CN109498643A - A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement - Google Patents
A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
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- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
Improve the old application lost in intelligence drug the invention discloses a kind of folate composition and its in preparation, the folate composition comprises the following components in parts by weight: 0.4-12 parts of folacin compound；Vitamin B120.4-3 parts of class compound and vitamin B610-30 parts of class compound；It can also include 0.1-5 parts of brain cell metabolic activation drug；Brain blood circulation promotes drug 0.02-2 parts and one or more of 0.16-5 parts of cerebrocrast object；A kind of drug for improving old mistake intelligence and its application treated and prevented in Alzheimer's disease, blood vessel nature feeble-mindedness and/or Mixed dementia disease drug in preparation are also disclosed simultaneously.Compared with prior art, the drug that composition of the invention and improvement old age lose intelligence is applied widely, Small side effects securely and reliably effectively can prevent and improve old dementia.
Description
Technical field
The invention belongs to medical domains, and in particular to one kind contains folate composition, is more particularly to a kind of folate composition
And its improve the old application lost in intelligence drug in preparation.
Background technique
Dementia is a kind of gradual cognitive functional deterioration sex expression because caused by brain damage or disease.Dementia
Most common with old dementia in patient, morbidity crowd is based on the elderly of over-65s, according to the pre- of the World Health Organization
It surveys, to the year two thousand fifty, old dementia patient numbers are likely to be breached 100,000,000 people or more.Not according to pathogenic factor and illness performance
Together, old dementia is broadly divided into three classes.
The first kind is degenerative dementia.This kind of dementia has accounted for accounting for about old more than half, the hereditary base that loses intelligence patient
The reasons such as cause, the reduction of climacteric women sex hormone, brain injury, drowned anoxic, anthracemia, all easily cause brain gradual
Atrophic type dementia.And one of the most common is exactly stages alzheimer's disease (Alzheimer's disease, AD).Stages alzheimer's disease
It (AD) is a kind of nervous system degenerative disease for carrying out sexual development that onset is hidden, clinically with memory disorders, aphasia, mistake
With, agnosia, visual space technical ability damage, execute dysfunction and the generalized dementias such as personality and behavior change performance be characterized,
The cause of disease is unknown so far.Patient was sent out before 65 years old, claimed alzheimer's disease；Hair patient claims senile dementia after 65 years old.
Second class is vascular dementia (vascular dementia, VD).This kind of dementia is by headstroke, glycosuria
Headstrokes such as disease, heart disease, hypertension, cardiovascular disease, blood fat are high, smoke etc. cause, because of cerebral vessels rupture or stifled
Plug causes brain cell impaired, and elaborative faculty is good or bad, and influences that intelligence, mood are out-of-sequence, and symptom ups and downs merge emotion and lose
Prohibit etc..
Third class is mixed type dementia (senile mixed dementia, MD).Mixed type dementia is first two
Mixture, early symptom is Alzheimer's disease, and followed by vascular type dementia, for example somatic reaction is blunt or side limb does not have
There is strength, checks that brain can find blood vessel blockage.The patient of this type, may two kinds of state of an illness front and back generations or alternately generation.
Currently, for the treatment of old dementia, mainly non-drug therapy and drug therapy.
(1) non-drug therapy
Non-drug therapy mainly includes dietary therapy, psychotherapy and training activity.Wherein, dietary therapy is to patient
Diet intervened and improved, supplement some pairs of beneficial foods of brain more, guarantee sufficient brain nutrition, accomplish high protein,
Homovitamin, high microsteping, low cholesterol, low fat, low sugar, low salt diet.Such as cereal, wheat, celery in vegetables, day lily,
Apple etc..
CN103621882A disclose a kind of enhancing memory containing slice prescription, include corn 100-160kg, milk powder 100-
160kg, egg powder 30-50kg, lotus root starch 30-50kg, longan powder 30-50kg, pineapple 40-60kg, orange 40-60kg, spinach
40-60kg, kelp 20-30kg, tealeaves 10-16kg, ganoderma lucidum 3-5kg, lecithin 40-60kg, multi-vitamins 0.8-1.2 are public
Jin, 2-3 kilograms of composite trace element, wherein the multi-vitamins are vitamin B1, vitamin B2, vitamin B6, dimension
Raw element D, vitamin K, vitamin B12, vitamin C, niacinamide, folic acid, pantothenic acid, combination several in biotin.The invention energy
Various amino acid needed for providing brain enhance central nervous system function, and help promotes brain cell to be metabolized, and enhancing brain is living
Power, improvement even are eliminated amnesia and enhance memory.But the invention improves memory by adjusting diet, acts on
It is smaller, and human body is also limited to the absorbability of certain nutrients, for more serious old mistake intelligence patient, changes
Kind degree is extremely limited.
CN103349291A discloses a kind of improvement memory composition, including 130 parts of phosphatidylserine, ginkgo leaf
100 parts of extract, 1.0 parts of vitamin B1,1.0 parts of vitamin B6,0.15 part of folic acid, 349.05 parts of linseed oil, beeswax
18.3 parts, 0.5 part of vitamin E, traditional Chinese medicine ingredients are contained in the invention, traditional Chinese medicine ingredients are complicated, while containing active constituent,
May contain a large amount of sensibiligens and the ingredient unknown to body effect or function curative effect, therefore its manufactured goods there are quality not
The stable or indefinite problem of side effect.
(2) drug therapy
Drug therapy is by pharmaceutical intervention, mainly using drug, promotion and the improvement brain blood for improving neurotransmission
Drug and calcium antagonist of circulation etc., such as almitrine-raubasine (Duxil), Piracetam, Doneppezil Hydrochloride (An Li
Shen), Co-dergocrine Mesylate piece (hydergene), Nimodipine etc..
Although drug therapy is more obvious to the improvement of old dementia, many drugs are in use (such as
Duxil will lead to slight digestive system disorder；Aricept will lead to nausea, diarrhea, insomnia, vomiting, muscle cramp etc.) often
There is stronger toxic side effect；Safety simultaneously is poor, all exists using taboo for special population, significantly limits drug and control
The use scope of therapy.Meanwhile current drug is mostly curative drug, after often there is apparent dementia shape in patient
Just start to take, can not prevent trouble before it happens.
Therefore, need to develop a kind of efficient, applied widely, Small side effects, safe and reliable composition and for making
It is standby to improve the old drug for losing intelligence.
Summary of the invention
The object of the present invention is to provide one kind to contain folate composition, and the composition is applied widely, Small side effects, safety
Reliably, it effectively can prevent and improve old dementia, while additionally providing the composition to improve old mistake intelligence medicine in preparation
Application in object.
To achieve the goals above, the present invention provides technical solutions below:
A kind of folate composition, comprises the following components in parts by weight:
0.4-12 parts of folacin compound；
Vitamin B120.4-3 parts of class compound；
Vitamin B610-30 parts of class compound.
Preferably, the folate composition comprises the following components in parts by weight:
0.6-10 parts of folacin compound；
Vitamin B120.6-2.5 parts of class compound；
Vitamin B610-25 parts of class compound.
It is further preferred that the folate composition comprises the following components in parts by weight:
0.8-5 parts of folacin compound；
Vitamin B120.8-2 parts of class compound；
Vitamin B612-25 parts of class compound.
Preferably, the folacin compound is folic acid, formyl tetrahydrofolic acid and its corresponding salt, L-5- methyl four
Hydrogen folic acid and its corresponding salt, folic acid officinal salt, folic acid or folic acid officinal salt active metabolite and can generation in vivo
It thanks and/or one or more of the substance for generating folic acid；The further preferably salt and L-5- of folic acid, formyl tetrahydrofolic acid
One or more of salt of methopterin；More preferably folic acid.
Preferably, the vitamin B12Class compound is cobalamin, Mecobalamin element, 5 '-deoxyadenosyl cobalamins, hydroxyl
Cobalamin, cyanocobalamin and above-mentioned substance derivative and can be metabolized and/or generate in vivo in the substance of such compound
It is one or more of；Into one of one preferably cobalamin, Mecobalamin element, 5 '-deoxyadenosyl cobalamins and hydroxocobalamine or several
Kind, more preferably cobalamin.
Preferably, the vitamin B6Class compound is pyridoxol, pyridoxal, pyridoxamine, pyridoxine phosphate, phosphoric acid
Pyridoxal, phosphopyridoxamine and above-mentioned substance derivative and can be metabolized and/or generate in vivo in the substance of such compound
One or more；The further preferably one or more of pyridoxol, pyridoxal and pyridoxamine.
Preferably, the folate composition further includes one or more of following parts by weight of component；
0.1-5 parts of brain cell metabolic activation drug；
Brain blood circulation promotes drug 0.02-2 parts；
0.16-5 parts of cerebrocrast object.
It is further preferred that the brain cell metabolic activation drug be Piracetam, aniracetam, Doneppezil Hydrochloride,
One or more of rivastigmine-hydrogentartrate, galanthamine hydrobromide, memantine, pentoxifylline；Further
Preferably one or more of Piracetam, aniracetam, Doneppezil Hydrochloride, rivastigmine-hydrogentartrate；Most preferably
Doneppezil Hydrochloride.
It is further preferred that it is dihydroergotoxine, nicergoline, almitrine trailing plants that the brain blood circulation, which promotes drug,
One or more of Ba Xin, ginkgo biloba p.e；It is still more preferably dihydroergotoxine or nicergoline；Most preferably
For dihydroergotoxine.
It is further preferred that the cerebrocrast object is Nimodipine.
The present invention also provides a kind of folate compositions to improve the old application lost in intelligence drug in preparation.
Improve the old drug for losing intelligence the present invention also provides a kind of, including above-mentioned folate composition and can pharmaceutically connect
The auxiliary material received.
Preferably, the drug is any one of tablet, capsule, oral solution, pill or injection.
The drug that intelligence is lost the present invention also provides the improvement old age of above-mentioned folate composition preparation, in preparation treatment and in advance
Application in anti-Alzheimer's disease, blood vessel nature feeble-mindedness and/or Mixed dementia disease drug.
Homocysteine (Hcy) level is positively correlated with ventricles of the brain aside matter degree of injury, intracerebral inflammatory cell number,
High-level Hcy can reduce intracellular adenosine concentration, and atherosclerosis is promoted to generate, and then influence cognitive function of patients, progress
It can promote dull-witted generation to cerebral vessels；High-level Hcy can effectively improve β-amyloid protein neurotoxicity, certain journey
The lower repair for inhibiting DNA to damage of degree, enhances human body to the neurological susceptibility of damage, to promote the generation of mistake intelligence.Hcy can
N- methyl D-ASP receptor is activated to nervous system there are direct toxicity, promotes nerve cell death.Meanwhile always
It loses intelligence patient's body Hcy level in year and is significantly higher than healthy elderly, show that the raising of Hcy is related with the old age mistake generation of intelligence.Cause
This, high Hcy level most likely results in the generation of old dementia.
Folic acid and vitamin B12It is involved in methylation reaction, methylation reaction is the particularly important biochemical reaction of brain,
Reaction level depends on the content of s-adenosylmethionine (SAM), and folic acid participates in the process that methionine generates SAM, the conjunction of methionine
At needing vitamin B again12, this process plays critically important effect in reducing internal Hcy concentration.Old age loses intelligence patient body
It is interior except exist higher Hcy it is horizontal in addition to, folic acid and vitamin B12Level reduces.Give high Hcy patient's folic acid and vitamin B12It is dry
After pretreatment, patient's body Hcy level is remarkably decreased.Therefore, folic acid and vitamin B12It can effectively reduce Hcy level, Jin Eryou
Effect prevents and treats old dementia.
Vitamin B6Using its active form phosphopyridoxal pyridoxal phosphate (PLP) as the coenzyme of many enzymes, except participate in neurotransmitter,
Glycogen, sphingomyelin, ferroheme, steroids and nucleic acid metabolism outside, also participate in all amino acid metabolisms, participate in a carbon list
Position, vitamin B12With the metabolism of folate.Vitamin B6It is cysteine sulphinate decarboxylase, cystathionie-beta-synthetase co-factor,
And these enzymes participate in Hcy and turn vulcanization approach to cysteine, therefore can promote the reduction of Hcy level.
Compared with prior art, the invention has the benefit that
(1) the present invention provides a kind of folate compositions, including folacin compound, vitamin B12Class compound and dimension
Raw element B6Three kinds of B family vitamin class compounds are combined by class compound, the present invention, can be given full play between each raw material
Synergistic function effectively can prevent and improve old dementia；And be found surprisingly that, when folic acid and vitamin B12Ratio
When value is 1:1, the effect of folate composition is preferable.
(2) B family vitamin is water solubility, and extra B family vitamin will not be stored in vivo, can be arranged with water metabolism
External out, highly-safe therefore of the invention folate composition, safe and reliable, toxic side effect very little, pregnant woman, hepatic and renal function are not
Entirely, the special populations such as Patients with Cardiovascular/Cerebrovascular Diseases are also very applicable, which improves old lose in intelligence drug in preparation
Application range it is extremely wide.
(3) the invention also includes brain cell metabolic activation drug, brain blood circulations to promote drug and/or cerebrocrast
Object, by with folacin compound, vitamin B6Class compound and vitamin B12Class compound is combined synergistic effect, can
Effectively to treat and prevent Alzheimer's disease, blood vessel nature feeble-mindedness and/or Mixed dementia disease.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this explanation
Other advantages and efficacy of the present invention can be easily understood for content disclosed by book.The present invention can also pass through in addition different tools
Body embodiment is embodied or practiced, and the various details in this specification can also not had based on different viewpoints and application
Various modifications or alterations are carried out under spirit of the invention.
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two of each numberical range
Any one numerical value can be selected between endpoint and two endpoints.Unless otherwise defined, all technologies used herein and
Scientific term has and the normally understood identical meaning of general technical staff of the technical field of the invention.
A kind of folate composition, comprises the following components in parts by weight:
0.4-12 parts of folacin compound；
Vitamin B120.4-3 parts of class compound；
Vitamin B610-30 parts of class compound.
Preferably, the folate composition comprises the following components in parts by weight:
0.6-10 parts of folacin compound；
Vitamin B120.6-2.5 parts of class compound；
Vitamin B610-25 parts of class compound.
It is further preferred that the folate composition comprises the following components in parts by weight:
0.8-5 parts of folacin compound；
Vitamin B120.8-2 parts of class compound；
Vitamin B612-25 parts of class compound.
Preferably, the folacin compound is folic acid, formyl tetrahydrofolic acid and its corresponding salt, L-5- methyl four
Hydrogen folic acid and its corresponding salt, folic acid officinal salt, folic acid or folic acid officinal salt active metabolite and can generation in vivo
It thanks and/or one or more of the substance for generating folic acid；；The further preferably salt and L-5- of folic acid, formyl tetrahydrofolic acid
One or more of salt of methopterin；More preferably folic acid.
Preferably, the vitamin B12Class compound is cobalamin, Mecobalamin element, 5 '-deoxyadenosyl cobalamins, hydroxyl
Cobalamin, cyanocobalamin and above-mentioned substance derivative and can be metabolized and/or generate in vivo in the substance of such compound
It is one or more of；Into one of one preferably cobalamin, Mecobalamin element, 5 '-deoxyadenosyl cobalamins and hydroxocobalamine or several
Kind；More preferably cobalamin.
Preferably, the vitamin B6Class compound is pyridoxol, pyridoxal, pyridoxamine, pyridoxine phosphate, phosphoric acid
Pyridoxal, phosphopyridoxamine and above-mentioned substance derivative and can be metabolized and/or generate in vivo in the substance of such compound
One or more；The further preferably one or more of pyridoxol, pyridoxal and pyridoxamine.
Preferably, the folate composition further includes one or more of following parts by weight of component；
0.1-5 parts of brain cell metabolic activation drug；
Brain blood circulation promotes drug 0.02-2 parts；
0.16-5 parts of cerebrocrast object.
It is further preferred that the brain cell metabolic activation drug be Piracetam, aniracetam, Doneppezil Hydrochloride,
One or more of rivastigmine-hydrogentartrate, galanthamine hydrobromide, memantine, pentoxifylline；Further
Preferably one or more of Piracetam, aniracetam, Doneppezil Hydrochloride, rivastigmine-hydrogentartrate；Most preferably
Doneppezil Hydrochloride.
It is further preferred that it is dihydroergotoxine, nicergoline, almitrine trailing plants that the brain blood circulation, which promotes drug,
One or more of Ba Xin, ginkgo biloba p.e；It is still more preferably dihydroergotoxine or nicergoline；Most preferably
For dihydroergotoxine.
It is further preferred that the cerebrocrast object is Nimodipine.
The present invention also provides a kind of folate compositions to improve the old application lost in intelligence drug in preparation.
Improve the old drug for losing intelligence the present invention also provides a kind of, including above-mentioned folate composition and can pharmaceutically connect
The auxiliary material received.
Preferably, the auxiliary material is one or more of filler, adhesive, disintegrating agent and lubricant.
It is further preferred that the filler is starch, Icing Sugar, calcium phosphate, two water object of calcium sulfate, dextrin, crystallite fibre
Tie up one or more of element, lactose, pregelatinized starch and mannitol.
It is further preferred that the adhesive is sodium carboxymethylcellulose, hydroxypropyl cellulose, starch slurry, methyl fibre
Tie up one of element, ethyl cellulose, hydroxypropyl methylcellulose and gelling starch or a variety of.
It is further preferred that the disintegrating agent is dried starch, crospovidone, croscarmellose sodium, carboxylic first
One of base sodium starch and low-substituted hydroxypropyl cellulose are a variety of.
It is further preferred that the lubricant is magnesium stearate, talcum powder, lauryl sodium sulfate and superfine silica gel powder
One of or it is a variety of.
Preferably, the drug is any one of tablet, capsule, oral solution, pill or injection.
The drug that intelligence is lost the present invention also provides the improvement old age of above-mentioned folate composition preparation, in preparation treatment and in advance
Application in anti-Alzheimer's disease, blood vessel nature feeble-mindedness and/or Mixed dementia disease drug.
In order to further illustrate the present invention, it to folate composition provided by the invention and its is making with reference to embodiments
The standby application improved in old mistake intelligence drug is described in detail.
The material that the present invention uses is all common commercially available product, can all be bought in market, the invention does not limit this.
Embodiment 1-12 and comparative example 1-6
A kind of folate composition, including component and parts by weight as shown in the table
Table 1 is raw material (parts by weight) component of embodiment 1-6 and comparative example 1-3
Table 2 is raw material (parts by weight) component of embodiment 7-12 and comparative example 4-6
Embodiment 1-12 is folate composition provided by the invention, when specifically used, can be added pharmaceutically acceptable auxiliary
Material, such as filler, adhesive, disintegrating agent and lubricant are made for tablet using conventional technical means, capsule, take orally
The drug of liquid, pill or injection.Wherein, the filler is starch, Icing Sugar, calcium phosphate, two water object of calcium sulfate, paste
One or more of essence, microcrystalline cellulose, lactose, pregelatinized starch and mannitol；The adhesive is carboxymethyl cellulose
One in plain sodium, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose and gelling starch
Kind is a variety of；The disintegrating agent is dried starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch and low
Replace one of hydroxypropyl cellulose or a variety of.The lubricant is magnesium stearate, talcum powder, lauryl sodium sulfate
One or more of with superfine silica gel powder.
In order to further prove that advantages of the present invention, the present invention provide embodiment 1-12, the effect test of comparative example 1-6
As a result, to prove beneficial effects of the present invention.
In order to preferably embody advantages of the present invention, the animal examination of folate composition provided by the present invention is given below
It tests and result.
Improve memory functional evaluation
Detect foundation: Ministry of Public Health's " health food is examined and assessment technique specification " (version in 2003).
1, preventive effect of the folate composition to Alzheimer's disease
1.1 experimental animal
Select C57 male white mouse, 6-8 week old, weight 20-24g.Animal room temperature: 22-25 DEG C, relative humidity: 55-
70%.
1.2AD mouse modeling (D- galactolipin)
By C57 small white mouse, model group and control group are randomly divided by weight, wherein negative control group 10；
Model group: intraperitoneal injection D- galactolipin 15mg/ml0.2ml continuous 90 days；
Negative control group: intraperitoneal injection 0.9% physiological saline 0.2ml continuous 90 days.
1.3 grouping
Model group mouse is randomly divided into 18 groups according to weight, every group 10, while model control group is set and feminine gender is right
According to group.
Raw material is weighed respectively according to the formula of embodiment 1-12 and comparative example 1-6, and above-mentioned raw materials are crushed, and crosses 60 mesh
Sieve is uniformly mixed and pulvis is made；The pulvis for respectively taking 0.419g embodiment 1-12 and comparative example 1-6 to prepare, respectively plus pure water extremely
100ml, is made into 4.19mg/ml solution, and stomach-filling volume is 0.2ml/10g weight, daily stomach-filling 1 time, model control group and feminine gender
Control group gives isometric pure water, continuous 30d.
The scoring of 1.4 Rats With Memory abilities
(1) Jumping test
Animal is put into reaction chamber and adapts to 3min, then passes to 36 volts of alternating currents, the normal reaction of animal is to jump back to
On insulated platform, most mouse may again or repeatedly be skipped on copper grid, be snapped back platform again by electric shock, training is primary
Afterwards, mouse is placed on the platform in reaction chamber, records every mouse in 5min and is made by the number (errors number) to shock by electricity
For school grade, rear cyclical test, record jump off incubation period and the errors number of platform for the first time for 24 hours.
3 folate composition preventive administration of table is on the preclinical influence of rat model
Note: compared with negative control group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 3, compared with negative control group, the incubation period of model control group is obviously shortened, and errors number obviously subtracts
It is few, have significant difference (P < 0.05), shows model group modeling success, and the incubation period of embodiment 1-12 group mouse is opposite
Significant difference is all had with model group, shows the result of the Jumping test for the positive.
Comparative example 1-6 and comparative example 1-3 discovery, 6 groups of folate composition mouse of embodiment 2 and embodiment hide
Phase has extremely significant difference (P < 0.01), shows when folic acid and vitamin B12Ratio be 1:1 when, the effect of folate composition
Preferably, better than only by folic acid, vitamin B12And vitamin B6The drug of two or three of raw material composition, the wherein leaf of embodiment 6
The effect of acid composition is best；Comparative example 6-12 is it can be found that the effect of embodiment 7 and 8 group folate composition is best.
(2) step-through test
Animal selection, test are grouped, to the same step down test of dosage, approach, time of tested material, continuously to after sample 30d
Start to carry out keeping away dark training.Mouse face is put into bright room backwards to hole when experiment, while starting timer, animal passes through hole
Mouthful enter darkroom shocked by electricity, timer stop, take out mouse, record every mouse from be put into bright room to enter darkroom in shocked by electricity
Required time, i.e. incubation period.The same time after for 24 hours carries out cyclical test, records every mouse and enter the incubation period in darkroom, 5min
Interior errors number.
4 folate composition preventive administration of table is on the preclinical influence of rat model
Note: compared with negative control group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 4, compared with negative control group, the incubation period of model control group is obviously prolonged, and has significant difference
(P < 0.05) shows model group modeling success, and the incubation period of embodiment 1-12 group mouse all has significantly with model group relatively
Sex differernce shows the result of the step-through test for the positive.
Comparative example 1-6 and comparative example 1-3 discovery, 6 groups of folate composition mouse of embodiment 2 and embodiment hide
Phase has extremely significant difference (P < 0.01), shows when folic acid and vitamin B12Ratio be 1:1 when, the effect of folate composition
Preferably, better than only by folic acid, vitamin B12And vitamin B6The drug of two or three of raw material composition, the folic acid group of embodiment 6
The effect for closing object is best；Comparative example 6-12 is it can be found that the effect of embodiment 7 and 8 group folate composition is best.
(3) water maze laboratory
Animal selection, test are grouped, to the same step down test of dosage, approach, time of tested material.It is opened to tested material 30d
Begin to carry out water maze test, water maze is tested using Morris water maze.
A constant-bearing navigation test
Water maze training continues 5d, and rat is faced barrel wall and is slowly put into from relative sector, records it from water is entered to finding
The time of platform is escape latency.If not finding platform in rat 1min, platform must be artificially directed it to, is stopped
5s-15s, escape latency are recorded as 60s.If finding platform in rat 1min, system, which automatically records it and escapes, hides
Phase.
Influence of 5 folate composition of table to rat model escape latency
Note: compared with negative control group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 5, compared with negative control group, the escape latency of model control group is obviously shortened, and has conspicuousness
Difference (P < 0.05) shows model group modeling success.And the escape latency of embodiment 1-12 group mouse is opposite equal with model group
With significant difference.
B space exploration test
Constant-bearing navigation test removes platform afterwards for 24 hours, and rat is put into the relative sector of target quadrant, carries out space exploration survey
It is fixed.System, which records, enters the percentage of the time of platform quadrant in its 60s, into the number of platform quadrant.
Influence of 6 folate composition of table to rat model space exploration
| Group | Target quadrant swim percentage/ | Spanning platform number/time | Swim cumulative distance/cm |
| Negative control group | 28.13±4.62 | 10.11±3.26 | 40385±3697 |
| Model control group | 22.17±5.54# | 6.11±1.45# | 53283±9002 |
| Embodiment 1 | 25.40±3.16* | 7.80±2.49* | 41229±6974 |
| Embodiment 2 | 26.02±5.65* | 7.20±4.39* | 40710±4540 |
| Embodiment 3 | 24.09±6.57* | 8.50±3.47* | 42089±5891 |
| Embodiment 4 | 25.59±7.91* | 8.44±5.13* | 44955±1025 |
| Embodiment 5 | 23.99±4.71* | 6.80±2.90* | 43797±6181 |
| Embodiment 6 | 26.38±4.01* | 9.50±5.48* | 40555±4130 |
| Embodiment 7 | 28.28±3.51* | 10.01±3.45* | 40355±2590 |
| Embodiment 8 | 28.06±5.26* | 10.20±2.85* | 40415±3130 |
| Embodiment 9 | 26.98±4.31* | 9.69±5.16* | 40500±4535 |
| Embodiment 10 | 26.75±3.28* | 9.59±4.18* | 40518±2508 |
| Embodiment 11 | 27.08±3.22* | 9.63±2.86* | 40541±3314 |
| Embodiment 12 | 26.88±3.22* | 9.50±5.31* | 40559±4129 |
| Comparative example 1 | 22.99±5.57 | 5.70±2.31 | 47434±1045 |
| Comparative example 2 | 23.47±4.23 | 6.35±4.35 | 48434±1045 |
| Comparative example 3 | 23.11±2.93 | 8.80±2.94 | 45919±8366 |
| Comparative example 4 | 26.72±5.61* | 7.28±4.38* | 40678±1540 |
| Comparative example 5 | 25.59±7.91* | 8.34±5.18* | 44751±2028 |
| Comparative example 6 | 24.69±4.58* | 8.29±6.53* | 44622±3126 |
Note: compared with negative control group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 6, compared with negative control group, it the swimming percentage of the target quadrant of model control group and passes through flat
The number of platform quadrant has significant difference (P < 0.05), shows that model group modeling is successful, and embodiment 1-12 group mouse
Spanning platform number is opposite to all have significant difference with model group.
By table 3-6 it is found that the folate composition auxiliary improvement Alzheimer's disease results of animal of embodiment 1-12 group is
It is positive.Show that folate composition of the invention can assist improving Alzheimer's disease.Wherein, when folic acid and vitamin B12Ratio
When value is 1:1, the effect of folate composition is preferable, better than only by folic acid, vitamin B12And vitamin B6Two of them or three kinds
The drug of raw material composition, meanwhile, the present invention can effectively be changed by being used in combination with the existing drug for the treatment of Alzheimer's disease
It is apt to and treats Alzheimer's disease.
2, preventive effect of the folate composition to vascular dementia
2.1 zoopery
Animal chooses SPF grades of SD rats, all-male, 180 ± 20g of weight.
2.2 grouping
SD rat be randomly divided into after being layered by weight sham-operation group, model control group, comparative example 1-6 group, embodiment 1,2,
6,7,9 and 11 groups, every group 20.Original is weighed respectively according to comparative example 1-6 group, 1,2,6,7,9 and 11 group of embodiment of formula
Material, and above-mentioned raw materials are crushed, 60 meshes are crossed, is uniformly mixed and pulvis is made, the preventive administration by the way of gastric infusion,
Dosage is 1.318mg/kg weight, and with normal saline dilution, administered volume 10mL/kg, sham-operation group and model control group are given
Isometric physiological saline, continuous preventive administration 30 days.
2.3VD modeling (2-VO method)
1h after prevention administration 30 days faces upward rat after all rats are anaesthetized with 9% chloraldurate (30mg/100g, ip)
Clinostatism is fixed on mouse platform, and skin of neck cropping preserved skin, Iodophor alcohol routine disinfection, notch, which is located at by neck median line left side, to be opened
At 0.5cm, it is about 1cm, after blunt separation subcutaneous tissue, the trapezius muscle neck visible with tracheae angle immediately below notch is total
Arteriopalmus isolates arteria carotis communis after removing vagus nerve, respectively with No. 4 operation suture threads at proximal part and distal end
Carry out dual ligation.It is acted softly in art, avoids clamp and excessively drawing vagus nerve, pay attention to sterile principle, in the ranks breaking joint
It closes, art finishes, to wound iodophor disinfection.Identical operation is carried out to right side after a week.
The scoring of 2.4 Rats With Memory abilities
After the completion of modeling, survival rats first carry out learning and memory function test, complete diving tower, keep away dark and Morris water fan
Palace detection, investigates the preventive effect of folate composition.
(1) Jumping test
Animal is put into reaction chamber and adapts to 3min, then passes to 36 volts of alternating currents, the normal reaction of animal is to jump back to
On insulated platform, most mouse may again or repeatedly be skipped on copper grid, be snapped back platform again by electric shock, training is primary
Afterwards, mouse is placed on the platform in reaction chamber, records every mouse in 5min and is made by the number (errors number) to shock by electricity
For school grade, rear cyclical test, record jump off incubation period and the errors number of platform for the first time for 24 hours.
7 folate composition preventive administration of table is on the preclinical influence of rat model
| Group | Incubation period/s | Errors number/training | Errors number/test |
| Sham-operation group | 85.8±34.7 | 1.3±0.15 | 0.4±0.19 |
| Model control group | 168.7±21.2# | 2.8±0.32 | 1.5±0.26# |
| Embodiment 1 | 102.6±13.7* | 1.5±0.25 | 0.6±0.21 |
| Embodiment 2 | 99.1±25.6* | 1.6±0.38 | 0.7±0.24 |
| Embodiment 6 | 94.7±21.7* | 1.4±0.15 | 0.5±0.28* |
| Embodiment 7 | 95.2±24.5* | 1.4±0.35 | 0.5±0.19* |
| Embodiment 9 | 86.2±14.9** | 1.3±0.28 | 0.4±0.31* |
| Embodiment 11 | 87.8±28.5** | 1.3±0.19 | 0.4±0.14* |
| Comparative example 1 | 165.9±31.4 | 2.5±0.31 | 1.3±0.18 |
| Comparative example 2 | 158.6±21.0 | 2.4±0.34 | 1.2±0.26 |
| Comparative example 3 | 162.2±12.4 | 2.3±0.48 | 1.1±0.19 |
| Comparative example 4 | 99.1±25.5* | 1.5±0.24 | 0.6±0.25 |
| Comparative example 5 | 93.8±31.5* | 1.5±0.33 | 0.6±0.34 |
| Comparative example 6 | 92.6±30.6* | 1.4±0.26 | 0.5±0.28* |
Note: compared with sham-operation group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 7, compared with negative control group, the incubation period of model control group is obviously shortened, and has significant difference
(P < 0.05), shows model group modeling success, and 1,2,6,7,9 and 11 group of mouse of embodiment incubation period is opposite and model group
Significant difference (P < 0.05) is all had, shows the result of the Jumping test as the positive, wherein embodiment 9 and 11 has extremely aobvious
It writes sex differernce (P < 0.01).
(2) step-through test
Animal selection, test are grouped, to the same step down test of dosage, approach, time of tested material, continuously to after sample 30d
Start to carry out keeping away dark training.Mouse face is put into bright room backwards to hole when experiment, while starting timer, animal passes through hole
Mouthful enter darkroom shocked by electricity, timer stop, take out mouse, record every mouse from be put into bright room to enter darkroom in shocked by electricity
Required time, i.e. incubation period.The same time after for 24 hours carries out cyclical test, records every mouse and enter the incubation period in darkroom, 5min
Interior errors number.Incubation period is longer, and reflection animal memory is better, and errors number is fewer, and learning ability is stronger
8 folate composition preventive administration of table is on the preclinical influence of rat model
| Group | Incubation period/s | Errors number/test |
| Sham-operation group | 60.1±16.2 | 0.7±0.11 |
| Model control group | 17.8±12.5# | 1.7±0.12 |
| Embodiment 1 | 49.9±14.5* | 0.9±0.16 |
| Embodiment 2 | 50.2±13.9* | 0.9±0.20 |
| Embodiment 6 | 54.9±11.3* | 0.8±0.16 |
| Embodiment 7 | 55.0±12.9* | 0.8±0.15 |
| Embodiment 9 | 60.0±11.9** | 0.7±0.21 |
| Embodiment 11 | 59.5±13.6** | 0.7±0.18 |
| Comparative example 1 | 30.9±21.3 | 1.1±0.18 |
| Comparative example 2 | 33.5±11.3 | 1.2±0.26 |
| Comparative example 3 | 27.2±16.8 | 1.1±0.15 |
| Comparative example 4 | 40.9±14.4* | 0.8±0.15 |
| Comparative example 5 | 44.9±13.9* | 0.7±0.16 |
| Comparative example 6 | 42.5±13.6* | 0.7±0.12 |
Note: compared with sham-operation group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 8, compared with negative control group, the incubation period of model control group has significant difference (P < 0.05),
Show model group modeling success, and the incubation period of 1,2,6,7,9 and 11 group of mouse of embodiment all has significantly with model group relatively
Sex differernce (P < 0.05) shows the result of the step-through test as the positive, and wherein the incubation period of embodiment 9 and 11 group mouse has
Extremely significant sex differernce (P < 0.01).
(3) water maze laboratory
Animal selection, test are grouped, to the same step down test of dosage, approach, time of tested material.It is opened to tested material 30d
Begin to carry out water maze test, water maze is tested using Morris water maze.
A constant-bearing navigation test
Water maze training continues 5d, and rat is faced barrel wall and is slowly put into from relative sector, records it from water is entered to finding
The time of platform is escape latency.If not finding platform in rat 1min, platform must be artificially directed it to, is stopped
5s-15s, escape latency are recorded as 60s.If finding platform in rat 1min, system, which automatically records it and escapes, hides
Phase.
Influence of the 9 folate composition preventive administration of table to rat model escape latency
Note: compared with sham-operation group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 9, compared with negative control group, the escape latency of model control group have significant difference (P <
0.05), show model group modeling success, and 1,2,6,7,9 and 11 group of mouse of embodiment escape latency is opposite and model group
All have significant difference (P < 0.05), wherein embodiment 9 and 11 group has extremely significant sex differernce (P < 0.01).
B space exploration test
Constant-bearing navigation test removes platform afterwards for 24 hours, and rat is put into the relative sector of target quadrant, carries out space exploration survey
It is fixed.System, which records, enters the percentage of the time of platform quadrant in its 60s, into the number of platform quadrant.
Influence of the 10 folate composition preventive administration of table to rat model space exploration
Note: compared with sham-operation group, #P < 0.05；Compared with model group, P < 0.01 * P < 0.05, * *.
As shown in Table 10, compared with negative control group, the spanning platform number of model control group has significant difference (P
< 0.05), show model group modeling success, and 1,2,6,7,9 and 11 group of mouse of embodiment spanning platform number is opposite and mould
Type group all has significant difference (P < 0.05), wherein embodiment 9 and 11 group has extremely significant sex differernce (P < 0.01).
By table 7-10 it is found that 1,2,6,7,9 and 11 group of folate composition auxiliary of embodiment improves the animal of vascular dementia
Experimental result is the positive.Show that folate composition of the invention can assist improving vascular dementia, meanwhile, leaf of the invention
Acid composition is used cooperatively with the existing drug for improving vascular dementia, can prevent vascular dementia.
3, therapeutic effect of the folate composition to vascular dementia
VD modeling is completed, and using comparative example 1-6 group, 1,2,6,7,9 and 11 group of embodiment of pulvis, therapeutic stomach-filling is given
Medicine, dosage is 3.474mg/kg weight, with normal saline dilution, administered volume 10mL/kg, sham-operation group and model control group
Give isometric physiological saline, continuous therapeutic 15 days.Carry out the detection of Morris water maze learning and memory function.Tool
Body test method is as follows:
(1) water maze laboratory
A constant-bearing navigation test
Water maze training continues 5d, and rat is faced barrel wall and is slowly put into from relative sector, records it from water is entered to finding
The time of platform is escape latency.If not finding platform in rat 1min, platform must be artificially directed it to, is stopped
5s-15s, escape latency are recorded as 60s.If finding platform in rat 1min, system, which automatically records it and escapes, hides
Phase.
Influence of the 11 folate composition therapeutic of table to rat model escape latency
Note: compared with sham-operation group, #P < 0.05；Compared with model group,*P < 0.05,**P<0.01.
As shown in Table 11, compared with negative control group, the escape latency of model control group have significant difference (P <
0.05), show model group modeling success, and 1,2,6,7,9 and 11 group of mouse of embodiment escape latency is opposite and model group
All have significant difference (P < 0.05), wherein 6,7,9 and 11 groups of embodiment have extremely significant sex differernce (P < 0.01).
B space exploration test
Constant-bearing navigation test removes platform afterwards for 24 hours, and rat is put into the relative sector of target quadrant, carries out space exploration survey
It is fixed.System, which records, enters the percentage of the time of platform quadrant in its 60s, into the number of platform quadrant.
Influence of the 12 folate composition therapeutic of table to rat model space exploration
| Group | Target quadrant swim percentage/ | Spanning platform number/time | Swim cumulative distance/cm |
| Sham-operation group | 22.16±3.03 | 12.00±7.54 | 40905±1813 |
| Model control group | 13.91±5.76 | 8.67±3.08# | 57004±4345 |
| Embodiment 1 | 17.29±4.17 | 9.91±1.51* | 43016±3561 |
| Embodiment 2 | 16.84±3.53 | 10.11±6.47* | 42876±2481 |
| Embodiment 6 | 19.92±6.87* | 11.29±2.46** | 42272±6401 |
| Embodiment 7 | 20.18±5.19* | 11.17±4.13** | 41156±3296 |
| Embodiment 9 | 22.20±5.87* | 11.78±2.96** | 40956±5119 |
| Embodiment 11 | 21.97±3.94* | 12.01±3.57** | 40911±3002 |
| Comparative example 1 | 14.90±5.45 | 9.83±6.95 | 51065±5817 |
| Comparative example 2 | 15.67±7.48 | 8.90±0.55 | 48245±4827 |
| Comparative example 3 | 14.75±4.73 | 9.50±2.38 | 50219±10291 |
| Comparative example 4 | 16.82±4.17 | 9.89±1.66* | 42819±2519 |
| Comparative example 5 | 17.52±6.97 | 10.00±2.57* | 42672±5451 |
| Comparative example 6 | 18.18±4.16 | 10.16±3.59* | 42272±2316 |
Note: compared with sham-operation group, #P < 0.05；Compared with model group,*P < 0.05,**P<0.01。
As shown in Table 12, compared with negative control group, the spanning platform number of model control group has significant difference (P
< 0.05), show model group modeling success, and 1,2,6,7,9 and 11 group of mouse of embodiment spanning platform number is opposite and mould
Type group all has significant difference (P < 0.05), wherein 6,7,9 and 11 groups of embodiment have extremely significant sex differernce (P < 0.01).
By table 11-12 it is found that 1,2,6,7,9 and 11 group of folate composition therapeutic of embodiment can be effectively improved
Vascular dementia.
The detection of 4 Pathomorphology
After each behaviouristics detection, after animal is excessively anaesthetized using 9% chloraldurate, 0.9% life is first used through the chambers of the heart
Salt water 20mL quick filling is managed, cranium is opened and takes brain, cut the closed fixation in 10% formalin of cerebral tissue containing hippocampus, go forward side by side
Row pathological score.Specific pathomorphism standards of grading are shown in Table 13- table 18.
The arrangement of 13. pyramidal cell of table and cellular layer thickness standards of grading
14. pyramidal cell quantity standards of grading of table
15. pyramidal cell of table is denaturalized standards of grading
16. pyramidal cell necrosis standards of grading of table
17. glial cells hyperplasia standards of grading of table
Note: each sample, 3 regions of every selection are counted, each Score index takes its average to be commented
Point.
The influence that 18 folate composition preventive administration of table integrates hippocampal tissue pathomorphism
Note: compared with sham-operation group, P < 0.05 △；Compared with model control group, P < 0.01 * P < 0.05, * *.
As shown in Table 18: compared with sham-operation group, the arrangement of model control group pyramidal cell and cellular layer thickness, cone are thin
Born of the same parents' quantity, pyramidal cell denaturation, pyramidal cell necrosis, glial cells hyperplasia pathological score increase, and have significant difference (P
< 0.05), illustrate that model group cones are disorganized, cones quantity is reduced, cones denaturation increases, centrum
Meronecrosis increases, glial cells hyperplasia, prompts modeling success.
Compared with model control group, the pyramidal cell arrangement of this test example 6-12 and cellular layer thickness have extremely aobvious
It writes sex differernce (P < 0.01).It is equal to can be seen that folic acid group object of the invention by Rat hippocampus pathomorphism integral analysis
There is improvement result to VD rat model hippocampal tissue pathomorphism, wherein when folic acid and vitamin B12Ratio be 1:1 when, leaf
The effect of acid composition is preferable, better than only by folic acid, vitamin B12And vitamin B6The drug of two or three of raw material composition.
The influence that 19 folate composition therapeutic of table integrates hippocampal tissue pathomorphism
Note: compared with sham-operation group, P < 0.05 △；Compared with model control group, P < 0.01 * P < 0.05, * *.
As shown in Table 19, compared with sham-operation group, the arrangement of model control group pyramidal cell and cellular layer thickness, cone are thin
Born of the same parents' quantity, pyramidal cell denaturation, pyramidal cell necrosis, glial cells hyperplasia scoring increase, have significant difference (P <
0.05), illustrate that model group cones are disorganized, prompt modeling success.
Compared with model control group, the pyramidal cell arrangement of this test example 1,2,6,7,9 and 12 and cell thickness
Degree has extremely significant sex differernce (P < 0.01).It can be seen that the present invention by Rat hippocampus pathomorphism integral analysis
Folic acid group object have therapeutic effect to VD rat model hippocampal tissue pathomorphism, wherein when folic acid and vitamin B12Ratio
When for 1:1, the therapeutic effect of folate composition is preferable, better than only by folic acid, vitamin B12And vitamin B6Two or three former
Expect the drug of composition.
In order to preferably embody advantages of the present invention, the clinic provided by the present invention containing folate composition is given below
Test and result.
Old mistake intelligence patient 350 in selection 60-85 years old, wherein Alzheimer's disease 175, mix by vascular dementia 88
Conjunction property is 87 dull-witted, and patient signs into research informed consent form.
It blind be randomly assigned principle using single patient is divided into 7 groups (every group of 50 people) at random.Wherein there is male patient for every group
25 people, 25 people of female patient.(gender, age, dementia type, coincident with severity degree of condition, medical history are long with regard to its general information by 7 groups of patients
It is short) statistical analysis comparison, P > 0.05 are carried out, no significant difference is comparable.
5. treatment method
Raw material is weighed according to the formula of comparative example 4-6, embodiment 6,7,9 and 11, the phosphorus after crushed 60 meshes, with 1%
Sour calcium mixing, is made tablet (5mg/ piece).
The tablet that control group gives comparative example 4-6 preparation is treated, and is taken orally.Dosage is 5mg/ times each (1), 1 time/
Day, it is taken before sleeping, it is continuous to treat January, depending on as a treatment course.
The tablet that observation group gives the preparation of embodiment 6,7,9 and 11 is treated, and is taken orally.Dosage 5mg/ times each (1
Piece), it 1 times/day, is taken before sleeping, it is continuous to treat January, depending on as a treatment course.Two groups are continuously treated 3 courses for the treatment of, after 3 courses for the treatment of
Carry out efficacy determination.
6. efficacy determination
(1) with the Cognitive function damage severity of Mini Mental State scale (MMSE) assessment patient.
MMSE integrates >=21 points, is slight；
MMSE integral is moderate between 10-20 points；
It is severe that MMSE, which integrates≤9 points,.
Intelligent improvement is indicated with the variation of MMSE integral mean value, that is, compares treatment group and control group in mean value
Whether have significant difference, using Nimodipine method curative effect determinate standard if improving:
Therapeutic index (Nimodipine method)=[(pre-treatment score-post treatment integral) ÷ pre-treatment score] × 100%
Wherein:
Clinical cure: independent symptom or sign disappear or mostly disappear, integral reduce >=95%；
Effective: independent symptom or sign is obviously improved, and integral reduces >=70%；
Effective: independent symptom or sign take a favorable turn, and integral reduces >=30%；
Invalid: independent symptom or sign is not improved, and integral is reduced less than 30%.
Control group and all patients of observation group treat 3 courses for the treatment of according to the treatment method, carry out by above-mentioned standard
Pretherapy and post-treatment compares, and to determine curative effect, the results are shown in Table 1.
20 two groups of patient's Comparison of therapeutic (MMSE) of table
| Group | Number of cases | It is effective | Effectively | In vain | Total effective rate/% |
| Embodiment 6 | 50 | 32 | 12 | 6 | 88 |
| Embodiment 7 | 50 | 36 | 13 | 1 | 98 |
| Embodiment 9 | 50 | 37 | 12 | 1 | 98 |
| Embodiment 11 | 50 | 36 | 12 | 2 | 96 |
| Comparative example 4 | 50 | 25 | 8 | 17 | 66 |
| Comparative example 5 | 50 | 23 | 11 | 16 | 68 |
| Comparative example 6 | 50 | 21 | 15 | 14 | 72 |
(2) with the activity of daily living recovery extent of daily living measuring scale (ADL) assessment patient.
ADL integral is that 100 points of expression daily life active abilities are good, needs not rely on other people.
ADL integral > 60, which divides, to be assessed as good, indicates slight dysfunction, but daily basic living is taken care of oneself substantially.
ADL integral, which is 60-41 points, indicates moderate dysfunction, and daily life obviously needs to rely on other people.
ADL integral < 20 divides to be completely disabled, and daily life is completely dependent on other people.
The improvement that viability is indicated with the variation of ADL integral mean value, that is, compare treatment group and control group in mean value
Improvement whether have significant difference.
Using Nimodipine method curative effect determinate standard:
Therapeutic index (Nimodipine method)=[(pre-treatment score-post treatment integral) ÷ pre-treatment score] × 100%
Wherein:
Clinical cure: independent symptom or sign disappear or mostly disappear, integral reduce >=95%；
Effective: independent symptom or sign is obviously improved, and integral reduces >=70%；
Effective: independent symptom or sign take a favorable turn, and integral reduces >=30%；
Invalid: independent symptom or sign is not improved, and integral is reduced less than 30%.
Control group and all patients of observation group treat 3 courses for the treatment of according to the treatment method, carry out by above-mentioned standard
Pretherapy and post-treatment compares, to determine curative effect, as a result as shown in table 21.
21 two groups of patient's Comparison of therapeutic (ADL) of table
In conclusion prepared by the present invention improve the old drug for losing intelligence, alzheimer can be obviously treated and prevented
Disease, blood vessel nature feeble-mindedness and/or Mixed dementia disease.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, which not uses
To limit the scope of the patents of the invention, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by skill of the present invention
In the range of art scheme.
Claims (10)
1. a kind of folate composition, which is characterized in that comprise the following components in parts by weight:
0.4-12 parts of folacin compound；
Vitamin B120.4-3 parts of class compound；
Vitamin B610-30 parts of class compound.
2. according to right want 1 described in folate composition, which is characterized in that comprise the following components in parts by weight:
0.6-10 parts of folacin compound；
Vitamin B120.6-2.5 parts of class compound；
Vitamin B610-25 parts of class compound.
3. according to right want 2 described in folate composition, which is characterized in that comprise the following components in parts by weight:
0.8-5 parts of folacin compound；
Vitamin B120.8-2 parts of class compound；
Vitamin B612-25 parts of class compound.
4. according to right want 1-3 any one described in folate composition, which is characterized in that the folacin compound be leaf
Acid, formyl tetrahydrofolic acid and its corresponding salt, L-5- methyl tetrahydrofolate and its corresponding salt, folic acid officinal salt, folic acid or
It the active metabolite of folic acid officinal salt and can be metabolized in vivo and/or one or more of the substance for generating folic acid；
The vitamin B12Class compound is cobalamin, Mecobalamin element, 5 '-deoxyadenosyl cobalamins, hydroxocobalamine, cyanocobalamin
It the derivative of element and above-mentioned substance and can be metabolized in vivo and/or one or more of the substance for generating such compound；
The vitamin B6Class compound is pyridoxol, pyridoxal, pyridoxamine, pyridoxine phosphate, phosphopyridoxal pyridoxal phosphate, phosphoric acid pyrrole
Tremble amine and above-mentioned substance derivative and can be metabolized in vivo and/or one or more of the substance for generating such compound.
5. folate composition according to claim 3, which is characterized in that further include one of following parts by weight of component or
It is several；
0.1-5 parts of brain cell metabolic activation drug；
Brain blood circulation promotes drug 0.02-2 parts；
0.16-5 parts of cerebrocrast object.
6. folate composition according to claim 5, which is characterized in that the brain cell metabolic activation drug is that pyrrole draws west
Smooth, aniracetam, Doneppezil Hydrochloride, rivastigmine-hydrogentartrate, galanthamine hydrobromide, memantine, ketone cocoa
One or more of alkali；
The brain blood circulation promotes drug in dihydroergotoxine, nicergoline, almitrine and raubasine, ginkgo biloba p.e
One or more；
The cerebrocrast object is Nimodipine.
7. according to claim 1, the described in any item folate compositions in 2,3,5 and 6 improve in the old drug for losing intelligence in preparation
Application.
Improve the old drug for losing intelligence 8. a kind of, including folate composition described in any one of claims 1-6 and pharmaceutically may be used
The auxiliary material of receiving.
9. drug according to claim 8, which is characterized in that the drug is tablet, capsule, oral solution, dripping pill
Agent or injection it is any.
10. a kind of old drug for losing intelligence of improvement according to claim 8 or claim 9, treats and prevents alzheimer in preparation
Application in disease, blood vessel nature feeble-mindedness and/or Mixed dementia disease drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811488930.0A CN109498643A (en) | 2018-12-06 | 2018-12-06 | A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement |
Applications Claiming Priority (1)
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| CN201811488930.0A CN109498643A (en) | 2018-12-06 | 2018-12-06 | A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement |
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| CN110664832A (en) * | 2019-11-18 | 2020-01-10 | 宣城柏维力生物工程有限公司 | Vitamin B6 vitamin B12 folic acid tablet and preparation method thereof |
| CN113730425A (en) * | 2021-09-06 | 2021-12-03 | 北京斯利安健康科技有限公司 | Folic acid-containing composition and application thereof |
| CN115868634A (en) * | 2021-09-28 | 2023-03-31 | 深圳芙莱特营养与健康有限公司 | Composition for enhancing endurance |
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