep is arranged.
Neuroprotective Agents comprises: memantine (Memantine): the brain hypoxic-ischemic can cause the presynaptic excitatory amino acid to discharge and again picked-up minimizing, excessive EAA can activate postsynaptic EAA receptor (mainly being nmda receptor and ampa receptor), increase the weight of neuronal damage, memantine can alleviate the nerve injury in the cerebrum ischemia anoxia process as non-unexpectedly striving property nmda receptor antagonist; Nimodipine (Nimodipine): be calcium channel blocker, can effectively regulate the 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 was stated from the blue or green heavily fortified point of Tibetan medicine and pharmacology scholar core and praises in " secret formula Margarita string " book of showing in 13rd century of Christian era.Its prescription is selected natural, precious, the rare Tibetan medicine material that is grown in roof of the world special ecological environment according to the Tibetanmedicine principle, and with modern scientific method refining the forming that combine with traditional handicraft.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; the 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; the artificial Moschus; bezoar pearl is female; Lignum Aquilariae Resinatum; 30 kinds of medical materials such as Radix Glycyrrhizae form; its function cures mainly and is heat clearing away; consciousness-restoring and orifice-opening; channels sootheing and network vessel quickening is used 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 the jewellery ball of complying with one's wishes, and 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 namely is provided.Described Tibetan medicine is made by 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, also can be the improved jewellery sheet as one wishes that provides with tablet form.
By the rat model (VD rat) of suffering from vascular dementia being used the jewellery sheet as one wishes of high, medium and low dosage, observe proof by Animal Behavior Science experiment, the experiment of mediator assay and rat brain blood flow, 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 the brain there are extraordinary protective effect, GABA in the serum is also had protective effect; Can significantly increase VD rat brain blood flow, thereby improve the brain injury that causes 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 better embodiment of the present invention, describe in detail but do not limit the present invention.
1, experiment material
1.1 test sample: 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; mixing; add suitable quantity of water granulation, drying with GANGCAO GAO; tabletting, coating, and get final product.
Character: this product is Film coated tablets, removes behind the film-coat aobvious brown to rufous; Feeble QI is fragrant, bitter in the mouth, sweet.
Specification: every heavy 0.5g.
Lot number: 20101113.
1.2 positive control medicine
1.2.1 donepezil hydrochloride sheet (aricept) is defended material (China) pharmaceutcal corporation, Ltd and is made, 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: source, Shanghai leaf bio tech ltd, lot number: 20110503.
1.3.9r-aminobutyric acid: source, Shanghai leaf bio tech ltd, 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/ props up.
1.4 instrument and consumptive material
The magnificent Educational Instrument Factory 1.4.1MG-3 type labyrinth stimulator, Yuanyang County, Henan Province shake.
1.4.2PB-203 the type electronic balance, METTLER-TOLEDO GROUP produces.
1.4.31200series high performance liquid chromatograph, Agilent Technologies co.
1.4.413300 the type refrigerated centrifuge, Thermo science co.
1.4.5G﹠amp; G T2000 type electronic balance, two outstanding brother's (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. route of administration, method, dosage, frequency and medication time limit determines
Route of administration: oral.
Administering mode: gavage.
Administration volume: rat: 10ml/kg.
The dosage design considerations:
Jewellery sheet as one wishes: an oral 4-5 sheet, 2 times on the one, every heavy 0.5g.The people is with the 70kg weighing machine, and rat body surface dose,equivalent is 0.419g/kg, and 1.6g/kg just has significant function of promoting blood circulation to disperse blood clots according to the blood stasis experimental result, 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 are 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
The jewellery sheet 3.1 comply with one's wishes
Get 64 of the jewellery sheets of complying with one's wishes, after adding a small amount of deionized water and grinding evenly, deionized water is settled to 200ml, is the high dose medicinal liquid, and concentration is 0.16g/ml.With deionized water with high dose medicinal liquid proportional diluted, (0.08g/ml), low (0.04g/ml) dosage medicinal liquid in the preparation.
3.2 donepezil
Get 2 of donepezil sheets (5mg/ sheet), after adding a small amount of deionized water and 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), after adding a small amount of deionized water and grinding evenly, deionized water is settled to 260ml, and dosage is 0.5mg/ml.
4. date processing and analysis
After adopting SPSS11.0One-Way ANOVA (one factor analysis of variance) that data are carried out variance analysis, 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 remain 199 rats and adopt the permanent ligation method of improvement bilateral common carotid arteries to make the VD animal model as sham operated rats.12h fasting before the rat art, rat is weighed, gavage gives metoprolol (0.5mg/kg), half an hour, pneumoretroperitoneum was injected 1% pentobarbital sodium (4.5ml/kg) anesthesia, eye socket blood-letting 3ml before the art, rat lies on the back fixing, preserved skin, sterilization, cervical region median incision, just can see carotid arterial pulse behind blunt separation sternohyoid and the sternocleidomastoid, the blunt separation bilateral common carotid arteries, No. 0 toe-in is pricked its proximal part far away, and cuts off from the centre, sew up the incision, put back to insulation raising in the cage, (dosage is that 6.4 ten thousand units/kg), the postoperative gavage gives metoprolol (0.5mg/kg) once a day to inject postoperative and next day 1% penicillin sodium 4ml/kg, gave continuously for 1 week, strengthen VD rat cerebral ischemia effect (in the operation process dead 28).Rats in sham-operated group is sewed up the incision after separating common carotid artery.
After operation finished, whether rat recovered to detect modeling after 2 days successful, and 171 operation rats carry out the Y Y-maze test, and the screening principle is that correct number of times is greater than eliminating more than 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, and each organizes rat gastric infusion in morning every day once, and in 3 weeks of successive administration, model group and sham operated rats give with the volume deionized water.10 rats of every group of random choose are cooked behavioristics's experiment, after the last administration finishes, inject 1% sodium pentobarbital (4.5ml/kg) anesthetized rat and carry out cerebral blood flow and detect, detect finish after directly broken end get brain and carry out that monoamine transmitters and amino acids mediator index detect in the brain.All the other respectively organize rat, and abdominal aortic blood immediately after administration finishes, centrifuging and taking supernatant carry out that amino acids mediator index detects in the serum, get brain carries out histopathology and detect.
The experiment of [embodiment 2] behavioristics
1 jewellery sheet as one wishes is on the impact of VD learning and memory in rats
Each is organized rat application MG-3 type Y-type labyrinth and tests its Memory result.The Y labyrinth is comprised of three identical arms, is called I arm, II arm, III arm.Lay diameter 0.2cm, long 14cm, the electric grid of spacing 1cm, the stimulation of can switching at the bottom of the labyrinth.The 15W signal lights respectively is equipped with on three arm tops, and light distinguishes that with trained rat light stimulates and the ability of clearing bearing as the signal of electric shock.Wherein have the lamp of the one arm end to send light during experiment, this moment, this arm bottom electrical grid no current passed through to be the place of safety, and the lamp of two arms does not work in addition, and bottom electrical Netcom electricity is non-security district.Place of safety and non-security district randomly changing.First rat is put into the labyrinth before the experiment, make it freely movable, adapt to 5min, the training Day rat shock by electricity in the starting area to be caused it and escapes to the place of safety, and light continues 10s, and the rest 5s that then turns off the light begins next operation, tests altogether 15 times.Be that test day operates with training Day next day, record 15 times the test in the correct response number of times carry out statistical analysis.Experiment is carried out under dark, quiet environment.Directly escape to be called " correct response " to the reaction of place of safety from the starting area after the regulation rat is shocked by electricity, otherwise be " wrong reaction ".The results are shown in Table 1.
The result shows, compares with sham operated rats, and the minimizing of the correct number of times highly significant of animal pattern before the administration shows VD modelling success.The minimizings of administration 2 week and the correct inferior number average highly significant of administration 3 all model group, the ability of learning and memory of VD rat significantly descends, administration 2 all P＜0.001 wherein, administration 3 all significances are P＜0.01.Compare with model group, 2 weeks of administration, (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), 3 weeks of administration, 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 the jewellery sheet of complying with one's wishes can improve the ability of learning and memory of VD rat space and conditioning stimulus significantly.
Table 1 jewellery sheet as one wishes is on the impact of 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, in 2 weeks of administration, the correct number of times of electricity irritation reaction is escaped in the increase of the jewellery sheet high dose group that complies with one's wishes energy highly significant, and in 3 weeks of administration, 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 the VD rat
In 3 weeks of administration, each group rat is held rope experiment, the coordination ability of test experience rat.The nylon rope horizontal direction that is 5mm with a diameter ties up to overhead 1m place, pad sponge cushion on the vertical lower ground.The two fore paws of experimental rat are placed on the 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.
The result shows, compares with sham operated rats, and the model group rat is held the reduction of rope time highly significant.Compare with model group, donepezil group, the high, medium and low dosage of jewellery sheet group of complying with one's wishes all can prolong significantly to be held the rope time.Experimental result shows that the jewellery sheet of complying with one's wishes can prolong significantly the 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 the VD rat
*P and sham operated rats ratio,
*P＜0.01; #P and model group ratio, #P＜0.05,
Hold the 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 the VD rat all significant prolongation, shows that the jewellery sheet of complying with one's wishes can significantly improve VD rat motor harmony.
The experiment of [embodiment 3] mediator assay
1 jewellery sheet as one wishes is on the impact of monoamine transmitters in the VD rat brain
The preparation of brain homogenate sample:
Rat directly breaked end after experiment finished, and separated rat whole brain (keeping brain and diencephalon) at the ice platform, weighed.The ratio that adds 1ml 5% perchloric acid in 0.1g brain (weight in wet base) adds perchloric acid, puts into the glass homogenate tube, homogenate under the ice bath.Homogenate is collected in the 1.5ml centrifuge tube, and in 12000r/min ,-4 ℃ of centrifugal 20min get the 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 the abscissa mapping, calculates equation of linear regression, sees Table 3.
Table 3NE, the equation of linear regression of DA and 5-HT
Table 4 result shows, compares 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 sham operated rats.Compare with model group, 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 in the brain three kinds of monoamine transmitterses and reduce (wherein DA high dose group significance P＜0.05, all the other significances are P＜0.001).Experimental result shows that the jewellery sheet of complying with one's wishes has extraordinary protective effect to three kinds of monoamine transmitters NE, DA, 5-HT in the brain.
Table 4 jewellery sheet as one wishes is on the impact of three kinds of monoamine transmitter contents in the VD rat brain
*P and sham operated rats ratio,
* *P＜0.001; #P and model group ratio, #P＜0.05, ###P＜0.001
Remarks: the model group rats death is 2 before the experiment, 2 samples of sham operated rats loss in 2 of donepezil group rats deaths, the mediator mensuration process.
2 jewellery sheets as one wishes are on the impact of amino acids mediator in the VD rat brain
The preparation of brain homogenate sample:
Rat directly breaks end, and separates rat whole brain (keeping brain and diencephalon) at the ice platform, weighs.The ratio that adds 1ml 5% perchloric acid in 0.1g brain (weight in wet base) adds perchloric acid, puts into the glass homogenate tube, homogenate under the ice bath.Homogenate is collected in the 1.5ml centrifuge tube, and in 12000r/min ,-4 ℃ of centrifugal 20min get the supernatant sample detection.
Chromatographic condition:
Chromatographic column: ZORBAX Eclipse Plus-C
18, 150 * 4.6mm, 5 μ m.
Mobile phase: 1) water: the 0.05M sodium acetate solution, transferring 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, adds again 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 and carry out injection liquid phase system behind the pre-column derivatization, adopt the 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 the abscissa mapping, calculates equation of linear regression.
The equation of linear regression of table 5ASP and GABA
Result's (seeing Table 6) shows, compares with sham operated rats, and ASP mediator content reduces (significance is P＜0.05) significantly in the model group rat brain, and GABA changes without significance.Compare with model group, 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 the jewellery sheet of complying with one's wishes has significant protective effect to ASP mediator in the brain.
Table 6 jewellery sheet as one wishes is on the impact of 2 seed amino acid class mediator content in the 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: the model group rats death is 2 before the experiment, 2 samples of sham operated rats loss in 2 of donepezil group rats deaths, the mediator mensuration process.
3 jewellery sheets as one wishes are on the impact of amino acids mediator in the VD rat blood serum
The preparation of blood serum sample:
Rat aorta was got blood 2ml after experiment finished, and in 3000r/min, centrifugal 10min gets supernatant.Get supernatant 100ul, add 5% perchloric acid in 1: 1 ratio, shake 2min in the 1.5ml centrifuge tube, leave standstill 2min, in 12000r/min ,-4 ℃ of centrifugal 20min get the supernatant sample detection.
Chromatographic condition:
Chromatographic column: ZORBAX Eclipse Plus-C
18, 200 * 4.6mm.
Mobile phase: 1) water: the 0.05M sodium acetate solution, transferring 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, adds again 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 and carry out injection liquid phase system behind the pre-column derivatization, adopt the 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 the abscissa mapping, calculates equation of linear regression.
The equation of linear regression of table 7ASP and GABA
Result's (seeing Table 8) shows, compares with sham operated rats, and mediator GABA content reduces (significance is P＜0.05) significantly in the model group rat peripheral blood, and ASP content changes without significance.With model group relatively, 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 the GABA mediator and reduce (significance is respectively P＜0.01, P＜0.01, P＜0.05).Experimental result shows that the jewellery sheet of complying with one's wishes has protective effect to GABA mediator in the serum.
Table 8 jewellery sheet as one wishes is on the impact of 2 seed amino acid class mediator content in the 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 the experiment.Lose in dosage group 1,5, No. 7 sample treatment processes 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 the amino acid neurotransmitters mensuration process in the serum.
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 the 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 the ASP mediator significantly to be reduced; the mediator content results shows in the serum; the high, medium and low dosage of jewellery sheet group of complying with one's wishes all can suppress the GABA mediator significantly to be reduced; experimental result shows; NE, DA, 5-HT, ASP mediator in the brain there are extraordinary protective effect, GABA mediator in the serum is also had protective effect.
The impact of jewellery sheet on VD rat brain blood flow complies with one's wishes [embodiment 4]
After experiment finished, each was organized rat and carries out the doppler ultrasound detection, detects the hemodynamic variation of rat brain.Testing result (seeing Table 9) shows, with the 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 be lower than sham operated rats, reflection cerebral blood perfusion and blood supply wretched insufficiency, with the 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 of complying with one's wishes can increase the rat brain blood flow by significance, thereby improves the brain injury that blood supply insufficiency causes.
Table 9 jewellery sheet as one wishes is on the impact of 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: donepezil group rats death is 2 before the cerebral hematoncometry experiment
Cerebral blood flow test experience result demonstration, the high, medium and low dosage of jewellery sheet of complying with one's wishes is to all risings of energy highly significant of cerebral blood flow peak systolic velocity, blood flow speed at the end of vasodilation, mean blood flow velocity.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 break away from spirit of the present invention, all should belong to appended claims limited range of the present invention.
Claims (4)
1. Tibetan medicine is preparing the purposes for the treatment of in the vascular dementia medicine, and described Tibetan medicine is made by 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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Cited By (2)
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| CN105381385A (en) * | 2015-12-16 | 2016-03-09 | 山东金诃药物研究开发有限公司 | Application of Ruyizhenbao preparation in preparing medicine for nerve injury protection and regeneration |
| CN113694055A (en) * | 2021-09-02 | 2021-11-26 | 中国科学院昆明植物研究所 | Application of agarotetrol in preparing medicine for treating vascular dementia |
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| CN102269752A (en) * | 2011-04-25 | 2011-12-07 | 甘肃奇正藏药有限公司 | Detection method for pharmaceutical composition preparation |
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| CN102269752A (en) * | 2011-04-25 | 2011-12-07 | 甘肃奇正藏药有限公司 | Detection method for pharmaceutical composition preparation |
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| 中华人民共和国药典委员会: "《中华人民共和国卫生部药品标准-藏药》", 31 December 1995 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105381385A (en) * | 2015-12-16 | 2016-03-09 | 山东金诃药物研究开发有限公司 | Application of Ruyizhenbao preparation in preparing medicine for nerve injury protection and regeneration |
| CN113694055A (en) * | 2021-09-02 | 2021-11-26 | 中国科学院昆明植物研究所 | Application of agarotetrol in preparing medicine for treating vascular dementia |
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