CN104368002B - For treating the combination medicine of dull-witted or cognition dysfunction - Google Patents
For treating the combination medicine of dull-witted or cognition dysfunction Download PDFInfo
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- CN104368002B CN104368002B CN201410551301.3A CN201410551301A CN104368002B CN 104368002 B CN104368002 B CN 104368002B CN 201410551301 A CN201410551301 A CN 201410551301A CN 104368002 B CN104368002 B CN 104368002B
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Abstract
The present invention provides the combination medicines for preventing and treating dull-witted and/or cognition dysfunction, specifically, the combination medicine includes a) non-steroidal anti-inflammatory drugs or its officinal salt of prevention and/or therapeutically effective amount and b) statin compound or its officinal salt of prevention and/or therapeutically effective amount and c) optional pharmaceutically acceptable carrier or excipient.Combination medicine of the invention can effectively improve and improve object identification ability, passive avoidance response ability, active avoidance response ability and the Spatial memory ability of Model of Dementia mouse, thus can be used for the prevention or treatment of the diseases such as dull-witted and/or cognition dysfunction.
Description
Technical field
The present invention relates to a kind of combination medicines, and in particular to for treating the joint of dull-witted and/or cognition dysfunction
Use drug.
Background technique
Dementia is syndrome caused by brain diseases, usually with the property of chronic progressive, and is realizing clear feelings
Occur a variety of advanced function of cortex disorders under condition, the damage of cognitive function is generally entailed, once in a while with emotion control and social action
Or the decline of motivation is premonitory symptom.Dementia belongs to acquired, duration disturbance of intelligence, disturbance of intelligence refer at least have with
3 obstacles in lower psychological activity field: 1. language, 2. memory, 3. visual space, 4. emotion, 5. personality, 6. cognition (abstract think of
Dimension, calculating, judgement and executive capability etc.).Thus dementia is posteriori intellectual dysfunction, rather than congenital Mental development is slow
It is stagnant, it is emphasised that the dysnoesia of duration.It is defined as 6 months or more about " duration " international Disease Diagnosis Standard, China
Mental disease diagnostic criteria is shorten to 4 months.Dull-witted state occur average age be 72 years old, 65 years old with senile dementia illness
Rate is 5%~10%, and it is 15%~20% that 80 years old added above.And population base of China is big, the rate of population increase is fast, the elderly
Absolute number has reached 100,000,000 or more, is up to 3.75 hundred million to the year two thousand thirty, accounts for the 24.75% of total population.Aging of population is more serious,
Dull-witted illness probability is also more, and the burden of family and society is also bigger.
Mainly have 3 classes to dull-witted classification in the world at present: 1. senile dementia is also referred to as Alzheimer disease
(Alzheiemr`s Disease, AD) is a kind of chronic progressive degeneration cerebral degeneration occurred in Senectitude and presenium
Disease, using progressive hypomnesia, cognitive disorder, personality change as main feature.Be divided into Familial Occurrence senile dementia and
Sporadic two kinds, and Familial Occurrence senile dementia is divided into Early onset and late hair style.2. vascular dementia (Vascular
Dementia, VaD), it is to cause ischemic, hemorrhagic and acute and chronic ischemic hypoxia brain blood due to cranial vascular disease
One based on the higher nerve cognition dysfunction group clinical syndrome generated on the basis of brain tissue damage caused by pipe disease.
It mainly include multi-infarct dementia, multiple lacunar is dull-witted, cerebral amyloid angiopathy becomes, brain Low perfusion is dull-witted and goes out
Hemorrhagic dementia etc..3. Mixed dementia, referring to existing senile dementia again has vascular dementia or other types dull-witted, other types
Dull-witted mainly includes Frontotemporal dementia (Fronto-Temproal Dementia, FTD), dementia with Lewy body (Dementia of
Lewy Body, DLB), dementia in Parkinson disease (Parkinson Disease Dementia), Huntington disease is with dull-witted
The dementias such as (Huntington Disease Dementia), corticobasal degeneration (Corticobasal Degeneration)
Type.Wherein Alzheimer disease accounts for 50%~60% in elderly stroke, is located at first, and second is that vascular is silly
It is slow-witted.
Mild cognitive impairment (mild cognitive impairment, MCI) refers in particular to those memories or decrease of cognitive function
But the people of not up to dull-witted standard, MCI develops into dull-witted risk and is higher than normal population, to Alzheimer disease
The year conversion ratio of (Alzheimer`s Disease, AD) is 10 times of normal population, and MCI is considered as usual aging to dementia
Transition stage.
In terms for the treatment of, since the pathogenic factor of senile dementia is complicated, influence factor is many, thus its remedy measures master
Have three aspects: etiological treatment delays process, improves symptom.Wherein improving symptom is to be proved to effective remedy measures at present,
These symptoms include cognition and secondary non-cognition symptom.It is proved that non-cognition symptom mainly includes behavior disorder and spirit
Symptom, be senile dementia important clinical performance, a large amount of psychosis drug be used for dementia patients behavior disorder and
The processing of mental symptom.What is be most widely used in the treatment for dementia patients cognitive disorder is anticholinesterase
(Cholinesterase Inhibitor, ChEI) and N-methyl-D-aspartate (N-methyl-D-aspartic acid,
NMDA) two class of receptor antagonist.
Acetylcholine plays an important role in terms of the learning and memory of humans and animals, and cholinergic antagonist hyoscine can draw
Memory disorders are played, and cholinergic agonist can promote ability of learning and memory, patients with Alzheimer disease basal forebrain cholinergic
Neure damage, the synthesis of acetylcholine, which is absorbed, to be reduced, therefore the cholinergic nerve meta function for increasing central nervous system can
Effectively improve or slow down the memory disorders of patients with Alzheimer disease.ChEI is able to suppress the drop of acetylcholine in synaptic cleft
Solution is current most successful cholinergic reinforcing agent, and ChEI has protection to the excitement of nicotine receptor and M-ChR
Effect.Clinical test shows that ChEI can alleviate Alzheimer disease symptoms, so as to improve its cognitive function.Glutamic acid is in brain
Important excitatory neurotransmitter, but glutamic acid can change Ca by activating nmda receptor2+、Na+、Cl-Plasma it is penetrating
Property, cytotoxicity is generated, cellular swelling, denaturation and death are made.The only approved nmda receptor antagonist of the states such as America and Europe is at present
Memantine, memantine are a kind of low-affinity, uncompetitive nmda receptor antagonist, can inhibit excitatory amino acid
Neurotoxicity without interference in learning memory needed for transience glutamic acid physiology release.Memantine can delay in, again
The clinical symptoms for spending patients with Alzheimer disease deteriorate, and the self care ability time of patient is made to extend 3 times or so.
Use individually non-steroidal anti-inflammatory drugs (Non-Steroidal Anti-Inflammatory Drugs,
NSAIDs) or statins (Statins) treatment senile dementia there are also the trials in terms of clinical test.One clinic
Double-blind randomized controlled test, administration time 12 months, totally 51 people (treatment group: 26 people, control group: 25 people, MMSE:10-26) joined
With 2 times/day of dosage 50mg, the results showed that Indomethacin is invalid for the treatment of AD[1].Another Clinical double-blind is random
Check experiment, administration time 6 months, totally 28 people (treatment group: 14 people, control group: 14 people, MMSE: > 16) participate in, dosage:
1 times/day of 100mg, the results showed that Indomethacin take a favorable turn trend for the treatment of AD[2], but have 42% ginseng during testing
It is exited with person because sb.'s illness took a turn for the worse (treatment group: 10 people, control group: 6 people), therefore the result of " take a favorable turn trend " is obtained for test
There is also disputes.For in the research of brufen, including that the clinic that severe AD patients last 1 year in 132 is random right at one
According in test, brufen does not improve the cognitive ability and clinical score of AD patient[3].In terms of clinical test, a clinic
Double-blind randomized controlled test, administration time 3~12 months, totally 63 people (treatment group: 32 people, control group: 31 people, MMSE:12-28)
It participates in, the results showed that Atorvastatin can reduce the MMSE scoring of AD patient[4].Another Clinical double-blind randomized controlled trial,
Administration time 3~18 months, totally 614 people (treatment group: 297 people, control group: 317 people, MMSE:13-25) participated in, the results showed that
Atorvastatin is invalid for the treatment of AD[5]。
In terms of epidemiological study, " Rotterdam study " has found in analysis, is similar to Indomethacin and brufen
The non-steroidal anti-inflammatory drugs that one kind can reduce A β 1-42 level is limited for reducing the effect of AD risk[6].At one
To not being found in the comprehensive analysis of 13499 dementia patients in 6 tests, Yin is similar in terms of reducing AD risk
Diindyl U.S. is pungent to have any advantage with the non-steroidal anti-inflammatory drugs that brufen one kind can reduce A β 1-42 level[7].One to 25 clinics
The Meta analysis of check experiment finds, reports that the therapeutic effect in relation to NSAIDs has in document and recalls, prescription and delivers
Bias[8].In addition, one for finding that NSAIDs makes in 1019 old age " Catholic clergy " 12 years follow-up
There is no significant correlation with AD risk, cognitive function improvement and the pathological change of AD[9]。
As can be seen that non-steroidal anti-inflammatory drugs and statins are not in clinical Double-blind randomized clinical trial and epidemic disease
Learn the result for obtaining to treat AD in investigation.
Unified approach there is no for the treatment of MCI at present, not over FDA approval prevention and/or treatment drug, one
As treatment be using neuroprotective drug and cereboactive drug, such as vitamin E, vitamin C and Piracetam, folic acid, vitamin B12It is low
In normal level, person is supplemented, but curative effect is also being studied.
In recent years, more and more experiments have shown that the process of the occurrence and development of senile dementia is related to various complexity
Regulated and control network and regulatory factor, this also illustrates the original of the compound curative effect is unsatisfactory for single target spot to a certain extent
Cause.Moreover, the drug that more clinical research discoveries act on multiple target spots can obtain more preferably the prevention and treatment of certain diseases
Effect.Clinically there are three types of modes for multiple target point drug therapy: first is that passing through drug combination, second is that passing through compound preparation, three
It is the single medicine molecule by being directed to multiple target point.Wherein, although the single medicine molecule for multiple target point can theoretically subtract
Few adverse reaction and reduction clinical dosage, but its at high cost, clinical efficacy of research and development cannot be guaranteed；And compound preparation is
It is substantially identical based on drug combination, therefore screening and evaluate effective combination medicine is prevention and treatment dementia or cognition function
The important channel of energy obstacle.
Currently, non-steroidal anti-inflammatory drugs and statins use in conjunction are for the treatment of senile dementia, there is not been reported.
Summary of the invention
The present inventor by groping and many experiments repeatedly, it was surprisingly found now that by non-steroidal anti-inflammatory class medicine
Object and statins combination have synergistic effect in terms of preventing or treating the diseases such as dull-witted and/or cognition dysfunction,
The therapeutic equivalence of curative effect and current first-line drug donepezil, the Memantine clinically used etc., has thus completed the present invention.
First aspect present invention is related to a kind of combination medicine comprising a) at least one prevention and/or therapeutically effective amount
Non-steroidal anti-inflammatory drugs (Nonsteroidal Antiinflammatory Drugs) or its officinal salt and b) it is at least one pre-
Anti- and/or therapeutically effective amount statin compound (Statins) or its officinal salt and c) it is optional pharmaceutically acceptable
Carrier or excipient.
Second aspect of the present invention is related to kit product comprising at least one first pharmaceutical preparation unit and at least one the
Two pharmaceutical preparation units, the first pharmaceutical preparation unit and second pharmaceutical preparation unit optionally mutually have an independent existence in the medicine
In box product；The first pharmaceutical preparation unit includes the non-steroidal anti-inflammatory drugs of prevention and/or therapeutically effective amount or its is pharmaceutically acceptable
Salt and optional pharmaceutically acceptable carrier or excipient, the second pharmaceutical preparation unit include that prevention and/or treatment are effective
The statin compound of amount or its officinal salt and optional pharmaceutically acceptable carrier or excipient.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, the non-steroidal anti-inflammatory drugs or its officinal salt are selected from aryl alkanoic acid non-steroid antiphlogistic.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, the aryl alkanoic acid non-steroid antiphlogistic are Arylacetic acids class or aryl propionic non-steroid antiphlogistic.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, the non-steroidal anti-inflammatory drugs are selected from Indomethacin (Indomethacin), brufen (Ibuprofen), sulindac
(Sulindac), Etodolac (Etodolac), Nabumetone (Nabumetone), C14H10Cl2NNaO2 (Diclofenac
Sodium), one of naproxen (Naproxen) or a variety of.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, the statin compound are selected from Lovastatin (Lovastatin), Simvastatin (Simvastatin), Pravastatin
(Pravastatin), mevastatin (Mevastatin), Fluvastatin (Fluvastatin), Atorvastatin calcium salt
(Atorvastatin Calcium), cerivastatin (Cerivastatin), rosuvastatin (Rosuvastatin) are cut down
One of statin (Pitavastatin) is a variety of.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, the statin compound or its officinal salt are Atorvastatin calcium salt.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, the statin compound or its officinal salt and non-steroidal anti-inflammatory drugs or the weight ratio of its officinal salt be 1:0.5~
1:50, for example, 1:1~1:25.
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
The molar ratio of product, the non-steroidal anti-inflammatory drugs or its officinal salt and statin compound or its officinal salt be 3:1~
140:1。
Described in any item combination medicines or the described in any item medicine boxs of second aspect according to a first aspect of the present invention
Product, further includes the information material subsidiary with the combination medicine or kit product, which includes using described
The information of the method for combination with medication or kit product；Preferably, wherein the information material includes following one or more letters
Breath:
The non-steroidal anti-inflammatory drugs or its officinal salt and statin compound or its officinal salt are simultaneously, substantially
Simultaneously, it is applied to treatment sequentially, periodically or in order and/or prevents the subject of demand；
The daily dose of the non-steroidal anti-inflammatory drugs or its officinal salt is 0.001~1000mg/kg weight；With
The daily dose of the statin compound or its officinal salt is 0.001~1000mg/kg weight.
Described in any item combination medicines according to a first aspect of the present invention are unit dosage form.Described in wherein
Unit dosage form is selected from: tablet, capsule, granule, injection, injectable powder, transdermal patch, ointment, gelling agent,
Suppository, oral administration solution, oral administration mixed suspension, emulsion for injection, Orally taken emulsion etc., sustained-release tablet, Dospan etc..According to the present invention
The described in any item combination medicines of first aspect, wherein the non-steroidal anti-inflammatory drugs or its officinal salt or Statins
Amount of the compound or pharmaceutically acceptable salt thereof in the unit dosage form can be according to the common agent of two kinds of drugs clinically
It measures and is readily determined in conjunction with the disclosure of invention.
In one embodiment, wherein the non-steroidal anti-inflammatory drugs or its officinal salt are in the unit dosage form
In amount be 0.001~1000mg/ unit dosage form, preferably 0.01~100mg/ unit dosage form, more preferably 0.1
~10mg/ unit dosage form.
In one embodiment, wherein the statin compound or its officinal salt are in the unit dosage form
In amount be 0.001~1000mg/ unit dosage form, preferably 0.01~100mg/ unit dosage form, more preferably 0.1
~10mg/ unit dosage form.
The third aspect of the present invention is related to non-steroidal anti-inflammatory drugs and statin compound or the combination of its officinal salt is being made
Purposes in the drug of standby prevention or treatment dementia and/or cognition dysfunction.
Described in any item purposes according to a third aspect of the present invention, wherein the dementia or cognitive disorder disease choosing
From (1) central nervous system degenerative disease: Alzheimer disease, mild cognitive impairment, volume-temporal lobe are dull-witted, Prion is sick, lewy body
Dementia, Parkinson's disease, Huntington disease；(2) non denatured disease is dull-witted: 1. vascular dementia；2. dementia caused by occupying lesion: swollen
Dementia caused by tumor, chronic subdural hematoma, chronic brain abscess；3. dull-witted caused by infection: meningoencephalitis, neurolues, Chinese mugwort
Grow disease dementia, Ruan's albumen disease；4. brain traumatic is dull-witted；5. dementia caused by normal cranium pressure hydrocephalus；6. endocrine metabolism hinders
Hinder caused dementia: dysendocrinism, Cushing syndrome, hyperinsulinemia, hypothyroidism, hypopituitarism,
Hypoglycemia, liver failure, kidney failure, lung failure, chronic electrolyte disturbance, hematoporphyria, vitamin (B1, niacin, leaf
Acid, vitamin B12 etc.) lack caused dementia；7. poisoning, anoxic (alcohol, heavy metal, carbon monoxide, drug, anoxic etc.) are drawn
The dementia risen；8. dementia caused by paraneoplastic syndrome.
Described in any item purposes according to a third aspect of the present invention, the non-steroidal anti-inflammatory drugs or its officinal salt are selected from virtue
Base alkanoic acid non-steroid antiphlogistic.
Described in any item purposes according to a third aspect of the present invention, the aryl alkanoic acid non-steroid antiphlogistic are aryl second
Acids or aryl propionic non-steroid antiphlogistic.
Described in any item purposes according to a third aspect of the present invention, the non-steroidal anti-inflammatory drugs are selected from Indomethacin
(Indomethacin), brufen (Ibuprofen), sulindac (Sulindac), Etodolac (Etodolac), Nabumetone
(Nabumetone), one of C14H10Cl2NNaO2 (Diclofenac Sodium), naproxen (Naproxen) or a variety of.
Described in any item purposes according to a third aspect of the present invention, the statin compound are selected from Lovastatin
(Lovastatin), Simvastatin (Simvastatin), Pravastatin (Pravastatin), mevastatin
(Mevastatin), Fluvastatin (Fluvastatin), Atorvastatin calcium salt (Atorvastatin Calcium), west are vertical
Cut down one of statin (Cerivastatin), rosuvastatin (Rosuvastatin) or Pitavastatin (Pitavastatin) or
It is a variety of.
Described in any item purposes according to a third aspect of the present invention, the statin compound or its officinal salt are atropic
Cut down statin calcium salt.
Described in any item purposes according to a third aspect of the present invention, the statin compound or its officinal salt and non-steroid
The weight ratio of body anti-inflammatory agent or its officinal salt is 1:0.5~1:50, for example, 1:1~1:25.
Described in any item purposes according to a third aspect of the present invention, the non-steroidal anti-inflammatory drugs or its officinal salt and statin
The molar ratio of class compound or pharmaceutically acceptable salt thereof is 3:1~140:1.
Combination medicine of the invention can effectively improve and improve the object identification ability of Model of Dementia mouse, passive avoidance
Respond, active avoidance response ability and Spatial memory ability, thus can be used for preventing and/or treating it is dull-witted and/or
The diseases such as cognition dysfunction.
It is further described to various aspects of the present invention with feature below.
The various terms and phrase that the present invention uses have well known to a person skilled in the art general senses, nonetheless,
The present invention remain desirable to the term and phrase that these terms and the more detailed description and interpretation of phrase, refer to again if any with public affairs
Know that meaning is inconsistent, the meaning that the present invention of being subject to is stated.
Terms used herein " combination medicine " is alternatively referred to as " composition " or " pharmaceutical composition ", it is intended that can pass through by
The drug that the approach such as compound preparation are treated is made in Drug combination.
Medicament universal name or product name used herein only indicate its active constituent, are not construed as to the medicament sources
Limitation, for example, " Indomethacin " only indicates that chemical name is " 2- methyl-1-(4- chlorobenzene formacyl)-5- methoxyl group-1H- Yin
The medicinal compound of diindyl -3- acetic acid ".
Terms used herein " treatment " has its general sense, and particularly refer to herein to suffered from it is dull-witted or
The mammal of cognition dysfunction is handled using combination medicine or kit product of the invention, to the dementia
Or cognition dysfunction generates the effects for the treatment of, healing, alleviation, mitigation.
Similarly, terms used herein " prevention " has its general sense, and particularly refers to herein to may suffer from
Suffer from dull-witted or cognition dysfunction or there is the mammal of risk to dull-witted or cognition dysfunction of the present invention
It is handled using combination medicine or kit product of the invention, it is anti-to be generated to the dull-witted or cognition dysfunction
Only, the effects of preventing, prevent, separating.
Terms used herein " pharmaceutically acceptable ", which typically refers to pharmaceutical field, can be used, to product or to mammal
It is harmless, or there is reasonable or acceptable interests/Hazard ratio.
Terms used herein " carrier " or " excipient " can be any conventional carrier and excipient in pharmaceutical field.Tool
The selection of the carrier and excipient of body will depend on the administration mode for being used to treat particular patient or disease type and state.For
The preparation method of the said synthetic processes of specific administration mode is completely in the knowledge of drug field technical staff.Example
Such as, it can be used as pharmaceutically acceptable carrier or excipient include the carrier of pharmaceutical field routine, excipient, diluent, fill out
Fill agent, solvent, supporting agent, adhesive, wetting agent, disintegrating agent, sorbefacient, surfactant, absorption carrier and lubricant
Deng.It when necessary, can also include flavouring agent, preservative and sweetener etc..
Terms used herein " effective quantity " refers to that the amount of active ingredient of the present invention, the amount can be to of the present invention silly
Slow-witted or cognition dysfunction is effectively prevented and/or is treated.
" the first pharmaceutical preparation unit " and " the second drug system in terms used herein " combination medicine " or kit product
Agent unit " has its general sense, and can narrowly refer to pharmaceutical preparation or pharmaceutical dosage form herein, may include or
Not comprising pharmaceutic adjuvant.The routine techniques in pharmaceutical field especially formulation art can be used, used to prepare joint of the invention
Drug or " the first pharmaceutical preparation unit " and " second pharmaceutical preparation unit ".Combination medicine according to the present invention or "
One pharmaceutical preparation unit " and " second pharmaceutical preparation unit ", for can be adapted for oral administration, parenteral or part to
The pharmaceutical dosage form of medicine, topical administration.According to the present invention, the pharmaceutical dosage form includes but is not limited to: tablet, capsule, particle
Agent, pulvis, injection, injectable powder, transdermal patch, ointment, gelling agent, suppository, oral administration solution, oral administration mixed suspension, note
It penetrates with emulsion, Orally taken emulsion etc., sustained-release tablet, Dospan etc..The drug of above-mentioned various dosage forms can be according to pharmaceutical field
Conventional method preparation.
Terms used herein " mammal " (alternatively, being properly termed as " individual ") has its general sense, and herein
In can refer to individual or the mammal that suffers from or may suffer from of the present invention dull-witted or cognition dysfunction, can also refer to and be
The mammal that certain purpose for example uses for scientific research purpose.Specifically, the mammal is, for example,
People, pig, dog, cat, ox, sheep, horse, rat, mouse, rabbit, cavy, monkey etc..More specifically, mammal of the present invention
It is people.
When combination medicine of the invention or or kit product in " the first pharmaceutical preparation unit " and " second pharmaceutical preparation
Unit " is as medicament administration when animal subject patient, they can be given with itself, that is, any above-mentioned pharmacy is not added can
Combination medicine or pharmaceutical composition of the invention or pharmaceutical preparation are directly applied to patient with original shape by the carrier of receiving；Or
Person can be with containing such as 1~99% (more preferably such as 10~90%) active constituent with pharmaceutically acceptable carrier group
Human or animal is given after synthetic drug composition or pharmaceutical preparation.
" the first pharmaceutical preparation unit " and " second pharmaceutical preparation list in combination medicine or kit product of the invention
The time-histories of active constituent in member ", actual dosage level and application can change, to obtain a kind of active constituent
Amount, the amount can effectively obtain desired therapeutic response for specific individual test subjects, composition and method of administration,
And to individual test subjects nontoxicity.The Exemplary dose ranges of people can be with reference to related tool book or textbook (for example, Chen Xin
Modest, etc. new pharmacology, 15 editions, Beijing, People's Health Publisher, 2003) in be directed to non-steroidal anti-inflammatory drugs or statins
Common dose determine, this to those skilled in the art be easy determination.Certainly, kit product of the present invention can be changed
In " the first pharmaceutical preparation unit " and " second pharmaceutical preparation unit " in each active constituent actual dose it is horizontal, so as to gained
Reactive compound amount effectively can obtain required therapeutic response for specific patient, composition and administration mode.It should recognize
It arrives, combination medicine of the invention or " the first pharmaceutical preparation unit " and " the second drug in pharmaceutical composition or kit product
Total consumption per day of preparation unit " must be maked decision in reliable medical judgment scope by attending physician.For any specific
Patient, specific treatment effective dose level must be depending on many factors, and the factor includes treated obstacle and the barrier
The severity hindered；The activity of used particular compound；Used concrete composition；It is age of patient, weight, general
Health status, gender and diet；Administration time, administration route and the excretion rate of used particular compound；When treatment continues
Between；The drug for being applied in combination with used particular compound or using simultaneously；And similar factor well known to medical field.
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit ", as described above, their specific dosage can by those skilled in the art according to existing knowledge come really
It is fixed.If desired, effective daily dose can be divided into multi-dose for administration purpose；Therefore, unit-dose composition or pharmaceutical preparation
Unit can contain this quantity or its divided dose, to constitute daily dose.For kit product of the present invention, therein " first
Pharmaceutical preparation unit " and " second pharmaceutical preparation unit " are applied to individual test subjects according to regular hour sequence, such as by the two
Be administered simultaneously, applied with the interval of optional order etc..
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit " can especially particular formulation in solid or liquid form it is for oral administration, for parental injection or for rectum
Administration.
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit " can by oral, rectum, parenteral, pond, in intravaginal, peritonaeum, part is (as passed through powder, ointment
Or drops), buccal gives the mankind and other mammals, or gives as oral spray or nasal mist.This paper institute
With term " parenteral " refer to including it is intravenous, intramuscular, intraperitoneal, in breastbone, subcutaneous and intra-articular injection and infusion administration
Mode.
On the other hand, " the first drug system in combination medicine of the invention or pharmaceutical composition or kit product
Agent unit " and " second pharmaceutical preparation unit " can be with one or more nontoxic physiologically tolerable or acceptable diluents, load
Body, auxiliary material or medium (they can be referred to as carrier herein) are configured to composition together, for parental injection, intranasal biography
It passs, oral administration, rectum or local administration etc. in solid or liquid form.
" the first medicine being suitable in the combination medicine or pharmaceutical composition or kit product of the invention of parental injection
Object preparation unit " and " second pharmaceutical preparation unit " may include physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion
Agent, suspension or emulsion, and the sterile powders for being reconstructed into Sterile injectable solution or dispersing agent.It is suitable aqueous or non-aqueous
Carrier, diluent, solvent or medium example include water, ethyl alcohol, polyalcohol (propylene glycol, polyethylene glycol, glycerol etc.), plant
Oily (such as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit " can also contain auxiliary material, such as preservative, wetting agent, emulsifier and dispersing agent.By various antibacterial agents and resist
Epiphyte pharmaceutical, such as parabens, anesin, phenol, sorbic acid etc., it can be ensured that prevent the effect of microorganism.It is also expected to
Including isotonic agent, such as carbohydrate, sodium chloride etc..It, can by using the substance that can postpone to absorb, such as aluminum monostearate and gelatin
The extension for reaching injectable drug form absorbs.
Suspending agent, such as ethoxylation i-octadecanol, polyoxyethylene mountain can also be contained in suspension in addition to the active compound
The pure and mild polyoxyethylene sorbitan esters of pears, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, agar and tragacanth or
The mixture etc. of these substances.
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit " can be in the form of injectable formulation, which can be for example by being filtered or being passed through with bacteria filter
The bactericidal agent for mixing aseptic solid composite form sterilizes, the solid composite can be before use dissolved or dispersed in it is sterile
Water or other sterile injectable mediums.
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit " can be in solid dosage forms for oral administration, and the solid dosage forms for oral administration includes capsule, piece
Agent, pill, powder and granule.In such solid dosage forms, reactive compound can be acceptable at least one inert drug
Excipient or carrier such as sodium citrate or Dicalcium Phosphate and/or following material mixing: a) filler or incremental agent such as starch, cream
Sugar, sucrose, glucose, mannitol and silicic acid；B) adhesive such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrole
Alkanone, sucrose and gum arabic；C) moisturizer such as glycerol；D) disintegrating agent such as agar, calcium carbonate, potato or tapioca,
Alginic acid, certain silicates and sodium carbonate；E) solution retarding agents such as paraffin；F) absorbsion accelerator such as quaternary ammonium compound；G) it moistens
Agent such as cetanol and glyceryl monostearate；H) adsorbent such as kaolin and bentonite and i) lubricant such as talcum powder, tristearin
Sour calcium, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate and their mixture.In capsule, tablet and pill
In the case of, it also may include buffer in the dosage form.
" the first pharmaceutical preparation unit " and " second in combination medicine or pharmaceutical composition of the invention or kit product
Pharmaceutical preparation unit " can be in liquid dosage form for oral administration, and the liquid dosage form for oral administration includes that drug can connect
Emulsion, solution, suspension, syrup and the elixir received.Liquid dosage form, which is removed, can also contain this field containing active ingredient beyond the region of objective existence
Common inert diluent, such as water or other solvents, solubilizer and emulsifier such as ethyl alcohol, isopropanol, ethyl carbonate, acetic acid
Ethyl ester, benzylalcohol, Ergol, propylene glycol, 1,3 butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil,
Corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl
Alcohol), the aliphatic ester and their mixture of polyethylene glycol and sorbitan.
" aryl alkanoic acid non-steroid antiphlogistic " of the present invention refers to general structure are as follows:
A kind of drug, wherein R=H or CH3；Ar=aromatic ring or heteroaromatic.
Different according to R base can be divided into Arylacetic acids class and aryl propionic non-steroid antiphlogistic again.As R=H, belong to
Arylacetic acids class；Work as R=CH3When, belong to arylprop acids.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
Model of Dementia mouse of the invention is divided into two classes, and one kind, which belongs to, distributes spontaneous type Model of Dementia, is quick aging mould
SAMP8 subbreed in type mouse P system (Senescence Accelerated Mouse-Prone), 10 monthly ages；Control mice is anti-
SAMR1 subbreed in Senescence-Accelerated Mouse R system (Senescence Accelerated Mouse-Resistant), October
Age；One kind belongs to familial inheritance type Model of Dementia, is APPswe/PS1dE9Bi-transgenic mice, 12 monthly ages.Wild type C57BL/6J
Mouse, 12 monthly ages.Above each model mice is purchased from Fukang Biotechnology Co., Ltd of Beijing China (Beijing SCXK 2009-
0004)。
Drug combination of the invention is divided into two groups, one group of selection Atorvastatin calcium salt and Indomethacin, as medicine group
Square A；Another group of selection Atorvastatin calcium salt and brufen, as medicament composing prescription B.
The present invention chooses memantine and Doneppezil Hydrochloride as positive drug control group respectively.
Drug molecule formula and molecular weight used in embodiment are as follows:
Atorvastatin calcium salt (Beijing is coupled Science and Technology Ltd., 134523-00-5), molecular formula: C66H68CaN4O,
Molecular weight: 1155；
Indomethacin (Beijing is coupled Science and Technology Ltd., 53-86-1), molecular formula: C19H16ClNO4, molecular weight: 358；
Brufen (Beijing is coupled Science and Technology Ltd., 15687-27-1), molecular formula: C13H18O2, molecular weight: 206；
Doneppezil Hydrochloride (Beijing is coupled Science and Technology Ltd., 120014-06-4), molecular formula: C24H29NO3HCl,
Molecular weight: 416；
Memantine (Beijing is coupled Science and Technology Ltd., 41100-52-1), molecular formula: C12H21N, molecular weight:
216。
Atorvastatin calcium salt, Indomethacin, Doneppezil Hydrochloride, memantine, use deionized water and PEG400
Mixed solvent dissolution, 4 DEG C save backup, according to a conventional method gastric infusion；Brufen and mouse feed are hybridly prepared into administration and raise
Material, room temperature preservation are spare.
The present invention is respectively to distributing spontaneous type Model of Dementia mouse and familial inheritance type Model of Dementia mouse has carried out animal
Experiment, successive administration 4 months.
In zoopery of the invention, the object identification memory capability of detection mouse is tested using strange object identification；It jumps
The passive avoidance response ability of platform experiment detection mouse；Shuttle box detects mouse active avoidance response ability；Morris water
The Spatial memory ability of maze experiment detection mouse.
Drug ratio and dosage as used in the following examples are as follows:
The drug dose of each component in the medicament composing prescription: Doneppezil Hydrochloride 10mg/kg weight, memantine
30mg/kg weight, brufen 62.5mg/kg weight, Indomethacin 2.5mg/kg weight, Atorvastatin calcium salt 2.5mg/kg body
Weight.
Shadow of the combination medicine of the invention of embodiment 1. for the object identification memory capability of Senescence-Accelerated Mouse
It rings
1. material
1.1 animals: Senescence-Accelerated Mouse SAMP8 (cleaning grade) and resistance to rapid Ageing Model mouse SAMR1 (cleaning
Grade), 29~33g of weight.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
Pungent (weight ratio 1:1)；Medicament composing prescription B, Atorvastatin calcium salt and brufen (weight ratio 1:25).
1.3 laboratory apparatus: for customized test box having a size of 30 × 30 × 30cm (width x length × height), cabinet is black non transparent
Organic glass, bottom are transparent organic glass.The acquisition of object video is probed by Anymaze software mouse.
2. method
2.1 medication
According to the weight of mouse, take the method being grouped at random that mouse is divided into five groups: normal solvent be (PEG400 and water
Mixture, ratio PEG400: water=4:6) control group (SAMR1), model solvent control group (SAMP8), positive drug control group
(Doneppezil Hydrochloride group and memantine group), medicament composing prescription A group, medicament composing prescription B group, every group 10.Dosage reference
Adult clinical dosage, with deionized water and PEG400 mixed solvent wiring solution-forming to mouse carry out the specific dosage of stomach-filling and
Drug concentration are as follows: Atorvastatin calcium salt 0.1~10 milligram/kg weight (0.01~1mg/mL), 0.1~10 milli of Indomethacin
Gram/kg weight (0.01~1mg/mL), brufen 1~100 milligram/kg weight (0.01~10mg/mL), Doneppezil Hydrochloride
0.1~10 milligram/kg weight (0.01~1mg/mL), memantine 0.1~30 milligram/kg weight (0.01~3mg/mL),
One time a day, the volume administration of 0.01mL/g weight is pressed every time, and normal solvent control group and model solvent control group are then with isometric
Stomach-filling.Drug dose: Doneppezil Hydrochloride 10mg/kg weight, memantine 30mg/kg weight, brufen 62.5mg/kg body
Weight, Indomethacin 2.5mg/kg weight, Atorvastatin calcium salt 2.5mg/kg weight
2.2 strange object identification experiments
Experiment is configured Anymaze software before starting, and whether detect its working condition normal.
Laundering period: every mouse is put into 20min, mouse in the test box without test object and is move freely.To adapt to
New environment.It needs to carry out necessary cleaning to the intracorporal environment of case between two mouse, removes peculiar smell, use 5% wine for identification object
Essence wiping, cabinet are cleaned using tap water.
Learning period: being respectively labeled as a and b for two identical objects, be put into tank ends side, small by each group respectively
Mouse is put into test cabinet other side center.Add up mouse in 16min respectively and detects two objects respective total time
(Exploratory Time), Ta, Tb.Judgment criteria are as follows: mouse touches or is less than close to object distance towards object, nose
1cm.Any non-frontal body is contacted with object, or is crossed, climbed up object and look into the distance and be not counted in mouse and detect the object time.
The test phase: being divided into short-term memory and long-term memory two stages are investigated.Short-term memory 1h after training period, long-term memory
Then in training period, perhaps the longer time (selects the length short-term memory of time or long-term memory can also as the case may be for 24 hours
It is according to circumstances selected).One of two same objects b is replaced with into new object (Novel object) c, other conditions are not
Become.Successively mouse is put into test box, adds up mouse in 4min respectively and detects new and old object respective total time
(Exploratory Time), is denoted as Ta2, Tc respectively.With priority index Preferential index (P.I)=(T c/
(Ta2+Tc)) as the index of cognitive function in mice.The index is higher, and the memory capability for representing mouse is higher.Normal mouse is preferential
Index is 70% or more.
2.3 statistical method
Statistical procedures: data are with mean ± standard deviationIt indicates, is united using 5.03 software of GraphPad
Meter analysis.
3. result
See Table 1 for details for experimental result.
Shadow of each administration group of table 1 to priority index in AD model mice (SAMP8 and SAMR1) strange object identification experiment
Ring (N=10)
Note: with normal solvent control group ratio,*P<0.05、***P<0.001；With model solvent control group ratio#P<0.05、##P<
0.01、###P<0.001
The result shows that medicament composing prescription A, medicament composing prescription B can significantly improve the preferential of SAMP8 mouse after learning period 1h
Index, the strange object identification of SAMP8 mouse can be significantly improved after learning period 1h by illustrating medicament composing prescription A, medicament composing prescription B
Ability.
Shadow of the combination medicine of the invention of embodiment 2. for the passive avoidance response ability of Senescence-Accelerated Mouse
It rings
1. material
1.1 animals: with embodiment 1.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.1.3 laboratory apparatus: diving tower device (DTT-2,
The Chinese Academy of Medical Sciences), cabinet is the open lighttight plastic rectangular in two sides of upper cover having a size of 22 × 28 × 36cm (width x length
× high), bottom surface is stainless steel grid, and grid spacing is 1.5cm (can lead to 36v voltage).Platform is a cuboid plastic foam: 8
× 8 × 2.5cm (width x length × height).Platform is put in cabinet center, is respectively 7,10cm away from cabinet two sides.
2. method
2.1 medications: with embodiment 1.
2.2 Jumping test
Experimental facilities is detected before experiment, whether normal observes its working condition.
Mouse: being gently put into one jiao of cabinet by the environment laundering period first, it is allowed to adapt to environment 2min；It is free of in environment at this time
Safety station.After adaptation, platform is placed in cabinet center.
Training period: being gently put into platform for mouse, and recording its lower platform (four claws of being subject to all land), the time is i.e.
For incubation period (T0), leave from office opens simultaneously power supply and gives lasting electro photoluminescence (~36V), and shock by electricity 10s.Mouse is put back into again flat
On platform, observation mouse time on platform is considered as the mouse and has learned if mouse does not jump off platform in 3min；If mouse
Platform is jumped off, then gives 10s again, the electric shock of 36V operates repeatedly, while recording leave from office number (N), until mouse stands
The platform time terminates more than 3min, and the record training time (tests 3 minutes) (T) without platform.Platform is not descended in first 15s, this is small
Mouse gives up do not have to but remain engaged in after experimental record errors number；Training period (testing 3 minutes without platform), should more than 10 minutes
Mouse gives up do not have to but remain engaged in after experimental record errors number.
The test phase: after training 90min, mouse is re-applied to platform center, observes whether it is able to maintain 3min.If
It leaves office in 3min, records the time (T1) of its lower platform.
2.3 statistical methods: with embodiment 1.
3. result
See Table 2 for details for experimental result.
Each administration group of table 2 is to leave from office number and escape latency in AD model mice (SAMP8 and SAMR1) Jumping test
Influence (N=10)
Note: with normal solvent control group ratio,**P<0.01、***P<0.001；With model solvent control group ratio#P<0.05、##P<
0.01
The result shows that medicament composing prescription A can be substantially reduced the leave from office number of SAMP8 mouse and improve its escape latency,
Illustrate that medicament composing prescription A can significantly improve the passive avoidance response ability of SAMP8 mouse.
Shadow of the combination medicine of the invention of embodiment 3. for the Spatial memory ability of Senescence-Accelerated Mouse
It rings
1. material
1.1 animals: with embodiment 1.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.
1.3 laboratory apparatus: Morris water maze (DNS-2, the Chinese Academy of Medical Sciences) includes following three parts: experiment dress
It sets and is made of labyrinth palace body (pond), video acquisition system, relevant PaintShop and computer: palace body diameter 100cm, fan
Palace wall is higher by water surface 30cm, and security platform (round, diameter 10cm, rough surface is caught in favor of animal) is hidden in 1~2cm's
Underwater, water temperature are 23 DEG C ± 3 DEG C.
2. method
2.1 medications: with embodiment 1.
2.2Morris water maze laboratory
Pond is filled into tap water before experiment, highly to be more than that 1~2cm of security platform is limited.Clip size is 15-20cm
The rectangle scraps of paper hang on water maze wall, it is to note that indoor object space must be kept fixed in experiment whole process.It closes indoor
Fluorescent lamp opens computer and image capture software, security platform is placed in the second quadrant center in pond, and make material object
Virtual location is unified in position and program.Animal group is set in a program, animal swimming time (60s) is set and platform stops
Time (10s).
Platform adapts to: before constant-bearing navigation experiment, animal being placed in 60s on platform, makees platform adaptation training；Then it guides
Animal climbs up platform from away from platform 2-3cm, adaptation training of going up on the stage.
Constant-bearing navigation experiment: i.e. learning training is tested, and is carried out 5 days altogether, and every animal is trained 4 times daily.Every time by animal
It is respectively put into pond from different place of entry, head is towards pool wall.Record animal is Zi water time to needed for climbing up platform is entered, as latent
Fu Qi；And the swimming track of animal in water is recorded, the foundation of used strategy when as analyzing animal search target.Animal
After climbing up platform, its 10s that stands on platform is allowed；If animal does not find platform in 60s or fails to climb up platform, by animal
It leads to the 10s that stands on platform, later removes animal from platform.Daily 4 being averaged for place of entry of every animal are counted to escape
(not climbing up platform, person is calculated in incubation period with 60s), swimming distance, swimming rate, the swimming time in outer region are kept away incubation period,
And the curve of cyclical fluctuations is drawn to observe trend.
Space exploration experiment: i.e. recall tests are tested.Platform is removed from its position, by animal from a place of entry
It is put into pond, record Animals Primiparous time is explored and swims across time of former gate position, explores in 60s and swim across former platform position area
The swimming time of number (the wearing ring number) and animal target quadrant where platform in domain.
2.3 statistical methods: with embodiment 1.
3. result
See Table 3 for details for experimental result.
Each administration group of table 3 to escape latency in AD model mice (SAMP8 and SAMR1) Morris water maze laboratory and
Wear ring number influence (N=10)
Note: with normal solvent control group ratio,***P<0.001；With model solvent control group ratio#P<0.05、##P<0.01、###P
<0.001
The result shows that medicament composing prescription A and medicament composing prescription B can significantly improve the escape latency of SAMP8 mouse and wear ring
Number illustrates that medicament composing prescription A and medicament composing prescription B can significantly improve the Spatial memory ability of SAMP8 mouse.
Shadow of the combination medicine of the invention of embodiment 4. for the active avoidance response ability of Senescence-Accelerated Mouse
It rings
1. material
1.1 animals: with embodiment 1.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.
1.3 laboratory apparatus: shuttle box (Med Corporation), each cabinet are that 50cm × 15cm × 40cm is rectangular
Structure, side wall are metal, and bottom is the fence that can be powered, and box house is separated by the door (10cm × 10cm) controlled by solenoid
The cell for being for two 25cm two side walls.Each room 20W bulb light covered positioned on organic glass, is made by oneself using having
Switch (0.5s is opened, 1.5s is closed) fixed resistance stimulator carry out electro photoluminescence, experimental situation for be protected from light, 60dB (noiseless).
2. method
2.1 medications: with embodiment 1.
2.2 Shuttle box
Learning period: opening software, noise stimulation and light stimulus time be set as 10s, and then electric stimulating time is 5s, intensity
For 0.2mA, inter-trial (Intertrial Interval, ITI) is 30s；Animal is put into shuttle box, journey is opened
Sequence.If animal in the 10s of beginning, from one end through the other end, then light and noise disappear, and electric shock also disappears, such
Reaction is denoted as avoidance；If animal will not receive electric shock through the other end in 10s, shocks by electricity and stop after 5s, mouse is in 5s
Through opposite side, it is denoted as escape；If being denoted as escape failure not through opposite side in animal whole process.；Every mouse connects daily
By 30 times (about 30 minutes) of training, minimum training 5 days, number of days is depending on training result.It is being reached with Normal group (C57) mouse
The standard trained as termination to 80% avoidance number.
The test phase: reseting software, and noise stimulation and light stimulus time are set as 10s, and then electro photoluminescence is cancelled, and ITI is
35s；Animal is put into shuttle box, opening program.If animal in the 10s of beginning, from one end through the other end, then lamp
Light and noise disappear, and such reaction is denoted as avoidance；If animal, through the other end, is denoted as escape in 15s；If animal whole process
In not through opposite side, be denoted as escape failure.
2.3 statistical methods: with embodiment 1.
3. result
See Table 4 for details for experimental result.
Each administration group of table 4 to active avoidance number in AD model mice (SAMP8 and SAMR1) Shuttle box influence (N=10)
Note: with normal solvent control group ratio,***P<0.001；With model solvent control group ratio#, P < 0.05
The result shows that medicament composing prescription A can significantly improve the active avoidance number of SAMP8 mouse, illustrate medicament composing prescription A energy
Enough significantly improve the active avoidance response ability of SAMP8 mouse.
Influence of the combination medicine of the invention of embodiment 5. for the object identification memory capability of bi-transgenic mice
1. material
1.1 animals: APPswe/PS1dEDouble transgenic model mice APPswe/PS1dE9(SPF grades) and C57BL/6J mouse
(SPF grades), 28~32g of weight.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.
1.3 laboratory apparatus: with embodiment 1.
2. method
2.1 medication
With embodiment 1.
2.2 strange object identification experiments
With embodiment 1.
2.3 statistical method
With embodiment 1.
3. result
See Table 5 for details for experimental result.
Each administration group of table 5 is to AD model mice (APPswe/PS1dEAnd C57BL/6J) preferential in strange object identification experiment
Index influence (N=9~15)
Note: with normal solvent control group ratio,*P<0.05、***P<0.001；With model solvent control group ratio,##P<0.01、###
P<0.001
The result shows that medicament composing prescription A and medicament composing prescription B can be improved APPswe/PS1dE9The bi-transgenic mice learning period
The priority index of 1h afterwards illustrates that medicament composing prescription A and medicament composing prescription B can significantly improve APP after learning period 1hswe/PS1dE9
The strange object identification ability of bi-transgenic mice.
Influence of the combination medicine of the invention of embodiment 6. for the passive avoidance response ability of bi-transgenic mice
1. material
1.1 animals: with embodiment 5.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.
1.3 laboratory apparatus: with embodiment 2.
2. method
2.1 medication
With embodiment 1.
2.2 Jumping test
With embodiment 2.
2.3 statistical method
With embodiment 1.
3. result
See Table 6 for details for experimental result.
Each administration group of table 6 is to AD model mice (APPswe/PS1dEAnd C57BL/6J) leave from office number and escape in Jumping test
Keep away it is preclinical influence (N=9~15)
Note: with normal solvent control group ratio,***P<0.001；With model solvent control group ratio,#P<0.05、##P<0.01、###
P<0.001
The result shows that medicament composing prescription A and medicament composing prescription B can significantly reduce APPswe/PS1dE9Under bi-transgenic mice
Platform number and its escape latency of raising, illustrate that medicament composing prescription A and medicament composing prescription B can significantly improve APPswe/PS1dE9Double turns
The passive avoidance response ability of DNA murine.
Influence of the combination medicine of the invention of embodiment 7. for the Spatial memory ability of bi-transgenic mice
1. material
1.1 animals: with embodiment 5.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.
1.3 laboratory apparatus: with embodiment 3.
2. method
2.1 medication
With embodiment 1.
2.2Morris water maze laboratory
With embodiment 3.
2.3 statistical method
With embodiment 1.
3. result
See Table 7 for details for experimental result.
Each administration group of table 7 is to AD model mice (APPswe/PS1dEAnd C57BL/6J) escape in Morris water maze laboratory
Incubation period and wear ring number influence (N=9~15)
Note: with normal solvent control group ratio,***P<0.001；With model solvent control group ratio,#P<0.05、##P<0.01、###
P<0.001
The result shows that medicament composing prescription A and medicament composing prescription B can significantly improve APPswe/PS1dE9Bi-transgenic mice is escaped
It keeps away incubation period and wears ring number, illustrate that medicament composing prescription A and medicament composing prescription B can significantly improve APPswe/PS1dE9Double transgenic is small
The Spatial memory ability of mouse.
Influence of the combination medicine of the invention of embodiment 8. for the active avoidance response ability of bi-transgenic mice
1. material
1.1 animals: with embodiment 5.
1.2 reagent chemicals: Doneppezil Hydrochloride；Memantine；Medicament composing prescription A, Atorvastatin calcium salt and indoles beauty
It is pungent；Medicament composing prescription B, Atorvastatin calcium salt and brufen.Specifically with embodiment 1.
1.3 laboratory apparatus: with embodiment 4.
2. method
2.1 medication
With embodiment 1.
2.2 Shuttle box
With embodiment 4.
2.3 statistical method
With embodiment 1.
3. result
See Table 8 for details for experimental result.
Each administration group of table 8 is to AD model mice (APPswe/PS1dEAnd C57BL/6J) active avoidance in Shuttle box
Several influence (N=9~15)
Note: with normal solvent control group ratio,***P<0.001；With model solvent control group ratio,#P<0.05、##P<0.01、###
P<0.001
The result shows that medicament composing prescription A and medicament composing prescription B can significantly improve APPswe/PS1dE9The master of bi-transgenic mice
It is dynamic to avoid number, illustrate that medicament composing prescription A and medicament composing prescription B can significantly improve APPswe/PS1dE9The master of bi-transgenic mice
Dynamic avoiding reaction ability.
Experiment conclusion
Combination medicine in the present invention can significantly improve Model of Dementia mouse administration group and control group and wild type are small
Object identification ability, passive avoidance response ability, active avoidance response ability and the Spatial memory ability of mouse.Prompt this hair
Bright combination medicine can be improved the cognitive function of Model of Dementia mouse, improve its ability of learning and memory.
Although a specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change in guarantor of the invention
Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.
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Claims (9)
1. a kind of for preventing and/or treating the combination medicine of dull-witted and/or cognition dysfunction comprising a) prevention and/
Therapeutically effective amount Indomethacin or its officinal salt and b) prevention and/or therapeutically effective amount Atorvastatin or its can medicine
With salt and c) optional pharmaceutically acceptable carrier or excipient.
2. a kind of for preventing and/or treating the kit product of dull-witted and/or cognition dysfunction comprising at least one first
Pharmaceutical preparation unit and at least one second pharmaceutical preparation unit, the first pharmaceutical preparation unit and second pharmaceutical preparation unit
It optionally mutually has an independent existence in the kit product；The first pharmaceutical preparation unit includes prevention and/or therapeutically effective amount
Indomethacin or its officinal salt and optional pharmaceutically acceptable carrier or excipient, the second pharmaceutical preparation unit packet
Atorvastatin or its officinal salt and optional pharmaceutically acceptable carrier or figuration containing prevention and/or therapeutically effective amount
Agent.
3. combination medicine according to claim 1 or kit product as claimed in claim 2, it is characterised in that: described
Atorvastatin officinal salt is Atorvastatin calcium salt.
4. combination medicine according to claim 1 or 2 or kit product, the Atorvastatin or its officinal salt with
The weight ratio of Indomethacin or its officinal salt is 1:0.5~1:50.
5. combination medicine according to claim 4 or kit product, the Atorvastatin or its officinal salt and Yin
Pungent or its officinal salt the weight ratio of diindyl U.S. is 1:1~1:25.
6. the combination of Indomethacin or its officinal salt and Atorvastatin or its officinal salt is dull-witted in preparation prevention or treatment
And/or the purposes in the drug of cognition dysfunction.
7. purposes according to claim 6, the dull-witted and/or cognition dysfunction is selected from (1) central nervous system degeneration
Disease: Alzheimer disease, mild cognitive impairment, volume-temporal lobe dementia, Prion disease, dementia with Lewy body, Parkinson's disease, Huntingdon
Disease；(2) non denatured disease is dull-witted: 1. vascular dementia；2. dementia caused by occupying lesion: tumour, chronic subdural hematoma, slow
Dementia caused by property brain abscess；3. dull-witted caused by infection: meningoencephalitis, neurolues, aids dementia, Ruan's albumen disease cause
Dementia；4. brain traumatic is dull-witted；5. dementia caused by normal cranium pressure hydrocephalus；6. being crazy about caused by endocrine metabolism obstacle
It is slow-witted: dysendocrinism, Cushing syndrome, hyperinsulinemia, hypothyroidism, hypopituitarism, hypoglycemia, liver function
Dementia caused by energy failure, kidney failure, lung failure, chronic electrolyte disturbance, hematoporphyria, hypovitaminosis；7. poisoning,
Dementia caused by anoxic；8. dementia caused by paraneoplastic syndrome.
8. purposes according to claim 7, wherein dementia caused by the hypovitaminosis be selected from vitamin B1, niacin,
Dementia caused by folic acid and vitamin B12 deficiency.
9. purposes according to claim 7, wherein dementia caused by the poisoning is selected from alcohol, heavy metal, carbon monoxide
Or dementia caused by drug poisoning.
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