CN101757624B - Composite for preventing and curing senile dementia - Google Patents

Composite for preventing and curing senile dementia Download PDF

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Publication number
CN101757624B
CN101757624B CN2009102006393A CN200910200639A CN101757624B CN 101757624 B CN101757624 B CN 101757624B CN 2009102006393 A CN2009102006393 A CN 2009102006393A CN 200910200639 A CN200910200639 A CN 200910200639A CN 101757624 B CN101757624 B CN 101757624B
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pqq
memory
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acetylcholinesteraseinhibitors inhibitors
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CN101757624A (en
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顾建新
恽小婧
周蕾
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Zhucheng Haotian Pharm Co ltd
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SHANGHAI MEDICINE BIOTIC SCIENCE RESEARCH CENTRE Co Ltd
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Abstract

The invention provides a composite for preventing and curing senile dementia, particularly, the invention provides a composite for improving the ability of memory and cognition, which comprises: (a) PQQ (pyrro-quinoline quinone), salt and/or ester which are (is) pharmaceutically or physiologically acceptable; (b) acetylcholinesterase inhibitor; and (c) carrier which can be pharmaceutically or physiologically acceptable, wherein the molar ratio of the group (a) and the group (b) is 1:100-100:1. The invention also provides the method for preparing the composite of the invention, the use of the composite, a kit containing the composite or a medicine box, and the preparation method of the composite. The composite of the invention can effectively and safely improve the ability of memory and cognition, can be optimally used to prevent and cure the senile degenerative neurologic disease.

Description

The compositions of a kind of prevention and treatment senile dementia
Technical field
The present invention relates to biomedicine field.More specifically, the present invention relates to prevent and to treat compositions, medicine box or the health-care box of senile dementia, they comprise PQQ (PQQ) and Acetylcholinesterase etc. as main active.Each composition of this compositions plays a role through different mechanism respectively, and significant each other collaborative facilitation is arranged between each composition, has the effect of improving memory, cognitive competence.
Background technology
At present, the alzheimer disease prevalence accounts for about 10% of 60 years old population, and wherein (Alzheimer Disease AD) accounts for about 5% Alzheimer.And along with every increase of age 5 years old, the prevalence of AD will increase twice, in the 80-85 patient in year, have 20% old people to suffer from alzheimer disease.
According to statistics, (Alzheimer Disease, AD) routine number is 4,500,000 examples to the U.S.'s Alzheimer in 2000.If Therapeutic Method can not make progress, then the U.S. is when the year two thousand fifty, and Symptomatic AD case load expection will rise to 1,320 ten thousand examples.
At present existing 1.29 hundred million populations of China surpass 60 years old, and the ratio that the old people accounts for total population has reached 10.15%, aged tendency of population serious day by day, thus make China become the country of veteran form population in advance.Therefore, alzheimer disease will day by day become a serious social concern, with the development that greatly hinders society.
And alzheimer disease has become the 4th cause of the death after heart disease, tumor and apoplexy, has caused very big burden and pressure for patient family, society.
So-called " alzheimer disease " is meant that the infringement that continues appears in acquired intelligence that the geratic period occurs in itself, and the intelligence disappearance reduces with social adaptation, be a kind ofly latently attack morbidity, fall ill gradually, be master's chronic progressive disease with the disturbance of intelligence.Its clinical manifestation is mainly: aspect intelligent, abstract thinking ability forfeiture, reasoning and judging and plan deficiency, attention disappearance occur; Aspect personality, occur interest with moving property forfeiture, Blunting of beginning or be difficult to suppress, social behavior is improper, regardless of trivial matters; Aspect memory, occur forgeing, can not learn, time, landform, vision and spatial orientation power are poor; It is unfluent aspect speech and cognitive function, to occur speaking, integration capability disappearance etc.
At present, the cause of disease of alzheimer disease is still not clear.In recent years, the emphasis of external big quantity research concentrates on: aspects such as hereditism, immunology, viral infection, neurotransmitter and neuroendocrine, result of study shows that many factors are relevant with the cause of disease with this disease pathogenesis.
Generally speaking, in the AD of complicacy Study of Etiology, the two is clearer and more definite to increase rheological properties change and inherited genetic factors.A large amount of neurofibrillary tangleses (neurofibrillary tangle, NFT) and senile plaque (senile plaques, existence SP) is its important pathological characters.
And in the process of disease development; The multiple factor that comprises oxidation and lipid peroxidation, the reaction of glutamic acid ability excitatory toxicity, viral infection, inflammation etc. finally can cause a large amount of cholinergic neurons at cerebral hippocampal and cortex position to be lost; Influenced to the learning and memory function, thus dementia caused.
For the treatment of alzheimer disease, still there is not the method that sure ten minutes is effective or cure at present.The drug main of treatment AD will be divided into two types:
The first kind: increase cholinergic nerve system function in the brain, be mainly cholinesterase inhibitor and M-cholinergic receptor agonist.The former mainly comprises aricept, tacrine etc., and this type medicine helps to improve light to moderate patient's clinical symptoms, and still, after neuron loss arrived to a certain degree, keeping of this medicine also was limited.
Second type: act on the cytoprotective of neurotransmission system, to delay the brain neuron degenerative process, theoretically, the blocking-up amyloid-beta forms, and suppresses neurotoxicity and the protection or the repair of neuron of amyloid-beta, reaches the purpose of control AD.Comprise antioxidant; NSAID, Hormone Replacement Therapy, neurotrophic factor, anti-neuronal apoptosis agent and short neurocyte metabolism medicine, calcium channel blocker, correction calcium homeostasis imbalance medicine, anti-4 amyloid forms medicine; Metabolism reinforcing agent; The cell membrane regulator, cerebrolysin, medicines such as glutamate receptor antagonist.Wherein, antioxidant reduces oxidative stress performance protective effect mainly through reducing the formation of free radical in AD patient's brain.
This area presses for develops the medicine of can be safely, effectively preventing and treating alzheimer disease (especially AD).
Summary of the invention
One of the object of the invention is just providing a kind of pharmaceutical composition of can be safely, effectively preventing and treating alzheimer disease (especially AD).
In first aspect of the present invention, a kind of compositions is provided, it comprises:
(a) PQQ, its pharmaceutically or the physiology go up acceptable salt and/or ester;
(b) acetylcholinesteraseinhibitors inhibitors; And
(c) pharmaceutically or the physiology go up acceptable carrier,
Wherein, the mol ratio of component (a) and component (b) is 1: 100～100: 1.
In one embodiment of the present invention, said compositions is pharmaceutical composition or health composition.
In a preference, said compositions is a pharmaceutical composition.
In another preference, the form of said compositions is: tablet, granule, powder, capsule, injection, solution or syrup.
In a preference, said compositions is oral formulations or injection preparation.
In another embodiment of the present invention, said compositions is used for: improve memory and cognitive competence.
In a preference, said compositions is used for prevention or treats senile degeneration sacred disease, is preferred for prevention or treatment alzheimer disease, more preferably is used for prevention or treatment Alzheimer or parkinson disease.
In another embodiment of the present invention, said component (b) acetylcholinesteraseinhibitors inhibitors be selected from down the group in one or more: huperzine A, tacrine or its salt, donepezil, physostigmine carbamate or hydrogen bromination galantamine.
In a preference, said component (b) is: huperzine A, tacrine, donepezil, physostigmine carbamate or hydrogen bromination galantamine, more preferably huperzine A.
In another embodiment of the present invention, the mol ratio of component in the said compositions (a) and component (b) is 1: 50～50: 1.
In a preference, the mol ratio of component (a) and component (b) does, more preferably 1: 25～25: 1, and more preferably 1: 1～25: 1.
In another preference, the weight sum of component (a) and component (b) accounts for 0.1%～99.9% of composition total weight, and more preferably 1%～99%, preferred again 10%～90%.
In another preference, the weight ratio of component (a) and component (b) is 1: 50～50: 1, more preferably 1: 25～25: 1, and more preferably 1: 20～20: 1, preferred again 1: 1～20: 1.
In another embodiment of the present invention, also contain coenzyme Q10 in the said compositions.
In a preference, component (a) is 1: 50～50: 1 with the mol ratio of coenzyme Q10, more preferably 1: 25～25: 1, and more preferably 1: 25～1: 1.
In another preference; Said compositions also contains prevention or treats other active substance of senile degeneration sacred disease; Preferred said active substance is: M-cholinergic receptor agonist, antioxidant, NSAID, neurotrophic factor, anti-neuronal apoptosis agent, short neurocyte metabolism medicine, calcium channel blocker, anti-4 amyloid form medicine, metabolism reinforcing agent, cell membrane regulator, cerebrolysin, glutamate receptor antagonist, more preferably glutamate receptor antagonist.
In second aspect of the present invention, a kind of preparation method for compositions is provided, said method comprises the component (a) and (b) and (c) mixes, and makes the step of compositions, wherein:
(a) PQQ, its pharmaceutically or the physiology go up acceptable salt and/or ester;
(b) acetylcholinesteraseinhibitors inhibitors;
(c) pharmaceutically or the physiology go up acceptable carrier,
Wherein, the mol ratio of component (a) and component (b) is 1: 100～100: 1.
In a preference, the mol ratio of component (a) and component (b) is 1: 50～50: 1, preferred 1: 25～25: 1, and more preferably 1: 1～25: 1.
In the third aspect of the invention, a kind of medicine box or health-care box are provided, it comprises:
(A) be equipped with the effective dose PQQ, its pharmaceutically or the physiology go up the container of acceptable salt and/or ester; With
(B) container of effective dose acetylcholinesteraseinhibitors inhibitors is housed.
In a preference, the mol ratio of said PQQ and said acetylcholinesteraseinhibitors inhibitors is 1: 100～100: 1, preferred 1: 10～50: 1, and more preferably 1: 1～25: 1.
In another preference, said medicine box or health-care box are used for: improve memory and cognitive competence.
In another preference, said medicine box or health-care box are used for prevention or treat senile degeneration sacred disease, are preferred for prevention or treatment alzheimer disease, more preferably are used for prevention or treatment Alzheimer or parkinson disease.
In another preference, before giving PQQ, give the acetylcholinesteraseinhibitors inhibitors of effective dose afterwards or simultaneously.
In another preference; Said acetylcholinesteraseinhibitors inhibitors be selected from down the group in one or more: huperzine A, tacrine or its salt, donepezil, physostigmine carbamate, hydrogen bromination galantamine; Be preferably huperzine A, tacrine, hydrogen bromination galantamine, more preferably huperzine A.
In another preference, said medicine box or health-care box also contain coenzyme Q10, and the mol ratio of preferred PQQ and coenzyme Q10 is 1: 100～25: 1, more preferably 1: 25～1: 1.
In fourth aspect of the present invention, a kind of method for preparing medicine box or health-care box is provided, said method comprises:
(I) with the PQQ of effective dose, its pharmaceutically or the physiology go up acceptable salt and/or ester and pack in first container;
(II) the effective dose acetylcholinesteraseinhibitors inhibitors is packed in second container; With
(III) first container and second container are placed same outer package, form medicine box or health-care box.
In aspect the of the present invention the 5th, provide PQQ, its pharmaceutically or the physiology go up acceptable salt or ester and acetylcholinesteraseinhibitors inhibitors in the purposes that is used for preparing the compositions, medicine box or the health-care box that improve memory and cognitive competence.
In a preference, said compositions, medicine box or health-care box are used for prevention or treat senile degeneration sacred disease, are preferred for prevention or treatment alzheimer disease, more preferably are used for prevention or treatment Alzheimer or parkinson disease.
In another aspect of this invention; The purposes of following compositions in improving memory and cognitive competence is provided; Preferably preventing or treating the purposes in the senile degeneration sacred disease; More preferably the purposes in prevention or treatment alzheimer disease is more preferably being prevented or is being treated the purposes in Alzheimer or the parkinson disease, and above-mentioned composition comprises:
(a) PQQ, its pharmaceutically or the physiology go up acceptable salt and/or ester;
(b) acetylcholinesteraseinhibitors inhibitors; And
(c) pharmaceutically or the physiology go up acceptable carrier,
Wherein, the mol ratio of component (a) and component (b) is 1: 100～100: 1.
In a preference, the mol ratio of component (a) and component (b) is 1: 50～50: 1, preferred 1: 25～25: 1, and more preferably 1: 1～25: 1.
In a preference, above-mentioned composition also contains coenzyme Q10, and the mol ratio of preferred PQQ and coenzyme Q10 is 1: 100～25: 1, more preferably 1: 25～1: 1.
Others of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Description of drawings
Fig. 1: through the Morris water maze test, test PQQ is to the influence of rat cognition and memory ability level, and the 1-5 representative group respectively 1-in the abscissa organizes 5; Vertical coordinate representes respectively to organize the memory maintenance level (%) of rat.
Fig. 2: through the Morris water maze test, test ChEI is to the influence of rat cognition and memory ability level, and the 1-5 representative group respectively 1-in the abscissa organizes 5; Vertical coordinate representes respectively to organize the memory maintenance level (%) of rat.
Fig. 3: through the Morris water maze test, the combination of test PQQ and ChEI or the combination of PQQ and ChEI and CoQ10 are to the influence of rat cognition and memory ability level, and the 1-5 representative group respectively 1-in the abscissa organizes 5; Vertical coordinate representes respectively to organize the memory maintenance level (%) of rat.
Fig. 4: through the Morris water maze test, test PQQ is to the influence of cognition of AD model mice and memory ability level, and the 1-5 representative group respectively 1-in the abscissa organizes 5; Vertical coordinate representes respectively to organize the memory maintenance level (%) of mice.
Fig. 5: through the Morris water maze test, test ChEI is to the influence of cognition of AD model mice and memory ability level, and the 1-5 representative group respectively 1-in the abscissa organizes 5; Vertical coordinate representes respectively to organize the memory maintenance level (%) of mice.
Fig. 6: through the Morris water maze test, the combination of test PQQ and ChEI or the combination of PQQ and ChEI and CoQ10 are to the influence of cognition of AD model mice and memory ability level, and the 1-5 representative group respectively 1-in the abscissa organizes 5; Vertical coordinate representes respectively to organize the memory maintenance level (%) of mice.
The specific embodiment
The inventor is through long-term and deep discovering: the combination of PQQ and acetylcholinesteraseinhibitors inhibitors or unite use; Has synergism for improving memory and cognitive competence; Delay senile dementia model mice disease time, therefore can be used for prevention and treat senile degeneration sacred disease (especially senile dementia).
And; The inventor also further finds in combination or unites on the basis of using PQQ and acetylcholinesteraseinhibitors inhibitors; Add coenzyme Q10 and can further significantly improve the effect of improving memory and cognitive competence, therefore can with these three kinds of active substance combination use or coupling to prevent and to treat senile degeneration sacred disease (especially senile dementia).
On this basis, the inventor has accomplished the present invention.
Related definition
Among this paper, term " contains " the various compositions of expression and can be applied to together in the compositions of the present invention.Therefore, term " mainly by ... form " be included in during term " contains " with " by ... composition ".
Among this paper, term " effective dose " is enough to obtain the effect of needs when referring to use by mode of the present invention and does not have excessive bad side reaction (like toxicity, stimulation and allergy), and the amount of the composition of rational benefit/risk ratio is promptly arranged.Obviously, concrete " effective dose " is different because of various factors, like age of the required object that gives, patient's condition etc.
Among this paper, term " PQQ " refers to PQQ or its salt or ester, and representational salt comprises (but being not limited to): sodium salt, potassium salt, zinc salt etc.Among this paper; Term " PQQ active substance " or " PQQ active substance " interchangeable use all comprise health care conduct and learning, physiology or pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or other derivative form or their mixture of PQQ, PQQ.Term " PQQ derivant " is meant and contains the product that PQQ obtains as primary structure or the metabolism through PQQ, as long as it also has PQQ effect in the present invention.
The structure and the known function of PQQ (PQQ)
PQQ (pyrroloquinoline quinone, it is Powdered PQQ) to be bronzing, is a kind of water soluble compound, and it is present in our diet, and is distributed widely in each histoorgan of human body, and in breast milk, exists.The molecular formula of PQQ is following:
Figure G2009102006393D00071
1979, it was a kind of coenzyme of redox reaction that PQQ is confirmed to be.2003, Nature magazine (Nature.2003 April 24; 422 (6934): 832) report PQQ has vitamin activity, thinks that it possibly be a kind of novel vitamin B group.
Research confirms that PQQ is a kind of to the very favorable material of health.Through the multiple function of animal experimental observation to PQQ: the PQQ of purification can avoid CCl by the liver protecting as a kind of antioxidant 4Or it is alcohol damaged.The cataract that the PQQ of purification reduces glucocorticoid inducible in the chick embryo development process forms, thereby possibly be to play a role through the reactivity that the recovery glutathione level reduces 17-hydroxy-11-dehydrocorticosterone.The NMDA oxidoreduction site of PQQ direct oxidation receptor, the protection cell is avoided the NMDA toxic effect, thereby prevents the brain hypoxic-ischemic, avoids animal model that serious shock takes place.Simultaneously, PQQ can also protect heart to prevent myocardial ischemia and myocardial infarction.
As far as nervous system, PQQ possesses oxidation resistance and neuroprotective, is mainly reflected in the following aspects:
1. antioxidation
PQQ can effectively regulate redox reaction.It can suppress: the 1) peroxidating of lipid; 2) proteic carbonylation; 3) oxidative stress is to inactivation (Stites TE etc., the J Nutr.2000Apr of mitochondrion internal respiration chain; 130 (4): 719-27)
2. neuroprotective
1) improves mitochondrial function; 2) suppress the neurotoxic effect that nmda receptor mediates; 3) neuronic protective effect; 4) raise nerve growth factor; And 5) suppress the proteic formation of fiber-like (Scanlon JM, EurJ Pharmacol.1997 May 12; 326 (1): 67-74; Urakami T etc., Biofactors.1995-1996,5 (3): 139-46; Liu S etc., Microsurgery.2005; 25 (4): 329-37)
Yet before the present invention, the combination that this area is never improved memory and cognitive competence, prevention to PQQ active substance and other or treated senile degeneration sacred disease (especially Alzheimer) is used or is united to use and make research.
Acetylcholinesteraseinhibitors inhibitors
As used herein; Term " acetylcholinesteraseinhibitors inhibitors " is meant that to the inhibited material of the acetylcholine degrading activity of Acetylcholinesterase it plays the effect that improves memory, alleviates senile dementia through the degraded that suppresses the inner acetylcholine of synapse.
" acetylcholinesteraseinhibitors inhibitors " among the present invention comprises any material of acetylcholine esterase inhibition activity, includes but not limited to: tacrine (Tacrine), donepezil (Donepezil), sharp this bright (Rivastigmine), high blue its bright (Galantamine), huperzine A (Huperzine A), coumarin derivative (for example Anseoulin etc.), plant or microbe-derived acetylcholinesteraseinhibitors inhibitors (for example in the methanolic extract of angelica root, the lilac grey streptomycete isolating cyclophostin etc.).About the kind and the purposes of acetylcholinesteraseinhibitors inhibitors, can referring to the summary of for example Zou Lei etc. (Food Science, 2005, the Vol.26 supplementary issue, pp105-108).
Though acetylcholinesteraseinhibitors inhibitors is the main medicine that is used to treat senile dementia at present, it can only alleviate the symptom of AD, and neuroprotective unit is not destroyed fully.Therefore, this area still presses for improves this type of effect of drugs, even the pharmaceutical composition that can cure AD.
Compositions
The invention provides a kind of compositions, it comprises: (a) PQQ, its pharmaceutically or the physiology go up acceptable salt and/or ester; (b) acetylcholinesteraseinhibitors inhibitors; And (c) pharmaceutically or the physiology go up acceptable carrier.
Said composition can be used for improving memory and cognitive competence, prolong the object life expectancy, reduce the generation of amyloid beta in the brain; Thereby prevent or treat senile degeneration sacred disease; Be preferred for prevention or treatment alzheimer disease, more preferably be used for prevention or treatment Alzheimer, parkinson disease.In the present composition, active component (a) and the mol ratio that (b) exists are 1: 100-100: 1, preferred 1: 1-25: 1, thus play synergism each other.
In a preferred implementation of the present invention, also preferably contain coenzyme Q10 in the compositions of the present invention.The inventor has confirmed that through test coenzyme Q10 can further strengthen compositions effect in the amyloid beta in improving memory and cognitive competence, prolongation object life expectancy, minimizing brain that the present invention contains PQQ and ChEI.In the compositions, the mol ratio of PQQ and coenzyme Q10 is 1: 100-25: 1, more preferably 1: 25-1: 5.
As used herein, term " pharmaceutically or physiology go up acceptable carrier " refers to be used for the carrier of health product or pharmaceutical preparation, comprises various excipient and diluent, and they itself are not necessary active component, and do not have or do not have undue toxicity after using.Suitable carriers is well known to those of ordinary skill in the art.For example, pharmaceutically acceptable carrier write up in " Lei Mingdun pharmaceutical science " (Remington ' sPharmaceutical Sciences, Mack Pub.Co., N.J.1991).
Acceptable carrier can contain liquid on combination of Chinese medicine is learned, like water, saline, glycerol and ethanol.In addition, also possibly there is complementary material in these carriers, like filler, disintegrating agent, lubricant, fluidizer, effervescent, wetting agent or emulsifying agent, correctives, pH buffer substance etc.Usually, can these materials be formulated in nontoxic, the inert and pharmaceutically acceptable aqueous carrier medium, wherein pH is about 5-8 usually, and preferably, pH is about 6-8.
Active substance in the compositions of the present invention (a) and (b) account for the 0.001-99.9wt% of composition total weight; Being preferably the 1-95wt% of composition total weight, more preferably is 5-90wt%, more preferably 10-80wt%.Surplus is materials such as carrier and other additive.
In another preferred implementation of the present invention, said compositions is unit dosage forms or multi-pharmaceutics.As used herein, term " unit dosage forms " is meant in order to take or easy to use, and preparation of compositions of the present invention is become single to take or uses required dosage form, includes but not limited to various solid formulation (like tablet), liquid agent, capsule, slow releasing agent.
In another preference of the present invention, use 1-6 agent compositions of the present invention every day, preferably use the 1-3 agent; Take 1 dose preferred every day when high dose.In a preference of the present invention, use the present composition of 0.001-10mg/kg body weight to object every day, preferred 0.01-5mg/kg body weight, more preferably 0.01-1mg/kg body weight.
The effective dose that should be understood that used active substance can decide with the individual instances (for example object body weight, age, health, the required effect that reaches) of the object of need preventions or treatment, and this is in the scope that skilled practitioners or nutritionist can judge.
Compositions of the present invention can be solid-state (like granule, tablet, lyophilized powder, suppository, capsule, sublingual lozenge) or liquid (like oral liquid, solution or syrup) or other suitable form.
Medicine box or health-care box
The present invention also provides a kind of medicine box or health-care box, wherein contains: (A) be equipped with the effective dose PQQ, its pharmaceutically or the physiology go up the container of acceptable salt and/or ester; (B) container of effective dose acetylcholinesteraseinhibitors inhibitors is housed.Said medicine box or health-care box be used to improve memory and cognitive competence, prolong the object life expectancy, reduce the generation of amyloid beta in the brain, thereby prevention or treat senile degeneration sacred disease is preferred for prevention or treatment alzheimer disease.
As used herein, term " health-care box " is meant the combination that the container of active substance with health role can be provided object is housed that it can be used as the object that health product offer to be needed.
In embodiments of the present invention, before giving PQQ, give the acetylcholinesteraseinhibitors inhibitors of effective dose afterwards or simultaneously.
Method of application
Compositions of the present invention, medicine box or health-care box can be used through conventional route, comprising (but being not limited to): approach such as oral, spraying, nasal cavity or transdermal.Preferred oral.Composition forms should be complementary with method of application.The amount of application of the present composition by active substance PQQ weight, is generally about 0.001-5mgPQQ/kg body weight every day, preferably about 0.01-1PQQ/kg body weight, preferred 0.01-0.5mgPQQ/kg body weight.
Compositions of the present invention, medicine box or health-care box can directly use, and also can unite use with other therapeutic agent or adjuvant.In preferred implementation of the present invention, be used for prevention and treatment during alzheimer disease, compositions of the present invention, medicine box or health-care box also can with effective dose (like 0.0005-0.1 gram/kg body weight/day; Preferred 0.001-0.05 gram/kg body weight/day) material of group is co-administered under being selected from: M-cholinergic receptor agonist, antioxidant, NSAID, neurotrophic factor, anti-neuronal apoptosis agent, short neurocyte metabolism medicine, calcium channel blocker, anti-4 amyloid form medicine, metabolism reinforcing agent, cell membrane regulator, cerebrolysin, glutamate receptor antagonist, more preferably glutamate receptor antagonist.
When combinations of substances more than three kinds or three kinds or administering drug combinations, preferably has the effect that is superior to giving separately respectively these materials.
Advantage of the present invention
Advantage of the present invention includes but not limited to:
(a) found that first uniting of PQQ and acetylcholinesteraseinhibitors inhibitors uses or combination is used for the generation that improves amyloid beta in memory and cognitive competence, prolongation object life expectancy, the minimizing brain; Thereby prevent or treat senile degeneration sacred disease to have synergism, can be used for the prevention or the treatment of relevant disease or symptom;
(b) PQQ exists in vivo, is natural chemical compound, has no side effect; And acetylcholinesteraseinhibitors inhibitors is the existing medicine that has been used for the senile dementia treatment in this area, and both combinations have high security;
(c) interpolation of PQQ also can replenish intravital endogenous PQQ, has alleviated the caused symptom of shortage of body endogenous cause of ill PQQ.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to the condition described in the normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
Only if definition separately, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any with the institute similar content of putting down in writing or the equalization method and material all can be applicable among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
The Morris water maze test
The Morris water maze be 1981 by Belgian scientist Morris invention, be the more satisfactory experimental system that is used for detecting rodent space learning memory ability.Memory in the experiment is equivalent to human recent memory, and this recent memory infringement is more serious in AD patient.This experiment adopts the Morris water maze to understand the influence of treatment to rat or mouse model ability of learning and memory, and the laboratory animal escape latency shortens its learning memory disorder of explanation and improves.
Designing special water maze mainly is made up of the platform of a column type pond and a removable position.The high 70cm in pond, diameter 80cm, platform diameter 8cm, the sky, pond is connected with computer through a digital camera.In the pond, inject clear water in advance, depth of water 15cm adds burnt black ink and makes Chi Shui become opaque black, and platform surface is a black, and laboratory animal can not be seen, the water surface exceeds platform surface 0.5cm.Water temperature is controlled at 22 ± 0.5 ℃, and subscript phasing same point is as the place of entry of each laboratory animal in the pond.Platform places in the middle of place of entry quadrant far away, and experimentation keeps gate position constant.Each experiment is exceeded with 120s; The record animal as the learning and memory achievement, is not found platform as if in the setting-up time with required time from place of entry in-track platform required time and during this period of time swimming distance and speed; Computer stops to follow the tracks of, and be 120s writing time.
Each experiment is carried out in sound damping room, the pond, and light source, the position of each objects of laboratory such as mouse cage remains unchanged.Training in the 3rd day if animal is found platform in 120s, is allowed to condition at and stops 20s on the platform after the modeling, if animal is not found platform, places it in and makes its stop 20s on the platform.In modeling the 4th day, the 5th day, the 7th day, carried out study of MORRIS water maze and test on the 11st day.
Embodiment 1. PQQs (PQQ) are to the influence of rat cognition and memory ability level
Experimental animal and grouping:
The Wistar rat (available from animal institute of the Chinese Academy of Sciences) in 4 ages in week, totally 60, be equally divided into 5 groups, 12 every group, male and female half and half.
Medication and dosage:
According to following setting dosage, to 8 weeks of rat oral administration (every day 2 times) of dividing into groups:
Group 1: contrast gives normal saline;
Group 2:PQQ 3.3mg/kg/d (through the normal saline solution form administration of PQQ);
Group 3:PQQ 5.0mg/kg/d (through the normal saline solution form administration of PQQ);
Group 4:PQQ 10mg/kg/d (through the normal saline solution form administration of PQQ);
Group 5:PQQ 20mg/kg/d (through the normal saline solution form administration of PQQ).
Appraisal procedure:
Rats by intraperitoneal injection pentobarbital sodium 40mg/kg sets up the dementia rats model.Adopt Morris water maze test (repeating 3 times), detect the influence of PQQ rat cognition and memory ability level.
Result of the test and discussion:
Each memory of organizing rat keeps percentages as shown in Figure 1.
Result of the test shows: the PQQ of 3.3mg/kg/d only makes the rat memory maintain faint raising, and along with the raising of PQQ dosage, memory keeps percentage ratio progressively to improve, and the PQQ of 20mg/kg/d can make the rat memory keep bringing up to more than 60%.
This result of the test shows: PQQ can improve cognition and the memory ability level of rat, and this raising effect has dose dependent.
Embodiment 2. acetylcholinesteraseinhibitors inhibitors huperzine As are to the influence of rat cognition and memory ability level
Experimental animal, grouping and medicine:
The Wistar rat (available from animal institute of the Chinese Academy of Sciences) in 4 ages in week, totally 60, be equally divided into 5 groups, 12 every group, male and female half and half.
Huperzine A: huperzine A capsule, available from multiple magnificent pharmaceutcal corporation, Ltd of Fudan University (get capsule 's content be dissolved in normal saline experimentize).
Medication and dosage:
According to following setting dosage, to 8 weeks of rat oral administration (every day 2 times) of dividing into groups:
Group 1: contrast gives normal saline;
Group 2:ChEI 0.1mg/kg/d (with the normal saline solution form administration of huperzine A);
Group 3:ChEI 0.2mg/kg/d (with the normal saline solution form administration of huperzine A);
Group 4:ChEI 0.5mg/kg/d (with the normal saline solution form administration of huperzine A);
Group 5:ChEI 1.0mg/kg/d (with the normal saline solution form administration of huperzine A).
Appraisal procedure:
Rats by intraperitoneal injection pentobarbital sodium 40mg/kg sets up the dementia rats model.Adopt Morris water maze test (number of repetition 3 times), detect the influence of ChEI rat cognition and memory ability level.
Result of the test and discussion:
Each memory of organizing rat keeps percentages as shown in Figure 2.
Result of the test shows: the ChEI of 0.1mg/kg/d can make rat memory maintenance level slightly improve, and along with the raising of ChEI dosage, memory keeps percentage ratio progressively to improve, and the ChEI of 1.0mg/kg/d can make the rat memory keep bringing up to 60%.
This result of the test shows: ChEI can improve cognition and the memory ability level of rat, and this raising effect has dose dependent.
The combination of embodiment 3. PQQs (PQQ) and acetylcholinesteraseinhibitors inhibitors (ChEI) huperzine A or The combination of this combination and coenzyme Q10 (CoQ10) is to the influence of rat cognition and memory ability level
Experimental animal and grouping:
The Wistar rat (available from animal institute of the Chinese Academy of Sciences) in 4 ages in week, totally 60, be equally divided into 5 groups, 12 every group, male and female half and half.
Medication and dosage:
According to following setting dosage, to 8 weeks of rat oral administration (every day 2 times) of dividing into groups:
Group 1: contrast gives normal saline;
Group 2:PQQ 3.3mg/kg/d (with the normal saline solution form administration);
Group 3:ChEI 0.2mg/kg/d (with the normal saline solution form administration);
Group 4:PQQ 3.3mg/kg/d+ChEI 0.2mg/kg/d (with the normal saline solution form administration);
Group 5:PQQ 3.3mg/kg/d+ChEI 0.2mg/kg/d+CoQ10 100mg/kg/d (with the normal saline solution form administration).
Appraisal procedure:
Rats by intraperitoneal injection pentobarbital sodium 40mg/kg sets up the dementia rats model.Adopt Morris water maze test (number of repetition 3 times), detect the influence of above-mentioned administration rat cognition and memory ability level.
Result of the test and discussion:
Each memory of organizing rat keeps percentages as shown in Figure 3.
The result of Fig. 3 shows: adopt the PQQ (3.3mg/kg/d) of low dosage and the administering drug combinations of ChEI (0.2mg/kg/d) can make the memory maintenance level of rat improve significantly to more than 60%.And on the basis of low dosage PQQ and ChEI combination, add CoQ10 again and more can make rat memory maintenance level reach about 80%.
Calculate the synergism between the medicine according to the Jin Shi formula, find to unite and use PQQ and ChEI to use PQQ or ChEI can significantly improve the memory maintenance level of rat more separately, and have synergism between two kinds of medicines:
(list of references: Nintaus is equal, the addition in the drug combination for synergy between the gold formula formula judgement medicine.Acta Pharmacologica Sinica 1980; 1:70-76):
Q value=E A+B/ (E A+ E B-E A* E B), q value＞1.15 o'clock, two medicines have synergism.
In the present embodiment, the E value is: compare the increase percentage ratio of each experimental group (2,3,4) memory hold facility with matched group (1).
E (PQQ?3.3mg/kg)＝(43.13％-37.00％)/37.00％＝16.57％
E (ChEI?0.2mg/kg)＝(44.00％-37.00％)/37.00％＝18.92％
E (PQQ+ChEI)＝(64.00％-37.00％)/37.00％＝72.97％
Q value=72.97%/(16.57%+18.92%-16.57% * 18.92%)=2.255＞1.15
The above results shows: the coupling of PQQ and ChEI can significantly improve cognition and the memory ability level of rat, and two kinds of active component have synergism.In this combination, further add CoQ10 (being mainly the antioxidative effect), then can further significantly improve the effect that keeps memory.
And; Because PQQ and ChEI improve the cognition of rat and the effect of memory ability level has dose dependent (referring to the result of embodiment 1 and embodiment 2), but rational expectation is united concentration higher PQQ and the ChEI of use in making up than used PQQ and ChEI in the present embodiment and can be obtained better effect.
Embodiment 4. PQQs (PQQ) are to the influence of AD model mice senile dementia formation time
Experimental animal and grouping:
APP transgene mice model can be simulated the disease process of senile dementia preferably; APP transgenic mice water maze laboratory and matched group (C57BL/6J mice) when 3 monthly ages relatively have statistical significance (P＜0.01); And prolongation along with the time; APP transgenic mice behavioral deficiency is day by day obvious, and this phenomenon meets by mild cognitive impairment to the senile dementia development law.And in the APP transgenic mice, use the related drugs treatment, and significantly improve the memory ability of mice, help to delay disease process.
Totally 30 of 4 monthly age APP transgenic mices (the AD model mice is available from Shanghai medicine institute of the Chinese Academy of Sciences) are equally divided into 5 groups, and 6 every group, male and female half and half.
Medication and dosage:
According to following setting dosage, to 8 weeks of mice oral administration (every day 2 times) of dividing into groups:
Group 1: contrast gives normal saline;
Group 2:PQQ 3.3mg/kg/d (with the normal saline solution form administration of PQQ);
Group 3:PQQ 5.0mg/kg/d (with the normal saline solution form administration of PQQ);
Group 4:PQQ 10mg/kg/d (with the normal saline solution form administration of PQQ);
Group 5:PQQ 20mg/kg/d (with the normal saline solution form administration of PQQ).
Appraisal procedure:
Adopt Morris water maze test (number of repetition 3 times), detect the influence of cognition of AD model mice and memory ability level.The forfeiture gradually of memory ability is that senile dementia also is the longest course of disease of time the earliest; Patient's memory ability reduces gradually in this process, if can delay memory ability and reduce, and prolongs the memory retention time; Then for the morbidity that delays senile dementia, prevention and treatment senile dementia have good effect.
Result of the test and discussion:
Each memory of organizing mice keeps percentages as shown in Figure 4.
Result of the test shows: the PQQ of low, middle dosage (3.3,5,10mg/kg/d) makes AD model mice memory maintenance level progressively, and the high dose PQQ of 20mg/kg/d can make the rat memory keep bringing up near 60%.
This result of the test shows: PQQ can improve the cognition and the memory ability level of senile dementia model mice, and this raising effect has dose dependent.
Embodiment 5. acetylcholinesteraseinhibitors inhibitors (ChEI, huperzine A) form AD model mice senile dementia The influence of time
Experimental animal and grouping:
Totally 30 of 4 monthly age APP transgenic mices (the AD model mice is available from Shanghai medicine institute of the Chinese Academy of Sciences) are equally divided into 5 groups, and 6 every group, male and female half and half.
Medication and dosage:
According to following setting dosage, to 8 weeks of mice oral administration (every day 2 times) of dividing into groups:
Group 1: contrast gives normal saline;
Group 2:ChEI 0.1mg/kg/d (with the normal saline form administration);
Group 3:ChEI 0.2mg/kg/d (with the normal saline form administration);
Group 4:ChEI 0.5mg/kg/d (with the normal saline form administration);
Group 5:ChEI 1.0mg/kg/d (with the normal saline form administration).
Appraisal procedure:
Adopt Morris water maze test (repeating 3 times), detect the influence of cognition of AD model mice and memory ability level.The forfeiture gradually of memory ability is that senile dementia also is the longest course of disease of time the earliest; Patient's memory ability reduces gradually in this process, if can delay memory ability and reduce, and prolongs the memory retention time; Then for the morbidity that delays senile dementia, prevention and treatment senile dementia have good effect.
Result of the test and discussion:
Each memory of organizing mice keeps percentages as shown in Figure 5.
Result of the test shows: the ChEI of low dosage (0.1mg/kg/d) only makes AD model mice memory maintenance level that raising is arranged slightly, and in or the ChEI of high dose can make the rat memory keep bringing up near 60%.
This result of the test shows: ChEI can improve the cognition and the memory ability level of senile dementia model mice, and this raising effect has dose dependent.
The combination of embodiment 6. PQQs (PQQ) and acetylcholinesteraseinhibitors inhibitors huperzine A (ChEI) or The combination of this combination and coenzyme Q10 (CoQ10) is to the influence of AD model mice senile dementia formation time
Experimental animal and grouping:
Totally 30 of 4 monthly age APP transgenic mices (the AD model mice is available from Shanghai medicine institute of the Chinese Academy of Sciences) are equally divided into 5 groups, and 6 every group, male and female half and half.
Medication and dosage:
According to following setting dosage, to 8 weeks of rat oral administration (every day 2 times) of dividing into groups:
Group 1: contrast gives normal saline;
Group 2:PQQ 3.3mg/kg/d (with the normal saline solution form administration);
Group 3:ChEI 0.2mg/kg/d (with the normal saline solution form administration);
Group 4:PQQ 3.3mg/kg/d+ChEI 0.2mg/kg/d (with the normal saline solution form administration);
Group 5:PQQ 3.3mg/kg/d+ChEI 0.2mg/kg/d+CoQ10100mg/kg/d (with the normal saline solution form administration).
Appraisal procedure:
Adopt Morris water maze test (number of repetition 3 times), detect the influence of cognition of AD model mice and memory ability level.
Result of the test and discussion:
Each memory of organizing mice keeps percentages as shown in Figure 6.
The result of Fig. 6 shows: adopt the PQQ (3.3mg/kg/d) of low dosage and the administering drug combinations of ChEI (0.2mg/kg/d) can make the memory maintenance level of rat improve significantly near 60%.And on the basis of low dosage PQQ and ChEI combination, add CoQ10 again and more can make rat memory maintenance level reach more than 60%.
Calculate the synergism between the medicine according to the Jin Shi formula:
E value: the increase percentage ratio of comparing each experimental group (2,3,4) memory hold facility with matched group (1).
E (PQQ?3.3mg/kg)＝(36.00％-27.00％)/27.00％＝33.33％
E (ChEI?0.2mg/kg)＝(36.00％-27.00％)/27.00％＝33.33％
E (PQQ+ChEI)＝(58.00％-27.00％)/27.00％＝114.81％
Q value=114.81%/(33.33%+33.33%-33.33% * 33.33%)=2.067＞1.15 (pointing out the two is synergism)
The above results shows: the coupling of PQQ and ChEI can significantly improve the cognition and the memory ability level of AD model mice, and two kinds of active component have synergism.In this combination, further add CoQ10 (antioxidation), then can further significantly improve the effect that keeps memory, thereby postpone the formation time of senile dementia.
And; Because PQQ and ChEI improve the cognition of AD model mice and the effect of memory ability level has dose dependent (referring to the result of embodiment 4 and embodiment 5), but rational expectation is united concentration higher PQQ and the ChEI of use in making up than used PQQ and ChEI in the present embodiment and can be obtained better effect.
All documents in that the present invention mentions are all quoted as a reference in this application, are just quoted such as a reference separately as each piece document.Should be understood that in addition after having read above-mentioned teachings of the present invention, those skilled in the art can do various changes or modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Claims (8)

1. compositions that is used to prevent or treat senile dementia, it is composed of the following components:
(a) PQQ, its pharmaceutically or the physiology go up acceptable salt;
(b) acetylcholinesteraseinhibitors inhibitors, it is selected from: huperzine A or its salt;
(c) pharmaceutically or the physiology go up acceptable carrier; And
Choose wantonly, (d) coenzyme Q10,
Wherein, the mol ratio of component (a) and component (b) is 1: 1～25: 1.
2. compositions as claimed in claim 1 is characterized in that, said compositions is pharmaceutical composition or health composition.
3. compositions as claimed in claim 1 is characterized in that, said component (b) acetylcholinesteraseinhibitors inhibitors is a huperzine A.
4. one kind prepares the method for compositions that is used to prevent or treat senile dementia, and said method comprises the component (a) and (b) and (c) mixes, and makes the step of compositions, wherein:
(a) PQQ, its pharmaceutically or the physiology go up acceptable salt;
(b) acetylcholinesteraseinhibitors inhibitors, it is selected from: huperzine A or its salt;
(c) pharmaceutically or the physiology go up acceptable carrier,
Wherein, the mol ratio of component (a) and component (b) is 1: 1～25: 1.
5. a medicine box or health-care box that is used to prevent or treat senile dementia, it comprises:
(A) be equipped with the effective dose PQQ, its pharmaceutically or the physiology go up the container of acceptable salt; With
(B) container of effective dose acetylcholinesteraseinhibitors inhibitors is housed, wherein, said acetylcholinesteraseinhibitors inhibitors is selected from: huperzine A or its salt.
6. one kind prepares the method that is used to prevent or treat the medicine box or the health-care box of senile dementia, and said method comprises:
(I) with the PQQ of effective dose, its pharmaceutically or the physiology go up acceptable salt and pack in first container;
(II) the effective dose acetylcholinesteraseinhibitors inhibitors is packed in second container, wherein, said acetylcholinesteraseinhibitors inhibitors is selected from: huperzine A or its salt; With
(III) first container and second container are placed same outer package, form medicine box or health-care box.
PQQ, its pharmaceutically or the physiology go up acceptable salt and being combined in of acetylcholinesteraseinhibitors inhibitors and be used for preparing improving and remember and the purposes of compositions, medicine box or the health-care box of cognitive competence; Wherein, said acetylcholinesteraseinhibitors inhibitors is selected from: huperzine A or its salt.
PQQ, its pharmaceutically or the physiology go up the purposes that is used for preparing the compositions, medicine box or the health-care box that are used to prevent or treat senile dementia that is combined in of acceptable salt and acetylcholinesteraseinhibitors inhibitors; Wherein, said acetylcholinesteraseinhibitors inhibitors is selected from: huperzine A or its salt.
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