CN1104096A - Snake-poison substitute medicine for giving up drug-taking and curing senile dementia and its preparation method - Google Patents
Snake-poison substitute medicine for giving up drug-taking and curing senile dementia and its preparation method Download PDFInfo
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Abstract
The present invention relates to a medicine prepared by using cobra-venom neurotoxin of Elapidae and snake-venom nerve growth factor of Agkistrodon to replace medicine for giving up taking drugs and resisting senile dementia. It is mainly made up by proportionally mixing neurotoxin and nerve growth factor obtained by using cobra-venom of Elapidae and snake-venom of Agkistrodon, passed through such processes of purification, enzyme and gene engineering treatments. The invented medicine can be substituted for medicine for giving up taking drugs, and has better abstinence effect, compared with the existent medicine for giving up taking drugs. Besides, it also can be used for resisting senile dementia, preventing acetylcholine from aggregating inward brain and making intracerebral acetylcholine and dopamine attain metabolic balance.
Description
The invention belongs to snake venom is used to produce the medicine that substitutes drug rehabilitation and treatment senile dementia.
At present, drug abuse all endangers very big to social security and people healthy, because the addiction after drugs are sucked, make the smoker be difficult to give up, now mainly adopting the drug rehabilitation method is to rely on some that addicted anti-additive medicament methadone is arranged, tinctura opii etc. and be aided with coercive methods, though got some drug abstinences, but because drug user's psychic dependence height, and alternative medicine itself also has certain addiction, it is also higher that junkie is given up the back relapse rate, with regard to present stage, also do not see the report of snake venom anti-additive medicament, the experiment report of some snake venom aspect drug rehabilitation only arranged abroad.Current, seek a kind of medicine and method of quitting drug abuse actual effect and not having addiction trend that truly have, be a urgent problem of modern medicine study.
With regard to alzheimer disease, be commonly considered as because the carrying out property hypophrenia that big brain organic or metabolic pathological changes cause.The scholar who has in the recent period thinks, because various illness cause the brain metabolism disorder, dopamine reduces, and acetylcholine (Ach) increases, and causes imbalance, cause the function imbalance of brain, dysnoesia appears, the slow movement that brain is commanded, and particularly the lipid diet increases in recent years, physical training reduces, form cerebrovascular acidify etc., cause the popularity brain atrophy, circumscribed atrophy of brain, cerebral blood flow is under-supply, cause alzheimer disease, at present, the treatment alzheimer disease does not still have specific medicament, the main activating blood and removing stasis drug that adopts, the existing various reports that snake venom is used for studying in this respect of also not seeing.
Purpose of the present invention to invent exactly a kind of with active component in the snake venom as primary raw material, production has the drugs property given up preferably, no addiction, lower relapse rate, can have than methadone, tinctura opii etc. has certain addicted medicine anti-additive medicament better to substitute anti-additive medicament.Medicative to alzheimer disease simultaneously, can promote the acetylcholine (Ach) of extremity, trunk to discharge, cause acetylcholine (Ach) and dopamine balance in the brain, the symptom of treatment and alleviation alzheimer disease reaches the medicine of the treatment alzheimer disease that can recover intelligence, memory to a certain extent.
Summary of the invention of the present invention is made up of neural poison of Elapidae snake venom and snake venom from agkistrodon nerve growth factor.Be characterized in that the neural poison of Elapidae snake venom is 45-80%, the snake venom from agkistrodon nerve growth factor is 20-55%, wherein effect is best when the ratio of neural poison and nerve growth factor is about 3: 1, its preparation method is that the Elapidae snake venom is got neural poison (peptide) through the carboxymethyl cellulose column chromatography purification with after proteolytic enzyme processing, snake venom from agkistrodon is got neural somatomedin after column chromatography purification and genetic engineering production, the neural poison of wherein said Elapidae snake venom is the neural poison of cobra-venom, the neural poison of king cobra venom, the neural poison of krait venom, the neural poison of Agkistrodon snake venom etc.Described Crotalinae snake venom nerve growth factor is agkistrodon halyx pallas venom nerve growth factor, Agkistrodon venom nerve growth factor, trimeresurus stejnegeri venom nerve growth factor, Trimeresurus mucrosquamatus (Cantor). snake venom nerve growth factor.Directly be processed into injection or be mixed and made into capsule after Elapidae snake venom nerve growth and snake venom from agkistrodon nerve growth factor be mixed in proportion with glucose, the use amount of described medicine is by the each crude drug consumption 500-800 microgram of adult, use every day two to three times, capsule crude drug charge weight is 300-400 microgram/grain.
Effect of the present invention is such, and the present invention is used for substituting drug rehabilitation and treatment alzheimer disease with snake venom.Because medicine of the present invention is with neural poison of active component in the described Serpentis kind snake venom or nerve growth factor preparation.Confirm through long-term basis pharmacology and toxicologic study, neural poison mainly acts on the postsynaptic position, is that nervus motorius is not held, the conduction of block nerves muscle, the acetylcholine effect there is striving property inhibitory action unexpectedly, the KCL effect there is not influence, end plate potential (EPPS) and miniature end-plate potential (MEPPS) result of study show not had influence by electrokinetic potential on teleneuron conduction and the sarolemma, show that its effect is identical with α-tubocurare.Import maincenter into by the periphery block nerves, tangible non-narcotic analgesic activity is arranged, main feature is that onset is slow, the length of holding time, toleration can not appear, addiction not, but after therapeutic effect occurring decrement, still can keep curative effect, and not see obvious toxicity and rely on potentiality.Chicken biventer cervicis specimen measurement result shows that after adding the purifying nerve poison, the muscle contraction that average 6+1 divides the internal stimulus nerve to cause disappears, and to the loss for reaction of acetylcholine, and the irritant reaction of direct stimulated muscle and 10%KCL does not disappear.Show that this nerve poison mainly is a postsynaptic nerve conduction blocking effect.The guinea pig ileum test; After tracing normal low-frequency electrostimulating on 5 specimen and causing that the ileum rhythm and pace of moving things shrinks, in bathing pipe, add morphine hydrochloride (final concentration 0.1 mcg/ml), guinea pig ileum is shunk and obviously is suppressed, reaching maximum suppresses, shrinking only is original 40+11%, with Krebs liquid eluting 3 times, after recovering normally to the ileum contraction, adding final concentration is the neural poison of 2 mcg/ml, and 2+1.2 divides the after-contraction baseline to move on slight, than original rising 20+9%, obvious decline appears in amplitude immediately, be maximum the inhibition to occur after 3 minutes, amplitude is not for adding preceding 45+10%, and singly with morphine inhibitory action similar (P＞0.5).The test of isolated mouse deferent duct; Experimentation is identical with the test of operation ileum, after tracing normal low-frequency electrostimulating and causing mouse vas deferens rhythm and pace of moving things contractile response, adding final concentration is 0.5 mcg/ml morphine, amplitude obviously descends, be the 40+13.5% before the administration, eluting was traced normal amplitude 3 times after 30 minutes, adding the neural poison of final concentration 2 mcg/ml moved in same the demonstration on the baseline about 1 minute, raise 15.6% than original, amplitude is reduced to about 75%, record adds morphine 12 micrograms behind the contractile response again, and mouse vas deferens shrinks that obviously to drop to administration immediately preceding about 40%, to the reduction amplitude with morphine similar (P＞0.5) separately.The mouse jump experiment; 1) the neural poison of different Elapidaes behind the mice morphine addiction, gives different Elapidae snake venom neural poison to the influence of mouse jump experiment, no matter oral the result show or intramuscular injection all have obvious therapeutic action (＜0.01-0.001) see Table 1;
2) the purifying nerve poison is to the effect of mouse jump experimental therapy, and with Elapidae purifying nerve poison, the result shows no matter inject or oral, still has better therapeutical effect, and P＜0.01-0.001 sees Table 2;
3) mouse jump experimental effect and dose relationship through further measuring cobratoxin and thick malicious dose-effect relationship proof behind commensurability morphine addiction, with increasing for the poison amount, the collaborative respiratory paralysis effect that causes then occurs behind doses.This shows further that in the result the neural malicious active component of oral and lumbar injection is absorbed.See Table 3;
Naloxone influences morphine, neural malicious analgesic activity:
The neural poison of rat injection, morphine are after 3 hours, and (P＜0.01) is all improved than matched group in the threshold of pain, and behind the injection naloxone 3mg/kg, the morphine group is reversed, and the threshold of pain descends, and neural poison group then only has slight decline, and analgesic activity is (P＜0.01) still clearly, sees Table 4.
Analgesic activity:
1, mouse test; Adopt hot plate method, before and after the administration own control or with normal saline group contrast P＞0.01-0.001, the results are shown in Table 5.
2, rat electricity irritation experiment; There were significant differences with own control and normal saline contrast before the experiment.P＞0.01-0.001 the results are shown in Table 6.The result shows that the neural malicious analgesia duration of snake venom is long, and more stable than morphine, the morphine group prolongs in time certain decline.
The physicochemical property of nerve growth factor is such, and molecular weight is 28000,21000,30000,38000 dalton.Isoelectric point, IP 6.8-10 is made up of 101,117,274 aminoacid.The main pharmacodynamics effect; Can significantly increase the chicken embryos nerve fiber regeneration.
The pharmacological evaluation of medicine of the present invention shows, can prolong fruit bat time-to-live and sexual maturity time, compare nearly 1/2 time of prolongation with matched group, there were significant differences, and (P＞0.01) can strengthen the resistivity of fruit bat to poor environment, compare with matched group that there were significant differences, can recover geriatric animals east Liang Mu alkali and cause memory impairment.Kinetic energy and clinical proof have remarkable proliferative effect to the bone lattice.Immunologic function significantly strengthens.
Heroin, morphine patient are treated after urine examination confirms, the result shows in treatment can remove physical dependence in 15 days.Remove the every day amount of sucking the greater and still have symptoms such as stomachache, vomiting to produce, the need long period just can give up.All the other patients withdrawal symptom do not occur substantially during substituting.Compare no addiction with methadone, successively decrease to give up with morphine and compare, withdrawal symptom significantly is lower than the morphine matched group that successively decreases.
The present invention presses the specification requirement of Ministry of Public Health Clinical Researches of New Drugs, has carried out 116 routine Naja class neurotoxin preparations clinical withdrawal of heroin dependency and rehabilitation effect are observed; The result shows that the heroin withdrawal symptom is had certain control and mitigation, and after medication group and the drug withdrawal of compound medication group, urine sample morphine qualitative experiment and naloxone are urged addiction experiment total negative separately; Opium withdrawal symptom quantizes scoring (OWS) pad value＞90%, clinical obvious effective rate (clinical withdrawal rate) 100%; Compound medication group (medicine+tinctura opii of the present invention or methadone) curative effect the best; Physiology and psychology index determining show, the present invention has obvious rehabilitation effect, particularly the heroin psychic dependence there is the trend of reduction, tracing study in four months shows, the present invention is multiple, and the addiction rate is lower than 40%, and the test grouping is to adopt the table of random number method that the volunteer is divided into medicine group of the present invention (80 example), methadone matched group (16 example) and tinctura opii mixture matched group (20 example).Wherein invention medicine list is with organizing: 40 people, compound medication I group (medicine+methadone of the present invention): 20 people, compound medication II group (medicine+tinctura opii of the present invention): 20 people, methadone matched group: 16 people, tinctura opii matched group: 20 people.Medication by all observe cases all under medical professional with single quantitative oral administration of blind legal time, viewing duration except that special circumstances are done general anti symptom treatment, stop using without exception other anti-additive medicament and method.Clinical efficacy evaluation is given up (withdrawal) syndrome rating scale (OWS) observed and recorded according to opioid drug, and its testing program and dosage see Table 7 the course of treatment, result of the test sees Table 8, table 9, table 10.
The present invention also has curative effect preferably to the treatment alzheimer disease, because neural poison mainly acts on the postsynaptic position, be that nervus motorius is not held, the conduction of block nerves muscle, to the competitive inhibitory action of acetylcholine (Ach) effect, because Neurotoxic effect, promote the acetylcholine (Ach) of extremity trunk not discharge after using medicine of the present invention to brain, acetylcholine (Ach) is not gathered in brain, allow acetylcholine (Ach) and dopamine balance in the brain, make the cerebral metabolism balance, the former regeneration of injured nerve, can treat and alleviate the symptom of alzheimer disease, intelligence has certain recovery, and memory has part to improve, self lives certain self-care ability, thinking and judgment have improvement, and emotion is progressive to some extent, thereby the normal function that recovers brain is had tangible curative effect, safe in utilization, side effect does not appear.It below is the treatment situation of several routine cases.Entered comatose state when first example is admitted to hospital, the extremity moving obstacle, the time heating arranged, unable to speak can not be taken action gatism, enter persistent vegetative state, clinical diagnosis is an alzheimer disease, vegetative state begins to take medicine of the present invention (every day secondary, each two) after being admitted to hospital, adhere to taking for a long time, after about 20 days, mind is recovered, and can cry stomachache.Take medicine approximately after two months, the patient can recover language, and clear recalling the past cried ailingly, and whom differentiates, and that whom gets well is bad, can swear at people when thoughtless.Right side hemiplegia of limb when second example is admitted to hospital, motor aphasia has a dull expression on one's face, and oppressiveness is asked and do not answered, and is perverse and pay no attention to, bed, defecation can not be taken care of oneself.Be diagnosed as the left side cerebral thrombosis, the vascular senile dementia.Begin to take medicament capsule of the present invention after being admitted to hospital, every day secondary, each two, mind is more preceding active behind the first quarter moon, the extremity reflex time is pain, and emotion is obviously active, and aggressivity is arranged, often walk about, emotion is obviously improved in the time of the bimester of approximately, can differentiate the people, but right side upper limb limitation of activity, out-of-bed activity is good, cigarette to take out, can speak behind two first quarter moons, no longer include aggressivity, be emotionally stable, can walk, play, the right upper extremity activity is good.Can greet people's " seat " when meeting after three months, what energy was correct when giving cigarette puts into mouth with filter end, the food of taking care of oneself, and freedom of movement, emotion is more preceding more tranquil, and intelligence state and self care ability all have made marked progress.The 3rd example was once done operation because of cerebral trauma, unconsciousness when being admitted to hospital, and talking nonsense, no resolving power, memoryless power, no computing power, no discriminative power, difficulty in walking, defecation can not automatic control.Be diagnosed as the cerebrovascular sclerosis thromboembolism, traumatic vascular senile dementia.The back use medicament capsule of the present invention of being admitted to hospital is treated, and every day, secondary each two, can be seen clearly former operator all around; can cry during urine, diet is normal, can initiatively do up the button; cigarette to take out, memory is obviously recovered behind the one and a half months, sees clearly messenger; certain emotion is arranged, and can state some other people situations, after three months; certain resolving power is arranged, and it is correct to answer a question, the seat of leaving the bed, upright; cigarette to take out, the words of then speaking more when giving cigarette, stable disease.According to Preliminary Clinical Observation, think that medicine of the present invention has tangible curative effect to the treatment alzheimer disease, safe in utilization, side effect does not appear, the therapeutic effect of alzheimer disease is better than the other medicines of present use.
Below for several embodiment of medicine of the present invention.
Embodiment 1, usefulness cobra-venom obtain the neural poison of cobra-venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With agkistrodon halyx pallas venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 45%, after the mixed of nerve growth factor 55%, be mixed and made into capsule with glucose by crude drug 400 micrograms/every.
Embodiment 2, usefulness KING COBRA snake venom obtain the neural poison of king cobra venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With agkistrodon halyx pallas venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 50%, after the mixed of nerve growth factor 50%, be mixed and made into capsule with glucose by crude drug 300 micrograms/every.
Embodiment 3, usefulness krait venom obtain the neural poison of krait venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With agkistrodon acutus venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 55%, after the mixed of nerve growth factor 45%, by crude drug 800 micrograms/make injection at every turn.
Embodiment 4, usefulness Agkistrodon snake venom obtain the neural poison of Agkistrodon snake venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With mountain habu venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 60%, after the mixed of nerve growth factor 40%, be mixed and made into capsule with glucose by crude drug 400 micrograms/every.
Embodiment 5, usefulness cobra-venom obtain the neural poison of cobra-venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With the Trimeresurus stejnegeri snake venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 70%, after the mixed of nerve growth factor 30%, be mixed and made into capsule with glucose by crude drug 300 micrograms/every.
Embodiment 6, usefulness cobra-venom obtain the neural poison of cobra-venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With agkistrodon halyx pallas venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 65%, after the mixed of nerve growth factor 35%, be mixed and made into capsule with glucose by crude drug 400 micrograms/every.
Embodiment 7, usefulness cobra-venom obtain the neural poison of cobra-venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With agkistrodon halyx pallas venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 75%, after the mixed of nerve growth factor 25%, be mixed and made into capsule with glucose by crude drug 400 micrograms/every.
Embodiment 8, usefulness cobra-venom obtain the neural poison of cobra-venom (peptide) after carboxymethyl cellulose column chromatography purification and proteolytic enzyme processing.With agkistrodon halyx pallas venom after column chromatography purification and genetic engineering with the nerve growth factor of gained by neural poison 80%, after the mixed of nerve growth factor 20%, be mixed and made into capsule with glucose by crude drug 400 micrograms/every.
The thick poison of the different Elapidae snake venom of table 1 is to mouse jump experimental therapy effect N=8
| Lumbar injection | Oral | |||||
| Give the poison amount | Jump for several times | The P value | To the toxic agent amount | Number of skips | The P value | |
| Contrast | Salt solution | 44.36 | 〈0.01 | |||
| Cobra | 5μg/20g | 16.4 | 〈0.01 | 40μg/20g | 21.9 | 〈0.01 |
| Banked krait | 5μg/20g | 17.3 | 〈0.01 | 10μg/20g | 19.12 | 〈0.01 |
| King cobra | 5μg/20g | 9.14 | 〈0.01 | 10μg/20g | 18.4 | 〈0.01 |
Table 2 cobratoxin is to mouse jump experimental effect N=8
| Lumbar injection | Oral | |||||
| Give the poison amount | Jump for several times | The P value | To the toxic agent amount | Number of skips | The P value | |
| Contrast | 0.1ml salt solution | 42.9 | 0.1ml salt solution | 43.5 | ||
| Cobra | 0.25μg/20g | 21.2 | 〈0.01 | 2μg/20g | 16.2 | 〈0.001 |
| King cobra | 0.2μg/20g | 18.4 | 〈0.01 | 2μg/20g | 19.3 | 〈0.01 |
The withrawal symptom subitem relatively before and after of the present invention group of table 9 and the randomized controlled treatment
Of the present invention group of table 10 and the clinical de-addiction observation of curative effect of control group result
Time gram poison closes I group gram poison and calms down and close I and organize methadone group tinctura opii group by flat single calming down with group gram poison
(my god) routine % example % example % example % example %
Produce effects 3 7.5 17 85 15 75 12 75.0 9 45.0
1 effective 7 17.5 3 15 4 20 2 12.5 7 35.0
Invalid 30 75.0 00152 12.5 4 20.0
Produce effects 4 10.0 20 100 17 85 14 87.5 14 70.0
2 effective 8 20.0 003 15 2 12.5 4 20.0
Invalid 28 70.0 0000002 10.0
Produce effects 6 15.0 20 100 19 95 16 100 17 85.0
3 effective 11 27.5 0015002 10.0
Invalid 23 57.5 0000001 5.0
Produce effects 11 27.5 20 100 20 100 16 100 19 95.5
4 effective 19 47.5 0000001 5.0
Invalid 10 25.0 00000000
Produce effects 14 35.0 20 100 20 100 16 100 19 95.0
6 effective 21 52.5 0000001 5.0
Invalid 5 12.5 00000000
Produce effects 31 77.5 20 100 20 100 16 100 20 100
8 effective 7 17.5 00000000
Invalid 2 5.0 00000000
Produce effects 40 100 20 100 20 100 16 100 20 100
10 effective 0000000000
Invalid 0000000000
Produce effects 40 100 20 100 20 100 15 93.8 17 80.5
15 effective 0000001 6.2 1 5.0
Invalid 000000002 10.0
Claims (10)
1, a kind of snake venom substitutes drug rehabilitation and snake venom anti senile dementia drug, it is characterized in that being formed by following combinations of substances:
The neural malicious 45-80% of Elapidae snake venom,
Snake venom from agkistrodon nerve growth factor 20-55%.
2, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that the neural poison of described Elapidae snake venom is the neural poison of cobra-venom.
3, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that the neural poison of described Elapidae snake venom is the neural poison of king cobra venom.
4, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that the neural poison of described Elapidae snake venom is the neural poison of krait venom.
5, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that the neural poison of described Elapidae snake venom is the neural poison of Agkistrodon snake venom.
6, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that described snake venom from agkistrodon nerve growth factor is the agkistrodon halyx pallas venom nerve growth factor.
7, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that described snake venom from agkistrodon nerve growth factor is the Agkistrodon venom nerve growth factor.
8, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that described snake venom from agkistrodon nerve growth factor is a Trimeresurus mucrosquamatus (Cantor). snake venom nerve growth factor.
9, snake venom as claimed in claim 1 substitutes drug rehabilitation and anti senile dementia drug, it is characterized in that described snake venom from agkistrodon nerve growth factor is the Trimeresurus stejnegeri snake venom nerve growth factor.
10, snake venom as claimed in claim 1 substitutes the preparation method of drug rehabilitation and anti senile dementia drug, it is characterized in that the Elapidae snake venom is through the carboxymethyl cellulose column chromatography purification, with the neural poison that makes after the proteolytic enzyme processing, with the nerve growth factor of snake venom from agkistrodon gained after column chromatography purification and genetic engineering, make after the neural poison of gained and nerve growth factor mixed to scale mutually.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113413461A (en) * | 2021-06-17 | 2021-09-21 | 林德球 | Medicine for resisting senile dementia and its preparing method |
| WO2022109758A1 (en) * | 2020-11-26 | 2022-06-02 | 沈喆景 | Application of proteolytic enzyme of pit viper in treatment of alzheimer's disease |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021068432A1 (en) * | 2019-10-11 | 2021-04-15 | 祁展楷 | Application of elapidae snake postsynaptic neurotoxin monomer molecule in treatment of alzheimer's disease |
| CN111000984A (en) * | 2019-11-16 | 2020-04-14 | 祁展楷 | Application of snake nerve growth factor and snake nerve growth factor precursor in treating senile dementia |
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1993
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022109758A1 (en) * | 2020-11-26 | 2022-06-02 | 沈喆景 | Application of proteolytic enzyme of pit viper in treatment of alzheimer's disease |
| CN113413461A (en) * | 2021-06-17 | 2021-09-21 | 林德球 | Medicine for resisting senile dementia and its preparing method |
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