CN1864675A - Use of naringenin and derivative in preparation of product for resisting cardiovascular and cerebrovascular disease - Google Patents
Use of naringenin and derivative in preparation of product for resisting cardiovascular and cerebrovascular disease Download PDFInfo
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Abstract
The present invention relates to the new use of narigenin and similar compounds in preparing medicines for treating cardiac and cerebral vascular diseases. These compounds include narigenin and its derivative, hesperidene and its derivative, isosakuranetin and its derivative, eriodictyol and its derivative, etc. These compounds may be used in preventing, diagnosing and treating cerebral infarction, myocardial infarction, cerebral ischemia-reperfusion injury, myocardial ischemia-reperfusion injury and other cardiac and cerebral vascular diseases as well as Alzheimer disease and its relevant diseases. These compounds have high pharmacological action, low toxicity, wide material source, low cost and other advantages.
Description
Technical field
The present invention relates to technical fields such as medicine, Food ﹠ Drink, specifically relate to the purposes of naringenin and derivant thereof, more particularly relate to the purposes that naringenin and derivant thereof are used to prepare anti-cardiac-cerebral vascular diseases product.
Background technology
(1) progress of naringenin and derivant thereof
1, overview
The plant origin of naringenin is the alabastrum of rosaceous plant oriental cherry Prunus yedoensis Mats., the alabastrum of prunus mume (sieb.) sieb.et zucc. P.mumeSieb.etZucc. etc., and the naringenin English name is naringenin, molecular formula and molecular weight C
15H
12O
5, 272.25, structural formula such as right figure.
Naringenin is white, needle-shaped crystals (methanol), 260 ℃ of fusing points, and naringenin is dissolved in ethanol, ether and benzene, and is water-soluble hardly.
Quite a few is present in naringenin and derivant thereof in the fruit and peel of both citrus (Citrus) plant, and fruit is immature more, naringenin and derivative content thereof are high more, as naringin, Hesperidin etc. (referring to Zhao Xuemei, Zhu Dayuan, Ye Xingqian etc., the progress of flavonoid in the both citrus, research and development of natural products, 2002,14 (1): 89-92), other derivant can also be made by respective physical or chemical method by the material that exists in the fruit of above-mentioned orange and the peel.
2, naringenin pharmacological action
Naringenin is the glycoside unit of naringin (narigen), has antibiotic, antiinflammatory, anticancer, spasmolytic and choleretic effect.
1. antibiotic: that staphylococcus aureus, large intestine, dysentery and Bacillus typhi are all had stronger antibacterial action.Naringenin also has effect to fungus, and 1000ppm is sprayed on and can reduces rice blast fungus infection 40-90% on the rice, and people and domestic animal are not had toxicity.
2. antiinflammatory: rat abdominal cavity is injected 20mg/kg every day, obviously suppresses to implant the caused inflammatory process of Pilus Caprae seu Ovis ball.
3. anticancer: that big murine leukemia L1210 and sarcoma are all had activity.
4. spasmolytic and function of gallbladder promoting: for having strong actor in the flavone compound.Naringenin also has the effect of stronger increase laboratory animal bile secretion.
Other has research data to show, naringenin and derivant thereof have anti-curing hyperlipemia, prevent and treat atherosclerosis, cough-relieving, reduce phlegm, effects such as endotoxin shock that anticancer, antiinflammatory and infection cause are (referring to WO98/16220; WO98/16221; WO98/16239; WO99/21549; WO99/21570; CN1430967A; CN1555793A; WO01/14396; Kawaguchi K, Kikuchi S, Hasunuma R et al.Suppression of infection-induced endotoxin shockin mice by a citrus flavanone naringin.Planta Med.2004; 70 (1): 17-22).
There is the report naringenin to suppress the platelet aggregation of arachidonic acid-induction (referring to Corvazier E, Maclouf J.Interference of some flavonoids and non-steroidal anti-inflammatory drugs with oxidativemetabolism of arachidonic acid by human platelets and neutrophils.Biochim Biophys Acta.1985835 (2): 315-21) and the deutero-flavonoids of citrus peels can be used as collagen-induced anticoagulant (referring to WO01/14396), but the preventive drug that anticoagulant only takes place as cerebral infarction or myocardial infarction is (referring to H.Darius, R.Erbel, G.G.Belz et al. anticoagulant, the application in disease treatment of anticoagulant and thrombolytics, Germany's medical science, 1994; 11 (2): 75-77; The assistant rattan is U.S. good etc., and antiplatelet drug is to the prevention of cerebral infarction recurrence, Japan medical science introduction, 2001; 22 (5): 202-203),, generally make motive, brain microcirculation improving agent (as: nitroglycerin, isosorbide mononitrate, nimodipine, vincamine, buflomedil etc.) at present for cerebral infarction that has taken place or myocardial infarction; Neurocyte matabolizing improvement agent (as: aniracetam, citicoline, aceglutamide etc.); Neural renovation agents (as: Monostalotetrahexosylgangliside) etc. also can not alleviate tissue injury that ischemia causes, alleviate ischemia about anticoagulant at present---the definite conclusion of reperfusion injury, control apoplexy sequela and vascular dementia.
The dry herb in the Dracocephalum moldabium ground of patent CN1401326A report phytolith has significant PAF antagonism through the total flavones that extracts, chromatography obtains, can suppress the inductive platelet aggregation of PAF, expansible coronary artery, increase coronary flow, make oral or injection, be used for the treatment of ischemic cardio cerebrovascular diseases, angina pectoris, myocardial infarction, cerebral infarction.Its total flavones main component is naringenin-7-O-glucoside and bear's weed element-7-O-glucoside.But this patent has only illustrated naringenin-7-O-glucoside and bear's weed element-7-O-glucoside and has accounted for 70% of total flavones, the activity relationship of naringenin-7-O-glucoside or bear's weed element-7-O-glucose and total flavones clearly or directly do not illustrated as yet.
(2) progress of cardiovascular and cerebrovascular disease
1, general introduction
Cardiovascular and cerebrovascular disease all is the formidable enemy who threatens human health all the time, the raising year by year in China along with living standard, and the change of life style, and China steps into aged society gradually, the threat of cardio-cerebrovascular disorder is serious day by day.Cardiovascular and cerebrovascular disease is first cause of the death of harm Chinese population health, wherein the mortality rate of cerebral infarction and myocardial infarction accounts for sizable ratio and is tangible ascendant trend, its harm is serious day by day, and the prevention of such disease and control are subjected to paying close attention to widely day by day.
2, epidemiology situation
Present epidemiological survey result shows, cardiovascular and cerebrovascular disease has been the primary disease that threatens Chinese population health, and along with the change of expanding economy and life style, dietary habit, the mortality rate of such disease rises year by year.The monitoring area reported cardiovascular and cerebrovascular disease 15405 examples altogether in 1998, and the report mortality rate is 173.66/10 ten thousand, has risen 9% than 1997.Studies show that this type of disease of Chinese patient group's main dead factor is coronary heart disease and apoplexy at present, these 2 kinds of cardio-cerebrovascular disorders also are the main causes that causes young and middle-aged people early dead or disabled, and are very high to the loss of China people potential life-span.
3, main medicine
The most effective treatment for cerebral infarction and myocardial infarction is a thromboembolism treatment at present, but the ischemia that causes behind the thrombolytic---reperfusion injury, and its mechanism is not also illustrated fully at present, lacks the effectively preventing medicine clinically yet.In the patient that cerebral infarction or myocardial infarction take place, quite a few is arranged in addition because health or miss reasonable time and can not obtain effective thromboembolism treatment, therefore reduce the tissue injury that ischemia causes, the medicine of control apoplexy sequela, vascular dementia still occupies critical role, but does not also have highly effective medicine at present.The present heart, the brain microcirculation improving agent (as: nitroglycerin, isosorbide mononitrate, nimodipine, vincamine, buflomedil etc.) that generally uses; Neurocyte matabolizing improvement agent (as: aniracetam, citicoline, aceglutamide etc.) is to reducing the tissue injury that ischemia causes; control apoplexy sequela, vascular dementia have certain effect; but curative effect is not obvious, and does not have the clear and definite conclusion of Protection of Reperfusion Injury effect.Neural renovation agent---Monostalotetrahexosylgangliside (is called for short: GM-1) can promote the central nervous system suffering to carry out functional rehabilitation after a variety of causes infringement, its mechanism of action is to promote " nerve remodeling " (existence, axon growth and the synapse that comprise neurocyte generate), it has certain effect to apoplexy sequela, vascular dementia, but late result is also in the middle of observing, this medicine price is very expensive in addition, and a lot of patients can't bear the financial burden of long-term treatment.
(3) progress of senile dementia
1, general introduction
Dementia comprise Alzheimer's disease (Alzheimer ' s Disease, or the title alzheimer's disease, be called for short: AD), multiple infraction type dementia (Multimfarct Dementia), alcoholic dementia (Alcoholic Dementia) and normal brain activity setting-out brain disease (Normal Pressure Hychocephalus).
AD is a kind of chronic former, carrying out property cerebral degeneration's old central nervous system degenerative disease, it is a kind of progressive neurodegenerative diseases that betides geratic period or presenium, be a kind of common stiff reaction that enters after the declining years, belong to the presenile dementia disease of improper aging state.Because AD falls ill in old people more than 60 years old well, so custom is called as senile dementia or degenerative brain disorder.
AD is with hypomnesis, cognitive disorder, personality changes, dystropy and linguistic competence's forfeiture are feature, the comprehensive obstacle and the cognitive function that mainly show as the acquired Premium Features of cerebral cortex are obviously impaired, the cerebral functional deterioration decline, be rapidly decay and identification ability obstacle of memory function, and with the change of behavior or personality aspect.
Along with global aged tendency of population, the control of AD has become a medical treatment outstanding, that need to be resolved hurrily and social problem.Such disease course is generally longer, is about 3～20 years.To the long-term nurse fees of AD patient is huge, and not only there is very big influence in the medical security system to entire society, also is great challenge to nuclear family's pattern of Chinese Future Society.Therefore, it takes place to give society, family all to bring heavy financial burden and mental burden, brings great misery also for patient self.
According to incompletely statistics, the ratio of suffering from severe AD at present among the over-65s crowd reaches more than 5%, just rises to 15% to 20% to 80 years old this ratio.And senile dementia patient's mean survival time (MST) is 5.5 years, makes this disease become main one of disease that causes death of modern society old people.But because the cause of disease of AD is not exclusively clear and definite, still do not have the effectively preventing medicine so far, this disease is still one of comparatively thorny disease in the whole world at present, and the new Therapeutic Method of active research exploitation is an instant thing.
2, pathological manifestations and pathogenesis
The main pathological manifestations of AD is the formation at forebrain substrate, Hippocampus and cerebral cortex extracellular neuritis's speckle, and the appearance of neurofibrillary tangles and neurocyte and number of synapses purpose reduce in the cell.Mainly (be called for short: (Beta-Amyloid Protein is called for short: A β) assemble and form protein hydrolysate amyloid-beta APP) speckle by amyloid precursor protein.Under normal circumstances, the APP hydrolyzate is the A β of solubility
40, and under pathological conditions, the APP hydrolyzate is the A β of the easy formation fiber of length
1-42, it exists with a kind of immature, non-fibrous dispersive speckle form earlier, finally passes through conformational change, aggregates into a kind of deleterious fibrous material, promptly forms speckle.Neurofibrillary tangles mainly is present in the interior and unusual neural axon of the neuronic born of the same parents of taper, it is a water-insoluble structure, its Double helix fibre structure that mainly consists of diameter 10nm (is called for short: PHF), main component is a kind of microtubule bindin, it is Protein tau, the proteic interaction of normal Protein tau energy stabilize microtubules, the Protein tau among the PHFs then exists with the form of super phosphorylation.
The etiology complexity of AD mainly contains two kinds of hypothesis at present: Protein tau hypothesis and amyloid hypothesis.The main argument of Protein tau hypothesis is: because the super phosphorylation of Protein tau causes the instability of tubulin, cause that the Golgi body structure changes, thereby influence the metabolism of APP, produce excessive A β.This hypothesis also is not confirmed at cell or animal individual level.The main argument of amyloid hypothesis is: the gathering of amyloid on every side in that the extracellular neuropathy takes place causes the formation of neuritis's speckle and the formation of neurofibrillary tangles subsequently.Therefore, amyloid is the cause of AD pathology chain formation.Support that the evidence of amyloid hypothesis is very extensive.
The senile plaque that the amyloid-beta abnormal deposition forms is the typical pathological characters of AD.To sexually revise the activation prompting A β with glial cell may be the reason that causes neuron loss and inflammatory reaction among the AD to significant neurological around the speckle.In nerve retrograde affection, the activation of glial cell and neuronic death have effect of equal importance, and exist between the two and necessarily get in touch (referring to Bales KR, Du Y, et al.The NF-kappaB/Rel family of proteins mediatesAbeta-induced neurotoxicity and glial activation.Brain Res Mol Brain Res.1998; 57 (1): 63-72.).Behind inoculation removing amyloid-beta speckle, the nervous system lesion relevant with AD can be repaired.This fact provides strong evidence for the amyloid-beta theory.Other evidences of amyloid-beta theory comprise: 21 main body syndrome patients are because A β produces too much, AD sample nervous system lesion can appear in early days, its young patient nervous system disease only becomes diffusivity A β deposition, illustrates that amyloid beta deposition may be neuro pathology's change the earliest; Behind some measures removing amyloids, nervous system lesion such as neuron shrinkage, microglial activation can reverse.The key link that these evidence explanation amyloid beta depositions are AD morbidities (referring to Zhou Huifang, Xue Bing, Wang Xiaomin, the sick progress of Alzheimer---amyloid-beta theory and main control strategy, the natural science progress, 2003,13 (2): 121-125.).
3, epidemiology situation
Along with developed country and the raising of developing country's average life span, the old number of suffering from dementia increases sharply.In all dementias, the ratio shared the highest (about 50%～60%) with AD.
According to document announcement, with advancing age, under the influence of and gene aging in tissue, the incidence rate of dull-witted phenomenon constantly raises; Wherein, AD, rose one times from 60 years old with old rapid rising in per 4 years～5 years; The sickness rate of AD accounts for 10% in the old people of one's mid-60s, account for 47% in the old people more than 85 years old, has become No. four human killer.
The past academia thought once that China was the low dangerous country of AD, yet in second Chinese elderly dementia's disease of holding in the Tunxi, Anhui in the early time and depression scientific seminar and the international senile dementia scientific seminar, this viewpoint is challenged.Have 5 parts of research reports to show, China also is the high-risk country of AD, and the lot of research of current meeting coverage also shows, China to the research of AD rapidly near international most advanced level.
Global at present patient's AD estimation is about 1,200 ten thousand, and the existing senile dementia patient of China is approximately 3,000,000～4,000,000, and is rapid ascendant trend, makes a definite diagnosis generally death in about 7 years～9 years of back.Have data to show, China more than 60 years old population reached 1.2 hundred million as far back as 1998, and, be much higher than the rate of population increase with average annual 3.2% speed increase.Old man more than 75 years old has that the old man has 8,000,000 more than 2,000 ten thousand, 80 years old, and increases with average annual 5.4% speed, and middle period next century can reach about 400,000,000, will become the maximum country of the aged in the world.
Sino-U.S.'s Shanghai investigation in 1988 shows, China over-65s old people's dementia incidence rate is 4.6%, wherein the proportion of AD is 63%, multi-infarct dementia is 28%, and the dementia that brain tissue impairment sequela, chemicals poisoning and nervous system disorder or malnutrition cause accounts for 10%.
The Epidemiological study in Shanghai shows that the prevalence of China 55 years old, over-65s dementia is respectively 2.57% and 4.6%.Senile disease medical research center, Beijing finds that to 2788 old man's more than 60 years old in Beijing area investigation have 208 old men to suffer from dementia, prevalence reaches 7.5%.Female patients 139 people wherein, prevalence reaches 9.7%, is significantly higher than male's 5.8%.Their research also shows, advanced age, low educational level, lives in the high risk factor that the rural area is a senile dementia.And PLA General Hospital shows 1728 retired veteran cadres' investigation, have in dull-witted family history, " Culture Revolution " be afflicted by persecution, electromagnetic field exposes, cerebral trauma also is the risk factor of senile dementia.In the investigation of Guangzhou City elderly dementia's prevalence more than 75 years old, the AD prevalence is 7.49%.
4, the medicine of senile dementia
AD is one of common complaint among the elderly, is a kind of gradual function of nervous system's degenerative deficiency disorder, and the cause of disease of primary disease is thrown a flood of light on as yet at present, is a thorny problem in the treatment always.
The research and development of antidementia agent has caused the great attention of countries in the world the world of medicine.In recent years, along with to the deepening continuously of aspect researchs such as old people's nervous physiology, biochemistry, pharmacology, cause the developmental research of related drugs constantly to make progress.Calendar year 2001 has 1270 multiple products to put on market, and 90% is the discovery eighties, the research and development success nineties in these products, and the new product of this type of drug development has outnumbered the number of any other treatment class drug development.
Through nearly 10 years clinical showing, (be called for short: AChE) inhibitor has certain therapeutical effect to AD to acetylcholinesterase, its main medicine tacrine, sharp this bright, donepezil, galantamine have been the representative kind in this field, thereby have also promoted the development process of dementia treatment drug market.
(1) brain metabolism agonist
Discover that patients of senile dementia has metabolism system disorders such as carbohydrate metabolism and nucleic acid, protein, lipid, its cerebral blood flow and oxygen consumption are starkly lower than normal person of the same age simultaneously.Therefore, brain metabolism agonist and cerebral circulation improving agent, the brain metabolism agonist that particularly has the cerebral vasodilators effect just becomes the medicine that the treatment primary disease can Gong be selected for use.This type of medicine has piracetam, pyritinol, dihydroergotoxin, duxil, vincamine, Vincamine, vinpocetine, nimodipine, cinnarizine, cyclandelate, meclofenoxane, pentoxifylline, nicergoline etc.These medicines have the different improvement effect of degree to some symptom such as hypomnesis, the accommodative ability of environment reduction etc. of senile dementia.
(2) cholinomimetic
Acetyl choline content is closely related with memory in the existing known brain, and the acetylcholine amount reduces in old age or the dementia human brain, replenishes the choline medicine and can improve its memory and ability of thinking.But directly giving choline or lecithin can not make acetylcholine increase.Someone tries with choline or lecithin and can share in this patient by the cholinesterase inhibitor physostigmine of blood brain barrier, can make its memory that raising is arranged, and give the lecithin DeGrain separately.Other has, and the people is single to give the quiet notes of this patient with physostigmine, and memory is measured achievement and improved approximately 20% than placebo, and finds also effective to behavior disorder.Research thinks that cholinesterase inhibitor can postpone the metabolism of acetylcholine and decompose, thus the excitement that prolongs postsynaptic receptor.In addition, the Huperzine A-Zhulin Antun of domestic development (huperzine A) is a kind of new alkaloids that the Chinese scholar is separated to from the plants of Huperzia Herba Lycopodii serrati, and pharmacological evaluation proves that this product has very strong plan choline activity, is a kind of efficient, reversible cholinesterase inhibitor.
(3) acetylcholinesteraseinhibitors inhibitors (Acetylcholinesterase Inhibitors)
Acetylcholinesteraseinhibitors inhibitors comprises physostigmine (trade name Synapton, the Forest Laboratory Production), tetrahydroaminoacridine (tacrine, trade name Cognex, the production of Parke-Davis company), donepezil. (trade name Aricept, Pfizer/Wei Cai company production), metrifonate (Beyer Co., Ltd's production) and rivastigmine (trade name Exelon, Novartis Co.,Ltd produces).These chemical compounds concentrate acetylcholine by acetylcholine esterase inhibition in neural tendon, and can continue longer action time.
Tetrahydroaminoacridine is first cholinesterase inhibitor that passes through FDA and treat Alzheimer's disease clinically, but regulation still need make improvements.This product bioavailability will be lower than rivastigmine and donepezil, and bigger side effect is arranged.Donepezil (Donopozil) is that the second filial generation also is second cholinesterase inhibitor that is used for the treatment of A Ermohaici disease (senile dementia) by the U.S. FDA special permission, be used for clinically in 1997 by FDA approval, can promote light, moderate senile dementia patient's cognitive competence and improve patient's the mental status and keep effect such as brain function activity.Compare with first generation cholinesterase inhibitor, these product have multiple advantages: 1. long action time, and every day need only be once oral; 2. strong drug action, curative effect height; 3. safe, selectivity is high, adverse effect is little.At present this product have entered Chinese sale, and domestic also have a manufacturer production.
Sanochemia Pharmazeutika AG company (Vienna, Austria) announces first acetylcholinesteraseinhibitors inhibitors-Reminyl (galantamine) in the Europe listing.These product go through in Sweden's listing, and report and submit European Union in the hope of getting permission to enter other market, Europe.
The NeuroSearch company of Denmark utilizes NS2330 to carry out development of clinical studies recently.NS2330 increases the activity of dopamine and norepinephrine, also activates it simultaneously and suppresses mechanism to stimulate acetylcholine in the cerebral cortex release of (comprising the perception position).The function of all three neurotransmitters all will be subjected to the influence of Alzheimer's disease like this.The said firm wishes that NS2330 can have better therapeutic effect, and the I phase clinical position of this medicine is finished at present, and FDA agrees that also the said firm continues II phase clinical position.
Other chemical compound that is used for studying also comprises xanomeline (Novo Nordisk/gift comes company to produce), besperidine (Hoechst AG's production) and talsaclidine (Boehringer Ingelheim/Pharmacia S.P.A.).
1. tacrine (is called for short: THA)
The chemistry of tacrine is called tetrahydroaminoacridine, trade name Cognex, this medicine is non-competing, the reversibility cholinesterase inhibitor of the cental system of U.S. Warner-Lambert AG Safnern's exploitation and first listing, obtained in 1993 at first to go on the market after the FDA approval in the U.S., be to improve cognitive disease new drug of AD and old nootropic drug, the same year, its chemical compound patent expired in 1996, mainly was American Pie moral-Davis's product in the market in the listing of states such as Britain, France, Canada.
Tacrine especially has significant curative effect to women AD disease, share with lecithin and can obtain ideal effect, can obviously improve patient's memory, thus tacrine be considered to treatment, prevention presenile dementia only several drugs it.
The weak point of tacrine is that liver function and transaminase's index are had considerable influence, has restricted the exploitation in market, and the growth of its sales volume also can not show a candle to other AD medicine.Through further research, addition screening on the basis of tacrine parent nucleus is developed that crin of dimension by your company of German Hirst Ruse.This medicine is 1 hydroxy derivatives of tacrine, and its mechanism of drug action is improved accordingly, but still has some untoward reaction, along with the development of medical science, will be substituted by acetylcholinesteraseinhibitors inhibitors of new generation.
2. donepezil
Donepezil is the medicine with high selectivity, reversibility treatment AD, be second filial generation central acetylcholine esterase inhibitor, be the medicine that Japan defends the exploitation of material drugmaker, the special permission approval of acquisition on November 25th, 1996 FDA is used for clinical, the trade name aricept.At first in U.S.'s listing, develop the world market jointly by defending material/Pfizer at the beginning of 1997, in October, 1999, aricept went on the market in China, had formed the sales network of more than 50 countries and regions, the world at present.
Donepezil is second medicine of getting permission to treat senile dementia, and its sharpest edges are that treatment dosage up to standard is little, toxic and side effects is low, better tolerance.The expert generally believes that this medicine maintains the leading position in the AD medicine, occupied 60% the market share in four principal items, estimate this advantage will be extended to can come out to the new drug that disease treatment produces material impact till.
According to Pharma Business magazine: in 500 kinds of medicines were in great demand in the whole world in 2000 most, Japanese Wei Cai company sales volume was 4.31 hundred million dollars, and the sales volume of Pfizer is 1.19 hundred million dollars, respectively than increasing by 27.3% and 30.8% last one year.Calendar year 2001, donepezil was arranged the 101st in the whole world, and sales volume adds up to about 6.83 hundred million dollars, surpassed 1,100 hundred million yen in the whole world in 2002, had been the outstanding person in the AD market.
Calendar year 2001, Traditional Chinese Medicine Research ﹠ Development Center, mulberry field, Chongqing Pharmaceutical were developed donepezil crude drug and tablet product thereof, and National Drug Administration ratifies it with four kind new medicine productions.
3. sharp this bright
Sharp the bright of this is aminoacid formic acid class brain selectivity cholinesterase inhibitor, belongs to the second filial generation product of such medicine, by the exploitation of Switzerland Novartis Britain company, and the trade name Exelon, in December, 1997 is at first in Switzerland's listing, and next year goes on the market in Britain.Obtained the FDA approval on April 21st, 2000, go on the market in the U.S. the same year by the end of June, thereby expanded the general layout in Alzheimer's disease medicine market.
Result of study shows: though this medicine half-life is shorter relatively, but can reach 10 hours to choline esterase inhibition, this medicine is without liver and P450 metabolism, to light, moderate degenerative brain disorder toleration is better, has the butyrylcholine esterase effect that suppresses in the brain simultaneously, carry out in 45 countries such as Europe, the U.S. one perspective, the higher evaluation of acquisition in the multicenter double-blind study at random.
Because sharp this bright obtains increasing share in pharmaceutical market, sales volume in 2000 is 1.195 hundred million dollars than increasing by 83% last one year, and calendar year 2001, sharp the bright of this increased by 101% at the global marketing volume, reached 2.4 hundred million dollars.
4. galantamine
Galantamine belongs to second filial generation acetylcholine esterase inhibitor medication, its pharmaceutical compositions is identical with the alkaloid that European mountain area Flos Narcissi chinensis bulb extracts, this plant amedica had had the clinical practice in more than 30 year in some countries, area, was used for the treatment of to reverse neuromuscular blockade, myasthenia gravis and child's brain type paralysis etc.
Galantamine is the chemical synthetic drug of Xi Lei and Johson ﹠ Johnson cooperative development, and preparation has tablet, capsule, oral liquid etc., clinically is used to improve AD patient's general function.This medical instrument has double action mechanism, can stimulate preferably and acetylcholine esterase inhibition, and can regulate the interior nicotine receptor site of brain, can significantly improve cognitive function light, moderate presenile dementia patient, delays the process that function of brain cell goes down.
Galantamine is ratified the back in Britain, Irish Initial Public Offering in July, 2000 by European Union, and calendar year 2001 is obtained the U.S. FDA permission and is used for the treatment of Alzheimer's disease, now 25 country's listings.Uncommon Thunder God department is responsible in Britain, Hibernian sale, and Johson ﹠ Johnson is responsible for the sale of the U.S. and other European countries.External report calendar year 2001 galantamine sales volume is 1.36 hundred million dollars.
Shanghai Shen Xing pharmaceutical factory had produced the galantamine crude drug in 1998, approval Suzhou No.6 Pharmaceutical Factory of National Drug Administration produced four kind new medicine galanthamine hydrobromide capsules in 1999, the emerging output in Shen, calendar year 2001 Shanghai increases by 3 times on a year-on-year basis, and annual production reaches 30kg.After this medicine came into the market, clinical expansion is considerable to be strided forward, and showed up prominently in China main cities emphasis hospital dementia medicine in 2000.
In recent years, acetylcholinesterase inhibitor has become the first-line treatment medicine of AD, confirmed its effectively status of alleviation cognitive dysfunction, the sales volume of the product has occupied the lion's share in the antidementia agent, studies show that huperzine A, physostigmine, U.S. bent phospholipid also has certain therapeutical effect to Alzheimer's disease, the huperzine A chemical compound that Chinese Academy of Sciences's Shanghai medicine is developed has been applied for international monopoly, its mechanism of action is carrying out deep research, the pharmacy of Fourth Ring, Beijing, magnificent pharmacy is stood in Ningbo, Shanghai Chinese Yin Dynasty's Pharmaceutical and Shanghai Medical Univ red flag pharmaceutical factory have obtained New Drug Certificate and have produced code.
(4) potassium channel antagonists
Studies show that nonselective potassium channel antagonists goes into to cause that by the calcium current of delay depolarization and prolongation presynaptic teleneuron neurotransmitter (comprising Ach) discharges increase.If wanting this class medicine is used for the treatment of senile dementia, then used medicine should possess the release that can increase acetylcholine and not reduce the advantage that the membrane phospholipid phatidylcholine is formed, and the composition of minimizing membrane phospholipid phatidylcholine may be the side effect that the AchE inhibitor exists.Phosphatidylcholine is the depots of choline, is used for synthesizing Ach by neuron.The loss of membrane phospholipid phatidylcholine is restricted the synthetic of acetylcholine, causes the choline output to reduce.Clinical research has shown that non-selective potassium channel antagonists only has the moderate effect to the identification ability that improves the patient, central nervous system's penetration power that its effect may not be by force these medicines is low, poor selectivity or active not enough etc., it is in addition perfect to await further research.
(5) glutamate receptor adjusting control agent
In the slow-witted disease patient's of old disease brain, cortex cortex and from the pyramidal cell of cortex approach nerve fiber to have taken place chaotic and degenerate.It is reported that these pyramidal cells are excitatory transmitter with glutamic acid.These neuronal damages can cause senile dementia during afunction; But if function is strong excessively, then can produce excitatory toxicity, cause neuronal death, cause multiple neurodegenerative disease.Therefore, the neuronic synaptic activity of glutamic acid of regulation and control degeneration is expected to treat senile dementia.Studies show that; the direct activation postsynaptic receptor will help the transmission of glutamic acid; its partial agonist has such advantage; promptly when being lower than normal level, plays by endogenous glutamic acid the agonist effect; and, glutamic acid plays antagonist action when excessive when discharging; therefore, partial agonist can produce neuroprotective to the exitotoxicity situation.The medicine such as the Memantine hydrochloride (memantine) of existing report, when glutamic acid discharged with the pathology amount, Memantine hydrochloride can reduce the neurotoxic effect of glutamic acid; When glutamic acid discharges when very few, Memantine hydrochloride can improve the transmission of the required glutamic acid of memory process, clinical research shows that Memantine hydrochloride is used for patients of senile dementia and has toleration preferably, produces the gentle remarkable improvement that statistical significance is arranged in psychopathology and behavior determination.
(6) 5-hydroxy tryptamine 3 receptor antagonists
(be called for short: 5-HT3) the former emesis that is used for of receptor antagonist, existing research infers that according to the distribution of 5-HT3 receptor in brain this type of antagonist should have other central nervous system's effect to 5-hydroxy tryptamine 3.Can improve the identification ability of the normal and insufficient animal of cholinergic nerve function such as Mus, Adeps seu carnis Rhiopithecus roxellanae etc. as 5-HT3 antagonist ondansetron ondansetron; In memory relevant with old age more than 50 years old impaired (AAMI) patient's clinical trial, ondansetron can make the memory that is equivalent to lose 6 years improve.Therefore, (tropisetron, granisetron etc. bring glad tidings for the senile dementia patient for ondansetron and other 5-HT3 receptor antagonists.
(7) research of natural drug aspect
A lot of now pharmaceuticals also look at natural drug, attempt therefrom to develop effective medicine.Equally also obtained certain progress in this respect.
1. apolipoproteins E4 (ApoE4)
We know that the incidence of Alzheimer's disease and gene have comparatively closely gets in touch, and apolipoproteins E4 ApoE4 is worth let us to go to note and study towards the direction of treatment and prevention Alzheimer's disease especially.In drug development, ApoE4 had carried out the human body clinical drug trial, and very likely became the more definite medicine of curative effect.
2. β-granulose (body) (Beta-amyloid)
β-granulose is a kind of undissolvable polypeptide.This kind material can effectively prevent the destruction of the neuronal that causes in the fierce oxidizing process.Be exactly to utilize the generation of β-granulose restraint of liberty base and remove free radical in being engaged in the Alzheimer's disease research theory, with the infringement that prevents that free radical from being brought.Such chemical compound comprises idebenone (Wu Tian company, Osaka Japan), this chemical compound be a kind of street cleaner of free radical also be the stimulus object of certain neural growth factor.Studies show that in early days idebenone can effectively treat moderate dementia disease.Although in a handful of country's listing, it is withdrawn from the market from Japan, and its III clinical trial phase is stopped for Glaxo Wellcome company (Britain) and American Home Products Corp.
(8) progress of other types of drug
The first half of the year in 2000, some studies show that controversies in hormone replacement in the elderly can delay the outbreak of women's Alzheimer's disease more significantly, and can reduce being in a bad way of Alzheimer's disease.Indivedual clinical researches find that also estrin treatment can improve perceptibility.Estrogen can reduce the probability of morbidity to the ability to function of antioxidant and anti-inflammatory agent, promote acetylcholine generation, promote the growth and the survival of neurocyte.
In year in 2000, the expectation beginning of the Toyama Chemical company of Japan is carried out the II phase clinical research of T-588 in Britain, and can carry out the test of morning in the U.S..Under the cooperation of New York University, company finds that T-588 can protect brain nervous cell.
The FK-960 of Japan rattan pool drugmaker carries out in the Japan and the U.S..This medicine can improve perceptibility, has new mechanism of action.Is to show recently about the research report, chew and can prevent aged people's hypomnesis, but its mechanism of action is still not clear and definite now.Research worker is come the aged sign of researching human body by the hereditary change of research mice.Experiment shows, pulls out tooth and will be inferior to normal control group with the memory of the mice that prevents to chew.In addition, research worker has also been studied the active situation of brain when chewing, and the concurrent activity of crust now can strengthen the signal of brain hippocampus.
Find to reduce amount from the research worker of University of Kentucky and can protect brain to avoid because of the age causes disorder, this disorder is similar to Alzheimer's disease.The research paper of publishing shows recently, and by feeding the mice that reduces quantity of food, research worker finds that the damage of their brains can reduce.Research to heat intake and human nerve degenerative disease does not also begin, but has some correlation researchs to show, than the U.S. and Canada, China and Japan are owing to take in less heat, and the sickness rate of therefore corresponding Alzheimer's disease also reduces.
Canadian neural biotech company has announced a comparatively definite product memantine the first half of the year in 2000.This product is a kind of noncompetitive N-methyl D-aspartic acid (NMDA) blocker, has carried out the III clinical trial phase in the U.S., is mainly used in the treatment Alzheimer's disease.
5, the market development prospect of senile dementia
The world's seven big drug markets showed in 2000, and the AD drug market has increased nearly one times from more than 400,000,000 dollar of the mid-90, calendar year 2001 nearly 1,200,000,000 dollars of whole world AD market value; External analyst's prediction AD patient in following 10 years will be increased to about 20%, and the growth rate of AD drug market will have rising by a relatively large margin.
Because the patient is on the increase, the market sales revenue of AD medicine is also always in steady-state growth.The nineties, such medicine became the situation of selling well medicine, nineteen ninety-five world's sales volume reached 5,000,000,000 dollars.At the beginning of 21 century, the sales volume of such medicine has surpassed the share in the treatment cardiovascular disease treating medicine, treatment gastrointestinal disease medicine and the anti-infectives market that are arranged in front three, and its growth momentum is good.
At present, such disease more and more is subjected to the great attention of China national and society, and because such disease is similar to affluenza such as diabetes, equally needs to take for a long time medicine, therefore its medication market enlarges gradually along with aged tendency of population, and market prospect is good.Based on this, for in time understanding the market situation of China treatment AD medicine, state food and drug administration south medication economics institute information centre chooses various schools of thinkers sampling hospital, 60 doctor experts and 120 consumers of China six main medication cities (Beijing, Shanghai, Guangzhou, Nanjing, Hangzhou, Chengdu), to China domestic senile dementia medication market (1999 and 2000) and mainly compete kind and carried out comprehensive market survey activity.
China's treatment medicine for senile dementia hospital administration amount of money situation analysis in (1) 1999 year～2000
From 1999～2000 six cities (Beijing, Shanghai, Guangzhou, Nanjing, Hangzhou, Chengdu) sampling hospitalize senile dementia medication amount of money formation situations, 2000 six city sampling hospitals sold total amount and increase by 28.49% than 1999 year-on-years.And in treatment senile dementia medicine principal item, use the bigger kind rank of amount of money percentage ratio to be followed successively by piracetam, gingko leaf preparation, dihydroergotoxin, almitrine/raubasine, aniracetam, nicergoline, citicoline, huperzine A, donepezil, pyritinol, vinpocetine, galantamine, meclofenoxane, idebenone.Wherein preceding four kind market shares (amount of money percentage ratio) are bigger.
In the concrete kind, the market share of piracetam (amount of money percentage ratio) 2000 rose 8 percentage points than 1999, still ranked first, and amount of money rate of increase reaches 55.59%.Gingko leaf preparation, dihydroergotoxin keep the more stable market share, use the amount of money all to keep certain growth.Kind has huperzine A, galantamine to use the amount of money to increase faster, and wherein the galantamine increasing degree is the highest.Atrophy appears in almitrine/raubasine, aniracetam, nicergoline, citicoline, vinpocetine and pyritinol overall market, the competition and idebenone is withdrawn from the market substantially.Donepezil was not seen sale owing to be newer kind in 1999, but 2000 the market share (using amount of money percentage ratio) account for 0.45%, demonstrate certain market potential.
(2) 1999 years～2000 China's treatment medicine for senile dementia hospital administration amount of money trend analysis
From 1999～2000 six city senile dementia medication amount of money tendency situations, whole drug level will ascendant trend occur apparently higher than whole drug level in 1999 in 2000.Wherein medication amount of money peak period in 1999 and medication amount of money peak period in 2000 all appear at (the dosage peak period was the third season in 2000) for the second quarter, show that in 2000 the use amount of high price kind wants high relatively for the second quarter.A medication trend that from six city medicining conditions, can reflect Chinese city.
(3) main medication policlinic medicining condition is analyzed
From the medication amount of money ordering situation of each kind in each city, its sales situation show preferably kind mainly contain gingko leaf preparation, piracetam, dihydroergotoxin and almitrine/raubasine.Wherein gingko leaf preparation 2000 in Shanghai, Guangzhou, Hangzhou and area, Chengdu make number one, be number two in the Beijing area, be number three in the area, Nanjing, show fairly goodly, increased to some extent than 1999, the market reaction of its several leading brand Tanakans, Semen Ginkgo Tian Bao, the Yiganning capsule of invigorating blood circulation, Gin Kgo Plus capsule, taponin, Ginkgo Biloba Leaf Preparation is celebrated; Secondly performance then be piracetam preferably, and this product 2000 occupy first position in Beijing and area, Nanjing, the row that also are front three in other several cities, only in the area, Hangzhou a little less than (rank the 5th); The dihydroergotoxin general status comes the 3rd, but rank in 2000 increases than rank in 1999.Dihydroergotoxin remains unchanged substantially in the rank in each city, and in cities such as Shanghai and Chengdu area rank rising individually, and in position of rank decline, area, Nanjing.
(4) market assessment of others
Along with popularizing that treatment AD clinical drug is promoted, AD more and more is subjected to the attention of society and family, feed back from the information about doctor of investigation, 68% doctor thinks that society has begun to be concerned about and to pay attention to AD, meanwhile, 8.16% doctor thinks that market supply wretched insufficiency, 63.2% doctor think market supply deficiency.As seen, AD medication market supply deficiency, market still has living space, and has nearly eighty per cant doctor to approve good market prospect.
Equally, flourish along with OTC market in recent years has suitable part kind (peroral dosage form) also to sell in retail pharmacy, owing to take medicine for a long time, increasing patient selects directly to purchase the medicine treatment from pharmacy.From south medication economics institute retail research department of Chinese National Drug Administration the monitoring result of this quasi drugs is shown, the market share of gingko leaf preparation (consumption sum percentage ratio) accounts for about 4 one-tenth of market, Chinese patent medicine is subjected to the favor of retail market, the market share of duxil (almitrine/raubasine) accounts for about 3 one-tenth, and all the other kinds then occupy the remaining market share.From the consumer situation reflection of being investigated, there is 67.80% consumer to obtain required medicine from hospital pharmacy; And there is 27.97% consumer directly to buy to pharmacy; 4.24% patient obtains from out-patient department of unit one belongs to; Also have 0.85% patient to locate to buy to the whole seller.This shows that present, though hospital is the main Sales Channel of old people's medication, also as can be seen, retail channel is also occupied very important ratio.
The treatment of AD accounts for the 7th of world's drug market, is worth 6,100,000,000 dollars to the end of the year 2005.And if present anti-AD drug main relief of symptoms is not contained the development of the state of an illness.Therefore; working out a kind of effective Therapeutic Method, to stop potential pathogenic process be very necessary, thus it is considered herein that development is used to prevent, diagnose, detect, protect and the product for the treatment of aspect such as AD particularly medicine can have remarkable social benefit and economic benefit.
But up to the present, do not find as yet by literature search etc., naringenin and derivant thereof report as anti-cardiac-cerebral vascular diseases product application facet; That is to say, up to now, do not see that as yet naringenin and derivant thereof are used to prepare the product of anti-cerebral infarction, myocardial infarction aspect,---reperfusion injury, myocardial ischemia---product of reperfusion injury aspect that is used to prepare anti-cerebral ischemia is used to the report for preparing the product of anti-apoplexy sequela, vascular dementia aspect and be used to prepare the product of Kang Aercihaimoshi disease aspect.
Summary of the invention
The technical problem that will solve required for the present invention is the new purposes that discloses a kind of naringenin and derivant thereof, to overcome the above-mentioned defective that prior art exists.
That is to say, the invention is intended to the concrete application of clear and definite naringenin and derivant thereof, and then naringenin and derivant thereof are used to prepare anti-cardiac-cerebral vascular diseases product at aspects such as cardiovascular and cerebrovascular disease, Alzheimer's disease;
Described cardiac-cerebral vascular diseases comprises one or more in cardiovascular and cerebrovascular disease and relevant disease, Alzheimer's disease and the relevant disease thereof etc., in reperfusion injury that wherein cardiovascular and cerebrovascular disease and relevant disease thereof comprise cerebral infarction, myocardial infarction, cerebral ischemia---reperfusion injury, myocardial ischemia---, apoplexy sequela or the vascular dementia etc. one or more, Alzheimer's disease and relevant disease thereof comprise one or more in Alzheimer's disease etc.
Described anti-cardiac-cerebral vascular diseases product is meant the product that is used to prevent, diagnose, detect, protect, treat and study cardiac-cerebral vascular diseases; be to comprise in the field products such as medicine, Foods or drinks one or more; for example comprise in medicine, reagent, food, health food, additive or the beverage etc. one or more; in preferred agents, health food or the additive etc. one or more, further preferred agents.
(1) technical conceive
The independent development original new drug is a present urgent task of China, the Chinese Medicine industry has long developing history, also accumulated rich experience at aspects such as prevention and treatment diseases, seeking effective active component from Chinese medicine is a valid approach, also is the place of the advantage of Chinese original new drug development.
In the active natural component process of screening tool cardiovascular and cerebrovascular vessel, the inventor finds the stronger cardiovascular and cerebrovascular vessel activity of ethanol extract tool of Chinese medicine Fructus Aurantii Immaturus (fruit of Citrusaurantium.L), by it being carried out the active separation of instructing, find that active site is the mixture that comprises naringenin and a series of flavone of its derivant, further separation obtains naringin (naringin), Hesperidin (hesperidin) waits each monomer, and each monomer all shows heart tonifying cerebrovascular activity.Utilize and separate the naringin that obtains, the derivant that Hesperidin prepares other naringenin, further study the cardiovascular and cerebrovascular vessel activity of naringenin related derivatives, found that naringenin and derivant thereof all have stronger cardiovascular and cerebrovascular vessel activity.
Described cardiovascular and cerebrovascular vessel activity is meant that particularly naringenin and derivant thereof are in the application for preparing anti-cardiac-cerebral vascular diseases product, for example, the application in the medicine of preparation treatment cerebral infarction, myocardial infarction of naringenin and derivant thereof, the application in preparation prevention or treatment cerebral ischemia---reperfusion injury, myocardial ischemia---medicine of reperfusion injury of naringenin and derivant thereof, the application in the medicine for preparing prevention or treatment apoplexy sequela, vascular dementia of naringenin and derivant thereof.
After described ischemia---reperfusion injury was meant and recovers blood flow on the basis of histoorgan ischemia, the damage of histoorgan increased the weight of on the contrary;
Described control apoplexy sequela is meant the generation that the cerebrovascular events that has taken place is reduced its sequela (as: hemiplegia, large and small fecal incontinence, aphasis etc.), and treats the sequela that has produced.
Naringenin and derivant thereof are especially showing great activity aspect the treatment of vascular dementia, Given this studied its effect again, found that naringenin and derivant thereof have great activity equally to preventing and treating Alzheimer's disease Alzheimer's disease.
The effect of present anti-AD medicine mainly is a relief of symptoms, does not contain the development of the state of an illness.Therefore, working out a kind of effective prevention, diagnosis, treatment and research method, to stop potential pathogenic process be very necessary.
According to the relevant documents and materials of being retrieved, the inventor studies by experiment, finds that naringenin and derivant thereof have the number of significant pharmacologically active.And further experiment and result of study, also prove and confirmed naringenin and derivant thereof in prevention, diagnosis, detect, aspects such as protection and treatment AD have significant activity.
(2) naringenin and derivant thereof
The chemical structure of general formula of described naringenin and derivant thereof is as follows:
Wherein, R
1Be to comprise in hydrogen (H) or the alkyl etc. one or more, preferably include hydrogen, methyl (CH
3) or ethyl (C
2H
5) in waiting one or more;
R
2Be to comprise in hydrogen (H), hydroxyl or the alkoxyl etc. one or more, preferably include in hydrogen, hydroxyl, the methoxy or ethoxy etc. one or more;
R
3Be to comprise in hydrogen, alkyl or the glycosyl etc. one or more, preferably include hydrogen, have the alkyl of 1～6 carbon atom or contain in the glycosyl etc. of 1～6 monosaccharide one or more, further preferably include hydrogen, methyl, ethyl or contain in the glycosyl etc. of 3 monosaccharide one or more.
Described alkyl is to comprise in straight chained alkyl, branched alkyl or the cyclic alkyl etc. with 1～6 carbon atom one or more, be to comprise in methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, tertiary pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopenta or the cyclohexyl etc. one or more, preferably include in alkyl with 1～3 carbon atom etc. one or more, preferably include in methyl or the ethyl etc. one or more especially;
Alkyl in the described alkoxyl is to comprise in straight chained alkyl, branched alkyl or the cyclic alkyl etc. with 1～6 carbon atom one or more, be to comprise in methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, tertiary pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopenta or the cyclohexyl etc. one or more, preferably include in alkyl with 1～3 carbon atom etc. one or more, preferably include in methyl or the ethyl etc. one or more especially;
Described monosaccharide is meant Glucopyranose., xylopyranose, arabopyranose, pyrans rhamnose, and sugar chain can be straight or branched, and connected mode can be (1-2), (1-3), (1-4) or (1-6) connection.
Described naringenin and derivant thereof preferably include one or more in monomer naringenin and derivant, hesperetin and derivant thereof, isosakuranetin and derivant thereof or eriodictyol and the derivant thereof etc., further preferred monomers naringenin and derivant thereof.
Work as R
1Be hydrogen and R
2During for hydrogen, expression monomer naringenin and derivant thereof;
Work as R
1Be methyl and R
2During for hydroxyl, expression hesperetin and derivant thereof;
Work as R
1Be methyl and R
2During for hydrogen, expression isosakuranetin and derivant thereof;
Work as R
1Be hydrogen and R
2During for hydroxyl, expression eriodictyol and derivant thereof.
Further preferred again particular compound is to comprise the monomer naringenin; naringin; naringenin-7-O-β-rutinoside; naringenin-7-O-glucoside; naringenin-7-O-rhamnoside; hesperetin; Hesperidin; neohesperidin; hesperetin-7-O-glucoside; hesperetin-7-O-rhamnoside; isosakuranetin; sakuranetin; poncirin; isosakuranetin-7-O-β-rutinoside; isosakuranetin-7-O-glucoside; isosakuranetin-7-O-rhamnoside; eriodictyol; eriocitrin; new eriocitrin; in eriodictyol-7-O-glucoside or eriodictyol-7-O-rhamnoside etc. one or more.The group such as the table 1 of above-claimed cpd.
Table 1, naringenin and relevant derivant thereof
| Sequence number | R 1 | R 2 | R 3 | The chemical compound title |
| 1 | Hydroxyl | Hydrogen | Hydrogen | The monomer naringenin |
| 2 | Hydroxyl | Hydrogen | α-L-pyrans rhamnose (1 → 2)-β-D-Glucopyranose. | Naringin |
| 3 | Hydroxyl | Hydrogen | α-L-pyrans rhamnose (1 → 6)-β-D-Glucopyranose. | Naringenin-7-O-β-rutinoside |
| 4 | Hydroxyl | Hydrogen | Glucose | Naringenin-7-O-glucoside |
| 5 | Hydroxyl | Hydrogen | Rhamnose | Naringenin-7-O-rhamnoside |
| 6 | Methoxyl group | Hydroxyl | Hydrogen | Hesperetin |
| 7 | Methoxyl group | Hydroxyl | α-L-pyrans rhamnose (1 → 6)-β-D-Glucopyranose. | Hesperidin |
| 8 | Methoxyl group | Hydroxyl | α-L-pyrans rhamnose (1 → 2)-β-D-Glucopyranose. | Neohesperidin |
| 9 | Methoxyl group | Hydroxyl | Glucose | Hesperetin-7-O-glucoside |
| 10 | Methoxyl group | Hydroxyl | Rhamnose | Hesperetin-7-O-rhamnoside |
| 11 | Methoxyl group | Hydrogen | Hydrogen | Isosakuranetin |
| 12 | Methoxyl group | Hydrogen | Methyl | Sakuranetin |
| 13 | Methoxyl group | Hydrogen | α-L-pyrans rhamnose (1 → 2)-β-D-Glucopyranose. | Poncirin |
| 14 | Methoxyl group | Hydrogen | α-L-pyrans rhamnose (1 → 6)-β-D-Glucopyranose. | Isosakuranetin-7-O-β-rutinoside |
| 15 | Methoxyl group | Hydrogen | Glucose | Isosakuranetin-7-O-glucoside |
| 16 | Methoxyl group | Hydrogen | Rhamnose | Isosakuranetin-7-O-rhamnoside |
| 17 | Hydroxyl | Hydroxyl | Hydrogen | Eriodictyol (bear's weed element) |
| 18 | Hydroxyl | Hydroxyl | α-L-pyrans rhamnose (1 → 6)-β-D-Glucopyranose. | Eriocitrin |
| 19 | Hydroxyl | Hydroxyl | α-L-pyrans rhamnose (1 → 2)-β-D-Glucopyranose. | New eriocitrin |
| 20 | Hydroxyl | Hydroxyl | Glucose | Eriodictyol-7-O-glucoside |
| 21 | Hydroxyl | Hydroxyl | Rhamnose | Eriodictyol-7-O-rhamnoside |
Said naringenin of the present invention and derivant major part thereof be extraction separation from orange (Citrus) fruit and peel, pertinent literature has been reported the extraction separation method of naringenin and derivant thereof, and the physicochemical data of naringenin and derivant thereof carried out detailed report, the present invention repeats no more.
Also have part naringenin and derivant thereof to transform preparation by the hydrolysis of natural naringenin derivant or other physico-chemical method that extracts in addition, pertinent literature also has report, and the present invention repeats no more.
(3) pharmacologically active of naringenin and derivant thereof
The present invention has carried out many-sided test to the cardiovascular and cerebrovascular vessel activity of naringenin and derivant thereof.Prove that by experiment 1. naringenin and derivant thereof have the effect of obvious prolongation mice mean survival time to the chmice acute cerebral ischemic model that adopts the ligation bilateral carotid; 2. focal cerebral ischemia in rats-the re-perfusion model that adopts the preparation of bolt collimation method there is obvious reduction brain water content, dwindles the effect of infarct size; 3. rat cerebral ischemia-reperfusion injury is caused the have clear improvement effect of learning and memory function of vascular dementia model; 4. cause myocardial infarction model that obvious reduction degree of myocardial ischemia and scope are arranged to the dog coronary artery ligation, reduce the effect of myocardial infarct size; 5. rat heart muscle Ischemia-reperfusion Injury damage model there is the effect of obvious minimizing myocardial infarct size.
The present invention has proved also that by experiment naringenin and derivant thereof are to the improve significantly effect of its learning and memory function of the inductive Alzheimer disease model rat of beta amyloid peptide.
(4) purposes of naringenin and derivant thereof
1, general introduction
The purpose of this invention is to provide a kind of product that is used to prevent, diagnose, detect, protect, treat and study anti-cardiac-cerebral vascular diseases; be to comprise in the field products such as medicine, Food ﹠ Drink one or more; for example comprise in medicine, reagent, food, health food, additive, the beverage etc. one or more; preferred agents, health food, additive, further preferred agents.
By pharmacologically active screening proof, naringenin and derivant thereof have the activity of prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases.Completed acute toxicity testing proves that the mouse stomach administration surpasses 2.0g/kg to the maximum tolerated dose of this active site, is equivalent to 440 times of clinical recommended drug dosage, shows that this naringenin and derivant thereof are safe and reliable.
In sum; the inventor has carried out theory study to naringenin and derivant thereof; through a large amount of particularly secular pharmacology tests of experimentation, the activity that naringenin that discovery is addressed and derivant thereof have significant prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases.Therefore, naringenin and derivant thereof and compositions thereof can be used for preparing anti-cardiac-cerebral vascular diseases product, are the medicine that feedstock production forms with naringenin of the present invention and derivant thereof preferably.
2, the using method of naringenin and derivant thereof and compositions thereof and requirement
Naringenin and the derivant thereof that reaches of the present invention can be united use separately or with other active component; comprise the product that is used to prepare prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases; be to comprise in the field products such as medicine, Food ﹠ Drink one or more; for example comprise in medicine, reagent, food, health food, additive, the beverage etc. one or more; preferred agents, health food, additive, further preferred agents.
Aspect concrete use, naringenin of the present invention and derivant thereof can be used separately, can also use with other many chemical substances.These chemical substances biologically active or have the function of treatment disease whether no matter, comprise miscellaneous function as collaborative amplification, antagonism or alleviate the side effect etc. of naringenin and derivant thereof, these chemical substances are to comprise in pharmaceutically acceptable carrier, food, natural product, chemical synthetic drug or the human medication etc. one or more; Preferably include in pharmaceutically acceptable carrier or the food etc. one or more; Further preferred pharmaceutically acceptable carrier.
" pharmaceutically acceptable carrier " used herein is to comprise in solvent, disperse medium, afterbirth, antibacterial and antifungal, isotonic agent or the absorption delay agent etc. that any He all physiology is suitable for one or more.The example of pharmaceutically acceptable carrier comprises one or more water, saline, phosphate-buffered saline, glucose, glycerol or ethanol etc. and in the compositions one or more thereof.In many cases, in said composition, preferably include isotonic agent, for example, sugar, such as in the polyhydric alcohol of mannitol, sorbitol, sorbitol or the sodium chloride etc. one or more.Pharmaceutically acceptable carrier can also comprise a spot of auxiliary substance, one or more in wetting agent or emulsifying agent, antiseptic or the buffer etc. for example, and they have strengthened the effect duration or the effectiveness of this naringenin and derivant thereof.
From concrete classification, said pharmaceutically acceptable carrier is meant the pharmaceutical carrier of medicine and pharmacology field routine, comprises excipient, as in starch or the water etc. one or more; Lubricant is as in glycerol or the magnesium stearate etc. one or more; Disintegrating agent is as in microcrystalline Cellulose, agar, calcium carbonate or the sodium bicarbonate etc. one or more; Filler is as in starch or the lactose etc. one or more; Bonding agent is as in pregelatinized Starch, dextrin, cellulose derivative, alginate, gelatin or the polyvinylpyrrolidone etc. one or more; Osmotic pressure regulator is as in glucose, sucrose, sorbitol or the mannitol etc. one or more; Diluent is as water etc.; Absorption enhancer is as quaternary ammonium compound etc.; Surfactant is as hexadecanol etc.; Absorption carrier is as in Kaolin or the soap clay etc. one or more; Lubricant is as in Pulvis Talci, calcium stearate, magnesium stearate or the Polyethylene Glycol etc. one or more; In addition, can also in compositions, add other adjuvant, as in flavouring agent or the sweeting agent etc. one or more.
For example, with active component naringenin and derivant dissolving thereof, suspendible or (for example be emulsifiable in the suitable aqueous solvent, distilled water, in normal saline or the Green's solution etc. one or more) or in the oil-based solvent (for example, vegetable oil is olive oil for example, Oleum sesami, Oleum Gossypii semen, in Semen Maydis oil or the propylene glycol etc. one or more) in, can make ejection preparation, wherein (for example can contain dispersant in the solvent, polyoxyethylene sorbitan monoleate, polyoxyethylene hardened castor oil 60, Polyethylene Glycol, benzyl alcohol, in chlorobutanol or the phenol etc. one or more), osmotic pressure regulator (for example, sodium chloride, glycerol, D9-mannose, in D-sorbitol or the glucose etc. one or more).In this case, if necessary, can add additive, for example solubilizing agent (for example, one or more in sodium salicylate or the sodium acetate etc.), stabilizing agent (for example, human serum albumin etc.), analgesic (for example, benzyl alcohol etc.) etc.
Of the present invention and naringenin and derivant thereof can also unite use with the form of compositions, particularly with other chemical substance such as medicine animal especially mammal is comprised that people or other animals treat compositions for use or similar compositions.Described mammal, comprise in people, mice, rat, sheep, monkey, cattle, pig, horse, rabbit, dog, chimpanzee, baboon, Adeps seu carnis Rhiopithecus roxellanae, macaque or the Rhesus Macacus etc. one or more, in preferred people, mice, rat, monkey, pig, rabbit or the dog etc. one or more, one or more in further preferred people, rat or the monkey etc.For example, naringenin of the present invention and derivant thereof can be added be suitable for to curee's Pharmaceutical composition in.Usually, this Pharmaceutical composition comprises naringenin of the present invention and derivant and pharmaceutically acceptable carrier.
The compositions of naringenin and derivant thereof particularly pharmaceutical composition can have various forms, comprises in the dosage forms such as liquid, semisolid and solid for example one or more; Wherein said pharmaceutical composition comprises that the naringenin and the derivant thereof for the treatment of effective dose are active component, and one or more pharmaceutically acceptable carriers.
The pharmaceutical composition of naringenin and derivant thereof can adopt conventional production method well known in the art to make various dosage forms, and active component is mixed with one or more carriers, is made into required dosage form then.Described dosage form comprises one or more in tablet, capsule, granule, suspensoid, Emulsion, solution, syrup or the injection etc., takes one or more route of administration in oral or injection (comprise in intravenous injection, intravenous drip, intramuscular injection or the subcutaneous injection etc. one or more), the mucosa dialysis etc. to carry out the treatment or the scientific research of anti-AD and associated conditions thereof.
It is 0.1～99.9% active component naringenin and derivant thereof that pharmaceutical composition preferably contains weight ratio, further preferably contain weight ratio and be 1%～95% active component naringenin and derivant thereof, preferably contain weight ratio again and be 5%～90% active component naringenin and derivant thereof, most preferably contain weight ratio and be 10%～40% active component naringenin and derivant thereof.
The pharmaceutical composition of naringenin and derivant thereof generally must be aseptic and stable under the production condition of storage.Said composition can be mixed with solution, microemulsion, dispersion liquid, liposome or other is suitable for the ordered structure of high drug level.By with a kind of of this naringenin of aequum and derivant and required mentioned component or combine to add in the appropriate solvent and then carry out aseptic filtration and prepare aseptic parenteral solution.Generally speaking, prepare dispersion liquid by this naringenin and derivant thereof being added in the aseptic solvent that contains basic disperse medium and required above-mentioned other composition.Under the situation of the sterile powder that is used to prepare aseptic parenteral solution, the preparation method of recommendation is vacuum drying and lyophilized preparation.For example, by passing through to keep required granular size such as the coating of lecithin, under the situation of dispersion liquid and, can keeping the adequate liquidity of solution by using surfactant.By comprising that in said composition the medicament (for example Monostearate or gelatin) that postpones to absorb can reach the prolongation absorption of injectable composition.
When being used for the patient, naringenin of the present invention and derivative doses thereof are 1～500mg/kg days (d), and this dosage or consumption decide preferred 5～20mg/kgd according to the age of patient or user and the situation of body weight and health or patient's symptom usually.That is to say that following dosage range all is safe and reliable, naringenin and derivative doses thereof are 1～3600mg/d (calculating with the 70kg body weight); Oral 1～2000mg, preferred 50～1000mg; Injection 2～400mg, preferred 50～200mg; Unguentum (lotion) 0.5～5%, preferred 1～2%.
Naringenin of the present invention and derivant thereof and Pharmaceutical composition thereof can comprise the naringenin of the present invention and the derivant thereof of " treatment effective dose " or " prevention effective dose "." treatment effective dose " is meant at the dosage of necessity and effectively reaches the amount of required therapeutic effect under the time.The treatment effective dose of naringenin and derivant thereof can be according to causing that at this individuality the factors such as ability of required reaction change such as the patient's condition, age, sex and the body weight of individuality and this naringenin and derivant thereof.The treatment effective dose also refers to that the useful therapeutic effect of this naringenin and derivant thereof surpasses the amount of its any toxicity or harmful effect." prevention effective dose " is meant the amount that effectively reaches required preventive effect under necessary dosage and time.Because preventive dose is used for the ill preceding or early stage curee of disease, the prevention effective dose is usually less than the treatment effective dose.The typical non-limiting scope of the treatment of naringenin of the present invention and derivant thereof or prevention effective dose is 5～20mg/kg, more preferably 5～10mg/kg.Should note, dose value will change according to disease type of desiring to alleviate and seriousness, that is to say when being used for the patient that naringenin of the present invention and derivative doses thereof or consumption decide according to the age of patient or user and the situation of body weight and health or patient's symptom usually.In addition; should understand; for any specific curee; should along with the time according to individual need and give with or supervision give with the people's of described compositions professional judgement and adjust the given dose system; and the dosage range that this paper sets only be illustrative, the scope or the practice of the compositions of can't requirement for restriction protecting.
That is to say, need be according to object, route of administration, institute's disease for the treatment of and the situation etc. of treatment, change naringenin of the present invention and derivant thereof at every turn and/or dosage or the consumption of every day.For example, give mammal through vein, adult (as body weight 60kg) especially, the single dose of described naringenin and derivant thereof is about 5～10mg, preferably about 10mg, preferred administration every day 1～3 time.Can adjust dosage unit, to propose the best required reaction of arch (for example, treatment or prevention are replied).For example, can single heavy dose of administration can give several divided doses or reduce or increase dosage in proportion according to the urgency of treatment situation in a period of time.The non-intestinal compositions that preparation is easy to the unified dosage unit form of administration and dosage is especially favourable.Dosage unit form used herein refers to be suitable for the physical separation unit of dosage unit of the mammalian subject of desire treatment; The calculating that each unit contains scheduled volume is used for together producing with required pharmaceutical carrier the active matter naringenin and the derivant thereof of required therapeutic effect.The specification of dosage unit form of the present invention, determine and directly depend on the specific characteristic of following (a) this naringenin and derivant thereof and the particular treatment of desiring to reach or preventive effect and (b) interior in mixing this technology that is used for the treatment of individual sensitivity naringenin and derivant thereof by following in restriction.
3, the pharmaceutical dosage form of naringenin and derivant thereof and compositions thereof and route of administration
The product that is used to prevent, diagnose, detect, protect, treat and study cardiac-cerebral vascular diseases of naringenin of the present invention and derivant thereof and preparation of compositions thereof, wherein the product according to the requirement of beverage, food technology field preparation can be used in prevention, protection and treats cardiac-cerebral vascular diseases; Can be used in patient's treatment or health care according to the product of the requirement of medical technical field preparation, can either be directly used in the medicine of preparation treatment or health care separately, also can mix with many chemical substances or make up, directly or indirectly be used to prepare the medicine of treatment or health care.Chemical substance described here is above described identical with this section.
In the present invention, required material comprises raw material of the present invention, above-mentioned matching used chemical substance etc., all should adopt the material of food stage or pharmaceutical grade according to practical situation and needs.
Naringenin of the present invention and derivant thereof and compositions thereof can be with the whole bag of tricks administration known in the art, although route of administration/administering mode of recommending in many therapeutic use is spray or oral administration.But the technical staff will appreciate that route of administration/administering mode changes with required result.In some concrete enforcement, the carrier that this reactive compound can avoid rapid release with this chemical compound of protection is preparation example such as empty release formulation together, comprises that graft transmission system, transdermal paste one or more in transmission system or the microcapsule transmission system etc.In addition, can also use biodegradable, biocompatible polymer, for example one or more in ethylene-ethyl acetate, polyanhydride, polyglycolic acid, collagen protein, polyorthoesters or the polylactic acid etc.Prepare the equal patent applied for of many methods of this preparation or generally known to those skilled in the art (referring to for example Sustained and Controlled Release Drug Delivery Systems, J.R.Robinson edits, Marcel DekkerInc., New York, 1978).
Naringenin of the present invention and derivant thereof and compositions thereof, usually by oral, snuffing is gone into, one or more modes in rectum or the parenteral etc., is applied to the patient who needs this treatment.
That is to say, the pharmaceutical composition of naringenin and derivant thereof can adopt method well known in the art to make various dosage forms, as tablet, capsule, granule, suspensoid, Emulsion, solution, syrup, injection etc., take oral or injection (comprising intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection etc.), sticking know well route of administration such as analyse and carry out the control of cardiovascular and cerebrovascular disease or Alzheimer's disease.
Be used for when oral, can be made into conventional solid preparation such as in tablet, powder, granule or the capsule etc. one or more.When implementing, naringenin of the present invention and derivant thereof can be together oral with for example inert diluent or assimilable edible carrier.This naringenin and derivant thereof (with its composition altogether, if desired) can also be wrapped in hard or soft shell gelatin capsules, are pressed into tablet or directly add in curee's the meals.About oral therapeutic administration, can with described naringenin and derivant adds with excipient and use with one or more forms in edible tablet, buccal tablet agent, lozenge, capsule, suspension, syrup or wafer or the like.
For to give naringenin of the present invention and derivant thereof outside the parenterai administration, may need together to give to this naringenin and derivant coating thereof or with this naringenin and derivant thereof with the material that prevents its inactivation.The reactive compound that replenishes can also be added in the said composition.In the specific implementation, naringenin of the present invention and derivant thereof and one or more other medicines that can be used for the treatment of disease are prepared altogether and/or given altogether.Thisly unite use, can utilize this medicine that gives primely, therefore avoid possible toxicity or the complication relevant with various monotherapies than low dosage.
Make in liquid preparation such as water preparation, oil-suspending agent or other liquid preparation one or more, as in syrup or the elixir etc. one or more; When being used for parenteral, can be made in solution, water preparation or the oiliness suspending agent etc. of injection one or more.
In the above-described type of service, preferred form is one or more in tablet, coated tablet, capsule, suppository or the injection etc., further one or more in preferred tablet, capsule or the injection etc., optimizing injection especially.
In sum; naringenin of the present invention and derivant thereof and compositions thereof can be used for preparing the product of prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases; be to comprise in the field products such as medicine, Food ﹠ Drink one or more; for example comprise in medicine, reagent, food, health food, additive, the beverage etc. one or more; preferred agents, health food, additive, further preferred agents.
(5) technology speciality
The present invention has expanded new medical usage to naringenin and derivant thereof, also provides a kind of new medicament sources for prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases.Naringenin of the present invention and derivant safety and low toxicity thereof, pharmacological action is stronger, can be used for preparing the product of prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases.
The present invention studies naringenin and derivant thereof targetedly, and naringenin and derivant pharmacological action thereof are stronger, and its raw material sources are abundant, extensive, inexpensive, and preparation technology is simple, the yield height; And safe in utilization, and the scope of application is wide especially, can play a role to greatest extent, easily applies, and can have a tremendous social and economic benefits in the short period of time.
Experiment showed, naringenin and the derivant thereof that reaches of the present invention, and pharmaceutical composition is a kind of safe, efficient, stable, the inexpensive control cardiovascular and cerebrovascular disease or the medicine of Alzheimer's disease.Its preparation cost is cheap, and content is up to 12% in some medical material as: naringin, and extracting method is simple; Active component is clear and definite; Active high, as: the naringin activity is higher than breviscapine; Toxicity is lower, maximum tolerated dose＞5g/kg that naringin is oral.
In addition; naringenin and derivatives chemical stable in properties thereof; the effect of prevention, diagnosis, detection, protection, treatment and research cardiac-cerebral vascular diseases is obvious, so it is more suitable for preventing, diagnose, detect, protect, treating and study the suitability for industrialized production of cardiac-cerebral vascular diseases product.
In a word, active adaption of the present invention modern medical service and the job demand of scientific research field and the needs of human nature service, be the safe raw material that is used to prevent, diagnose, detect, protect, treat and study aspects such as cardiac-cerebral vascular diseases.
The specific embodiment
The present invention has studied the new pharmacological action of existing naringenin and derivant thereof and new purposes, and a kind of raw material that can be used in the anti-cardiac-cerebral vascular diseases product of preparation is provided, and is convenient to the safe handling in medical industry and fields such as relevant industries such as food, beverage.
The present invention prepares injectable powder and generally adopts conventional freeze-drying, as solvent, the steps include: to get naringenin and derivant thereof with water, adds excipient, is dissolved in water, and adds active carbon, filtration sterilization, and plug is partly rolled in fill, and lyophilization, tamponade are rolled lid and are got final product.Used excipient is selected from one or more in mannitol, gelatin hydrolysate, glucose, lactose, the dextran etc.Every bottle contains naringenin and derivant 10～100mg thereof.
The present invention prepares injectable powder also can adopt spray drying method, as solvent, the steps include: to get naringenin and derivant thereof with water, adds or do not add excipient (excipient is the same), be dissolved in water, add active carbon, filtration sterilization, spray drying, aseptic subpackaged, tamponade is rolled lid and is got final product.Every bottle contains naringenin and derivant 10～100mg thereof.
When the present invention prepared small-volume injection, preparation got final product as solvent with water for injection, also can add appropriate amount of auxiliary materials, and adjuvant is selected from one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol, benzyl benzoate, the dimethyl acetylamide.Every contains naringenin and derivant 10～100mg thereof.
The present invention prepares glucose infusion liquid or sodium chloride transfusion, with water for injection as solvent, add the preparation of an amount of glucose or sodium chloride and get final product, also can add appropriate amount of auxiliary materials, adjuvant is selected from one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol, benzyl benzoate, the dimethyl acetylamide.Every bottle contains naringenin and derivant 10～100mg thereof.
The present invention prepares oral formulations such as tablet, capsule, granule, oral liquid, and adjuvant can be lactose, starch, dextrin, stearate etc., technology preparation routinely.
In the present invention, the example of the above-described specific embodiment and the following stated all is in order to set forth the present invention better, is not to be used for limiting scope of invention.
Below by embodiment the present invention is described in detail.
Embodiment 1, naringenin and derivant thereof are to the influence of chmice acute cerebral ischemia
Grouping:
1. blank group: give and the isopyknic normal saline of medicine group;
2. positive control drug group: give medicine Herba Erigerontis tablet (Shanghai Leiyun Pharmaceutical Industry Co., Ltd., batch number 031111), dosage 200mg/kg;
3. trial drug group: give detected medicine, dosage is 200mg/kg;
Method:
Each organizes gastric infusion 1 time every day, successive administration 7d.Behind the last administration 1h, anesthetized mice is faced upward the position be fixed in operation and close, cut skin of neck, separate bilateral carotid,, write down mouse diing time with No. 4 surgical threads vagal left and right sides of ligation band common carotid artery respectively.
Table 2, to the influence of chmice acute cerebral ischemia (x ± S, n=20)
| Group | Dosage | Mice mean survival time (min) |
| Physiological saline group Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | - 200mg/kg 200mg/kg 200mg/kg 200mg/kg 200mg/kg 200mg/kg 200mg/kg 200mg/kg 200mg/kg | 7.6±3.1 18.3±6.3 ** 19.1±8.2 ** 18.5±7.4 ** 18.7±6.8 ** 17.4±7.1 ** 18.2±7.5 ** 17.9±8.0 ** 18.0±7.2 ** 17.8±8.3 ** |
P＜0.01 vs normal saline group
As seen from Table 2; naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin and positive control drug breviscapine all can obviously prolong the time-to-live that mice is caused acute cerebral ischemia because of the ligation both sides vagal common carotid artery of band; with normal saline group comparing difference highly significant (P＜0.01), the prompting naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin, cerebral ischemia has significant protective effect to breviscapine to chmice acute.
Embodiment 2, naringenin and derivant thereof are to the protective effect of focal cerebral ischemia in rats-reperfusion injury
Group:
1. blank group: give and the isopyknic normal saline of medicine group;
2. positive control drug group: give medicine Herba Erigerontis tablet (Shanghai Leiyun Pharmaceutical Industry Co., Ltd., batch number 031111), dosage 50mg/kg;
3. trial drug group: give detected medicine, dosage is 50mg/kg;
Method:
With the SD rat, 280～300g, with 10% chloral hydrate 3ml/kg intraperitoneal injection of anesthesia, neck median incision, separation, ligation right carotid proximal part, external carotid artery and bifurcated artery thereof.Separate the right side internal carotid artery, separate wing jaw tremulous pulse downwards along internal carotid artery, this branch of root ligation.Be equipped with line, internal carotid artery far-end and common carotid artery at the external carotid artery near-end and place bulldog clamp, the common carotid artery crotch inserts the 4-0 nylon wire by external carotid artery side otch, its degree of depth is 17～20mm, the bolt line enters internal carotid artery, goes into cranium to anterior cerebral artery, all blood flow sources of blocking-up middle cerebral artery.Remove bulldog clamp, tighten line fully, stay the long the end of a thread of 1cm outward, skin suture.Ischemia while gastric infusion or filling stomach are given normal saline.Continue ischemia perfusion again after 2 hours, need not anaesthetize and cut skin once more, prompting nylon wire head end is to the external carotid artery incision when resistance is arranged to lift institute's the end of a thread that stays gently, and blood flow is logical again.Sham operated rats is except that plug wire not, and all the other steps are the same.Pour into the Mus that survives behind the 24h again, 8 every group of parts) brain is got in execution, claim left and right sides brain hemisphere weight in wet base, put in 160 ℃ of baking boxs and claim dry weight after 24 hours, calculate brain water content as follows: brain water content (%)=(weight in wet base-dry weight)/weight in wet base * 100%; A part (8 every group) broken end is fast got the Mus brain, downcuts the crown brain sheet of thick about 2mm, places 2%TTC solution at once, hatches 30 minutes for 37 ℃.Infarct presents white, and non-infarct presents redness.Digital camera is taken record, and (Nanjing Mei Yi scientific ﹠ technical corporation) measures brain sheet cumulative volume and infarct volume with Medbrain 2.0 softwares, and calculates the percentage ratio (%) that infarct accounts for whole cerebral tissue.
As seen from Table 3; the brain water content of normal saline group ischemia side (right hemisphere) is significantly higher than sham operated rats (P＜0.01); the brain water content of naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin and breviscapine group ischemia side (right hemisphere) is significantly higher than its left hemisphere (P＜0.01), with its left hemisphere there was no significant difference.Experimental result shows; naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin all can reduce the water content of ischemical reperfusion injury cerebral tissue; alleviate ischemia side brain hemisphere edema degree, the Ischemia and Reperfusion in vivo in Rats brain injury is had protective effect.
As seen from Table 4; the sham operated rats cerebral tissue does not have infraction; normal saline group ischemia side cerebral tissue has the infraction phenomenon; the percentage ratio that infarct accounts for whole cerebral tissue is 31.2 ± 8.50%; naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin and breviscapine group all can significantly be dwindled ischemia side cerebral tissue infarct volume, have compared highly significant difference (P＜0.01) with the normal saline group.Experimental result shows that the cerebral infarction that naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin cause cerebral ischemia is plugged with remarkable protective effect.
Table 3, to the influence of rat ischemia-pour into again brain water content (x ± SD, n=8)
| Group | Dosage | Left hemisphere water content (%) | Right hemisphere water content (%) |
| Sham operated rats | - | 80.1±0.92 | 79.9±0.84 |
| Physiological saline group Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | - 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg | 79.6±0.88 79.8±0.69 79.7±0.71 79.3±0.73 79.5±0.59 79.4±0.94 79.1±0.96 79.4±0.84 79.2±0.67 79.8±0.75 | 84.7±1.06 ## 80.6±0.86 ** 80.2±0.84 ** 80.9±0.95 ** 81.2±0.81 ** 81.8±0.99 ** 81.7±0.94 ** 81.5±0.91 ** 81.4±0.88 ** 81.9±0.95 ** |
*Compare with the normal saline group P＜0.01; Compare with left hemisphere ##P＜0.01
Table 4, to the influence of the cerebral infarct volume of cerebral ischemic reperfusion in rats (x ± SD, n=8)
| Group | Dosage | Infarct volume accounts for whole cerebral tissue percentage ratio (%) |
| Sham operated rats | - | 0 |
| Physiological saline group Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | - 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg 50mg/kg | 31.2±8.50 15.5±7.40 ** 14.9±6.19 ** 15.6±5.90 ** 15.4±6.20 ** 16.3±7.27 ** 15.7±7.34 ** 16.1±6.73 ** 16.5±7.08 ** 16.8±6.86 ** |
Compare with normal saline group (model group),
*P＜0.01
Above experimental result prompting naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin have protective effect to cerebral ischemia reperfusion injury.
Embodiment 3, naringenin and derivant thereof are to the influence of vascular dementia rats learning and memory
Group:
1. blank group: give and the isopyknic normal saline of medicine group;
2. positive control drug group: give medicine Herba Erigerontis tablet (Shanghai Leiyun Pharmaceutical Industry Co., Ltd., batch number 031111), dosage 100mg/kg;
3. trial drug group: give detected medicine, dosage is 100mg/kg;
Method:
With the SD rat, 280～300g, with 10% chloral hydrate 3ml/kg intraperitoneal injection of anesthesia, neck median incision, separation, ligation right carotid proximal part, external carotid artery and bifurcated artery thereof.Separate the right side internal carotid artery, separate wing jaw tremulous pulse downwards along internal carotid artery, this branch of root ligation.Be equipped with line, internal carotid artery far-end and common carotid artery at the external carotid artery near-end and place bulldog clamp, the common carotid artery crotch inserts the 4-0 nylon wire by external carotid artery side otch, its degree of depth is 17～20mm, the bolt line enters internal carotid artery, goes into cranium to anterior cerebral artery, all blood flow sources of blocking-up middle cerebral artery.Remove bulldog clamp, tighten line fully, stay the long the end of a thread of 1cm outward, skin suture.Continue ischemia perfusion again after 2 hours, need not anaesthetize and cut skin once more, prompting nylon wire head end is to the external carotid artery incision when resistance is arranged to lift institute's the end of a thread that stays gently, and blood flow is logical again.Sham operated rats is except that plug wire not, and all the other steps are the same.Rat is poured into gastric infusion behind the 8h again, and sham operated rats and model group are irritated stomach and given pure water.1 time/d of rat oral gavage, continuous irrigation stomach 7d carries out the learning and memory ability that the Morris water maze test is estimated rat then.The orientation navigation test: experiment lasts 4d, and rat is put into water towards pool wall from 4 different quadrants, and the record rat seeks platform required time (escape latency), surpass 2min person, press 2min and calculate, the meansigma methods note of 4 tests is made the incubation period that rat seeks platform, follow-on test 4d.After each quadrant finishes, allow rat rest 10s on platform.In whole experiment, keep the relatively stable of operator position and surrounding.
Table 5 result shows after focal cerebral ischemia in rats 2h pours into 7d again and causes the vascular dementia rats model; the model group's learning and memory function is impaired; the 4th day water maze escape latency time of undergoing training is compared significant prolongation (P＜0.01) with sham operated rats; naringin; naringenin; Hesperidin; hesperetin; isosakuranetin; poncirin; eriodictyol; eriocitrin and breviscapine all can improve the learning and memory function of vascular dementia rats; significantly reduce the time of vascular dementia rats water maze escape latency; the 4th day water maze escape latency time of undergoing training is compared with model group; difference has significance meaning (P＜0.01); the result shows naringin; naringenin; Hesperidin; hesperetin; isosakuranetin; poncirin; eriodictyol; eriocitrin and breviscapine have therapeutical effect to vascular dementia, improve its learning and memory function.
Table 5, to the influence of the experimental vascular dementia rats water maze of postoperative 7d escape latency (S, x ± SD, n=10)
| Group | The 1st day | The 2nd day | The 3rd day | The 4th day |
| Sham-operation group model group Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | 91.3±20.2 100.5±28.1 94.5±21.3 101.2±22.4 95.6±24.7 97.8±30.5 93.7±23.6 98.3±28.2 94.9±29.8 96.7±30.5 95.1±27.9 | 51.4±18.9 96.0±26.2 61.2±19.7 42.6±18.6 68.3±21.1 72.5±22.5 73.1±20.4 77.4±28.1 79.8±25.6 70.7±21.3 76.3±21.9 | 30.9±17.2 93.5±24.7 48.3±19.0 36.7±15.2 51.0±18.6 55.2±23.4 60.4±18.5 57.6±21.3 61.2±21.7 58.9±20.1 62.3±22.6 | 25.9±16.3 83.4±21.9## 35.8±18.6 ** 29.2±12.5 ** 38.5±20.8 ** 41.1±28.7 ** 46.3±19.4 ** 44.7±19.9 ** 42.9±22.6 ** 45.0±23.8 ** 45.3±21.5 ** |
Compare ##P＜0.01 with sham operated rats; Compare with model group
*P＜0.01
Embodiment 4, naringenin and derivant thereof the dog coronary artery ligation is caused the therapeutical effect of myocardial infarction model
Group:
1. blank group: give and the isopyknic normal saline of medicine group;
2. positive control drug group: give medicine Herba Erigerontis tablet (Shanghai Leiyun Pharmaceutical Industry Co., Ltd., batch number 031111), dosage 50mg/kg;
3. trial drug group: give detected medicine, dosage is 50mg/kg;
Method:
Dog is weighed the back with the quiet notes anesthesia of 3% pentobarbital sodium 30mg/kg.Separate trachea and also insert tracheal intubation, connect SC-M5 type anesthesia respirator (Shanghai Medical Instruments factory), wait out row mechanical ventilation behind the breast, respiratory frequency 16～18 times/minute, tidal volume 350～550ml.Open breast along left border of sternum the 4th intercostal, expose heart, cut off pericardium and make the pericardium hammock.Free coronary artery between ramus descendens anterior arteriae coronariae sinistrae second to the 3rd branch, and under it, wear two rhizoid lines, be ready for use on two step ligation.Adopt Harris two steps ligation method: preceding 2 minutes of ligation first, from the quiet notes lignocaine of femoral artery 5mg/kg prevention arrhythmia.Steel wire with one section diameter 1mm when ligation inserts in first untwisting, with the coronary artery ligation, then extracts steel wire out steel wire.Complete ligation second knot after 30 minutes.
Ligation is cored dirty after 2 hours, take by weighing weight whole-heartedly; Cut atrium and right ventricle, weigh up left ventricular mass, and under the coronary ligation line, be parallel to coronary sulcus left ventricle is cut into 5 of uniform thickness, clean, put 37 ℃ of dyeing of 0.05% chlorination nitro blue tetrazolium (N-BT) liquid 30 minutes with normal saline.Shaking dyeing liquor in the dyeing course frequently makes it fully to contact with cardiac muscle.After the dyeing immediately water wash away excess dyestuff.Infarcted region is not painted, and non-infarcted region skipper, cuts off coloured part, and uncoloured infarcted region is weighed, and calculates infarct weight and accounts for the percentage ratio that reaches left ventricular mass whole-heartedly.
The result:
1, the quantitative tissue of myocardial infarct size is learned the influence that detects
Learn to detect myocardial infarct size with quantitative tissue and promptly show that with N-BT dyeing breviscapine, naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin are consistent with the result of epicardial electrogram mensuration to the influence of myocardial infarct size.Breviscapine, naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin reduce myocardial infarct size, and myocardial infarction area is with the ratio of weight and the ratio and the normal saline group of infarct and left ventricular mass relatively have significant differences (P＜0.01) whole-heartedly.The results are shown in Table 6.
Table 6, N-BT dyeing measured the influence (x ± s, n=5 only/group) of myocardial infarct size
| Group | Dosage | Infarct/(%) whole-heartedly | Infarct/left ventricle (%) |
| Physiological saline Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | 10ml/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg | 15.22±1.71 10.23±1.36 ** 10.14±1.43 ** 11.79±1.52 ** 10.86±1.67 ** 12.05±1.59 ** 11.82±1.49 ** 11.98±1.70 ** 12.13±1.58 ** 11.74±1.46 ** | 25.64±2.38 16.84±1.84 ** 16.56±1.79 ** 18.15±2.07 ** 17.29±1.65 ** 18.33±1.96 ** 18.37±1.58 ** 18.29±1.72 ** 18.52±1.44 ** 18.53±1.53 ** |
*Compare with the normal saline group P＜0.01
Above experimental result proves; breviscapine, naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin can significantly reduce the degree of myocardial ischemia of coronary ligation dog; dwindle the myocardial ischemia scope, myocardial ischemia is had therapeutical effect.
The protective effect to the rat myocardial ischemia and reperfusion damage of embodiment 5, naringenin and derivant thereof
1, modeling: the SD rat, 2% pentobarbital sodium 40mg/kg intraperitoneal injection of anesthesia, dorsal position is fixed.With electrocardiograph record II lead electrocardiogram monitoring heart condition.Throat medisection, the circulation of qi promoting cannula connects artificial respirator, and frequency is 55 times/minute, tidal volume 1ml.Separating a side femoral vein supplies with medicinal.Cut off the 4th and the 5th rib at breast left side the four or five intercostal place incision thoracic wall and along left border of sternum 2mm place, cut off pericardium, expose heart, under ramus descendens anterior arteriae coronariae sinistrae, wear 1 No. 0/3 stitching thread, stablize 10min (stable back electrocardiogram deviant discards), two the end of a thread are passed a bit of thin silica gel tube, knotting is as ischemia ligation (no ST section and T ripple changer eliminate) on the thin silica gel tube of another segment, behind the ischemia 10min from the slow drug administration by injection of femoral vein, cut off ligature behind the 30min, make anterior descending branch pour into 30min again.
2, the mensuration of lactic acid dehydrogenase (LDH), creatine kinase (CK): after perfusion finished again, femoral artery was got blood, and ultraviolet spectrometry is measured Serum LDH, CK activity.
3, myocardial infarct size algoscopy: under the coronary ligation line, be parallel to coronary sulcus, wait heavy back that the ventricular muscles crosscut is become 5,5 cardiac muscles are placed nitro blue tetrazolium (N-BT) dye liquor, take out behind 37 ℃ of jolting dyeing 15min, normal myocardium dyes and is skipper, and the infarct cardiac muscle is then not painted.Under anatomical lens, separate infarct, weigh respectively, account for the percentage ratio (%) of myocardium weight as the index of weighing infarction size with infarct cardiac muscle weight.
Behind the myocardial ischemia-reperfusion, Serum LDH, the active obviously increase of CK, myocardial infarction area weight obviously increases, and with Sham-operated control group significant differences (P＜0.01) is arranged relatively; Breviscapine, naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin reduce Serum LDH activity, CK activity, myocardial infarction area/percentage by weight is lower than model group whole-heartedly; difference has highly significant meaning (P＜0.01), and prompting breviscapine, naringin, naringenin, Hesperidin, hesperetin, isosakuranetin, poncirin, eriodictyol, eriocitrin have protective effect to myocardial ischemia reperfusion injury.The results are shown in Table 7.
Table 7, to the influence of rat heart ischemical reperfusion injury (x ± s, n=10)
| Group | Dosage | CK(U/dL) | LDH(U/dL) | Infarct/(%) whole-heartedly |
| Sham-operation group physiological saline group Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | 10ml/kg 10ml/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg 100mg/kg | 524.6±102.3 1123.5±185.6 △△ 692.7±158.2 ** 645.9±137.7 ** 725.1±160.5 ** 712.3±140.9 ** 744.8±145.7 ** 733.1±153.8 ** 754.7±157.9 ** 759.2±161.4 ** 762.4±162.0 ** | 428.9±90.6 970.6±163.7 △△ 611.5±89.8 ** 562.9±78.4 ** 640.5±103.9 ** 652.8±85.6 ** 702.5±91.2 ** 669.2±110.3 ** 650.8±92.1 ** 671.4±97.6 ** 693.7±107.5 ** | 0±0 30.4±5.8 △△ 21.6±3.6 ** 20.5±2.8 * 22.8±3.3 ** 22.6±3.7 ** 23.4±3.1 ** 24.1±3.9 ** 24.2±2.9 ** 23.9±3.4 ** 23.7±3.5 ** |
*Compare with the normal saline group P＜0.01;
△ △Compare with the normal saline group P＜0.01
The influence to the inductive Alzheimer disease model rat of (beta amyloid peptide) A β 1-40 of embodiment 6, naringenin and derivant thereof
1, grouping:
1. blank group: give and the isopyknic normal saline of medicine group;
2. positive control drug group: give medicine Herba Erigerontis tablet (Shanghai Leiyun Pharmaceutical Industry Co., Ltd., batch number 031111), dosage 100mg/kg;
3. trial drug group: give detected medicine, dosage is 100mg/kg;
2, method: A β 1-40 is dissolved in sterile distilled water (10ug/ul), under preceding 37 ℃, hatched for 1 week.SD rat, 250～300g adopt lumbar injection 10% chloral hydrate (0.35g/kg) anesthesia, the head unhairing, and sterilization skin also cuts.The stereotactic apparatus fixing head exposes skull, and selecting bilateral hippocampal dentate dorsal part cell band is injection zone.The elements of a fix are (AP-3.5mm, ML ± 2.0mm, DV 2.7mm), open skull with bit drills, slowly inject A β 1-40, and let the acupuncture needle remain at a certain point, and 5min spreads fully with assurance solution, slowly removes pin then.The continuous 10d of difference gastric infusion behind the modeling 24h.Matched group and model group are only irritated stomach with the equivalent distilled water.Continuous irrigation stomach 10d carries out the learning and memory ability that the Morris water maze test is estimated rat then.The orientation navigation test: experiment lasts 4d, and rat is put into water towards pool wall from 4 different quadrants, and the record rat seeks platform required time (escape latency), surpass 2min person, press 2min and calculate, the meansigma methods note of 4 tests is made the incubation period that rat seeks platform, follow-on test 4d.After each quadrant finishes, allow rat rest 10s on platform.In whole experiment, keep the relatively stable of operator position and surrounding.
Table 8, to the influence of the experimental Alzheimer's Disease Rats water maze of postoperative 10d escape latency (x ± SD, n=10, s)
| Group | The 1st day | The 2nd day | The 3rd day | The 4th day |
| Sham-operation group model group Breviscapinun aurantiin naringenin aurantiamarin hesperetin isosakuranetin poncirin eriodictyol eriocitrin | 82.2±15.4 92.7±20.3 90.1±16.8 91.4±17.6 89.6±19.7 87.9±21.2 88.4±18.9 90.8±19.5 92.2±18.8 89.0±17.1 85.3±20.2 | 55.8±13.5 90.1±18.9 83.2±17.4 66.5±19.1 77.5±18.3 79.1±19.2 80.5±14.7 72.0±19.1 73.8±15.6 74.6±17.4 78.3±16.5 | 32.5±12.8 91.0±19.7 76.6±19.0 53.8±16.2 60.7±16.6 66.3±20.5 71.1±16.9 64.2±19.4 68.4±17.3 70.3±18.2 72.5±17.8 | 27.3±11.7 85.6±17.1## 68.4±18.2 44.7±12.3 * 49.1±11.1 * 52.6±12.4 * 57.2±10.8 * 55.8±11.5 * 56.2±11.7 * 56.5±12.3 * 56.9±10.5 * |
Compare ##P＜0.01 with sham operated rats; Compare with model group
*P＜0.05
The result shows that rat hippocampus injection beta amyloid peptide makes Alzheimer disease model; the model group's learning and memory function is impaired; the 4th day water maze escape latency time of undergoing training is compared significant prolongation (P＜0.01) with sham operated rats; naringin; naringenin; Hesperidin; hesperetin; isosakuranetin; poncirin; eriodictyol; eriocitrin all can improve the learning and memory function of Alzheimer's Disease Rats; significantly reduce the time of Alzheimer's Disease Rats water maze escape latency; the 4th day water maze escape latency time of undergoing training is compared with model group; difference has significance meaning (P＜0.01); the result shows naringin; naringenin; Hesperidin; hesperetin; isosakuranetin; poncirin; eriodictyol; eriocitrin has therapeutical effect to Alzheimer, improves its learning and memory function.The results are shown in Table 8.
The preparation of embodiment 7, naringenin and derivatives powder injection thereof
Get naringenin and derivant 30g thereof, add dextran 30g, add 500ml water for injection, stir and make its dissolving; Add the injection water to 2000ml, add the 3.0g needle-use activated carbon, fully stirred 30 minutes; Decarbonization filtering; With 0.22 μ m filtering with microporous membrane; Be filled in the aseptic cillin bottle, every bottle of 2ml partly rolls plug; Lyophilization, tamponade is rolled lid and is got final product again.
The preparation of embodiment 8, naringenin and derivatives powder injection thereof
Get naringenin and derivant 60g thereof, add 500ml water for injection, stir and make its dissolving; Add the injection water to 1000ml, add the 1g needle-use activated carbon, fully stirred 30 minutes; Decarbonization filtering; With 0.22 μ m filtering with microporous membrane; Lyophilization gets sterilized powder, is distributed into 1000 bottles.
The preparation of embodiment 9, naringenin and derivatives powder injection thereof
Get naringenin and derivant 40g thereof, add lactose 50g, add 100ml water for injection, stir and make its dissolving; Add the injection water to 1000ml, add the 1.5g needle-use activated carbon, fully stirred 30 minutes; Decarbonization filtering; With 0.22 μ m filtering with microporous membrane; Spray drying gets sterilized powder, is distributed into 1000 bottles.
The preparation of embodiment 10, naringenin and derivatives powder injection thereof
(1) prescription
Injection naringenin and derivant semi-finished product 150g thereof
Mannitol 400g
Water for injection adds to 10000ml
Make 10000 bottles altogether
(2) preparation technology
Take by weighing recipe quantity naringenin and derivant thereof by above prescription, join in an amount of water for injection, stir and make its dissolving; Add recipe quantity mannitol, stir and make dissolving fully, add to the full amount of water for injection; Add 0.1% needle-use activated carbon of amount of liquid, fully stirred 30 minutes; Decarbonization filtering; With 0.22 μ m filtering with microporous membrane; Plug is partly rolled in fill; Lyophilization, lid is rolled in tamponade.Make 9735 bottles altogether, yield rate is 97.35%.
The preparation of embodiment 11, naringin injection
Prescription:
Naringin 20g
Ethanol (95%) 2000g
Propylene glycol (C.P.) 1000g
Water for injection adds to 10000ml
Make 1000
Technology:
Get 20 ℃ of ethanol (95%) 2000g, add active carbon 5g and stir, through core group filtration under diminished pressure, standby.Getting the recipe quantity naringin adds among the above-mentioned ethanol 2000g, be heated to about 40 ℃, fully stir, make it to dissolve clear and bright, add the recipe quantity propylene glycol then, add fresh water for injection again and make full dose become 10000ml, fully stir mixing, add active carbon 3g, clear and bright through core group filtration under diminished pressure, filtrate before and after merging is clear and bright with special-purpose core fine straining again.Check the qualified back embedding of content and clarity, 100 ℃ of circulation steam sterilization 30min promptly get the injection that every 10ml contains naringin 20mg.
The preparation of embodiment 12, naringenin and derivant small-volume injection thereof
Get naringenin and derivant 5g thereof, add 100ml water for injection, stir and make its dissolving; Add the injection water to 1000ml, with 0.22 μ m filtering with microporous membrane; The packing embedding, every bottle of 10ml, sterilization gets final product.
The preparation of embodiment 13, naringenin and derivant small-volume injection thereof
Get naringenin and derivant 10g thereof, add propylene glycol 30g, add 200ml water for injection, stir and make its dissolving; Add the injection water to 1000ml, add the 1.5g needle-use activated carbon, fully stirred 30 minutes; Decarbonization filtering; With 0.22 μ m filtering with microporous membrane; The packing embedding, every bottle of 5ml, sterilization gets final product.
The preparation of embodiment 14, naringenin and derivant glucose infusion liquid thereof
Get naringenin and derivant 2g thereof, add Polyethylene Glycol 10g, add glucose 500g, add 2000ml water for injection, stir and make its dissolving; Add the injection water to 5000ml; With 0.22 μ m filtering with microporous membrane; The packing embedding, every bottle of 100ml, sterilization gets final product.
The preparation of embodiment 15, naringenin and derivant glucose infusion liquid thereof
Get naringenin and derivant 2g thereof, add glucose 250g, add 1000ml water for injection, stir and make its dissolving; Add the injection water to 5000ml; With 0.22 μ m filtering with microporous membrane; The packing embedding, every bottle of 250ml, sterilization gets final product.
The preparation of embodiment 16, naringenin and the transfusion of derivant sodium chloride thereof
Get naringenin and derivant 1g thereof, add sodium chloride 90g, add 1000ml water for injection, stir and make its dissolving; Add the injection water to 10000ml; With 0.22 μ m filtering with microporous membrane; The packing embedding, every bottle of 250ml, sterilization gets final product.
The preparation of embodiment 17, naringenin and derivant tablet thereof
(1) prescription
Naringenin and derivant 1000.0g thereof
Microcrystalline Cellulose 1170.0g
Pregelatinized Starch 690.0g
Lactose 125.0g
The 5%PVP dehydrated alcohol is an amount of
Magnesium stearate 15.0g
Make 10000 altogether
(2) preparation technology
Take by weighing the principal agent and the adjuvant of recipe quantity respectively by above prescription, progressively increase behind the method mix homogeneously according to making soft material, system granule under the formulation and technology item by equivalent, dry, processes such as granulate, the heavy back of sheet single punch tablet machine and 10.5mm shallow concave punch tabletting have been calculated, control nude film hardness 5～7kg makes 9698 in tablet altogether, and yield rate is 96.98%.
Adopt lift-over nebulization coating, art for coating is as follows:
The preparation of coating solution: gastric solubleness thin film dress material: 85G61235 is provided by Shanghai Colorcon Coating Technology Co., Ltd
Art for coating: will treat that (hardness 5kg～7kg) puts into coating pan to the coating nude film, start agitating device and air blast heater, when treating that the nude film temperature rises to 40 ℃, last 1/3 place that begins to open spray gun alignment tab bed sprays into the coating solution coating, 38 ℃～42 ℃ of control strip bed tempertaures, gas pound pressure 6kg, the coating solution flow velocity is 50mL/min, coating membrane heavily account for coated tablet heavy 3%.
The preparation of embodiment 18, naringin tablet
Prescription:
Naringin 100g
Starch 30g
Lactose 40g
Carboxymethyl starch sodium 5g
Starch slurry (7%) is an amount of
Magnesium stearate 1% (1.45g)
Make 1000
Technology:
Get the recipe quantity naringin, pulverized 100 mesh sieves, again starch, the lactose of recipe quantity were pulverized 100 mesh sieves, mixing.Naringin is added in the starch and lactose of mixing mixing.Add an amount of 50% ethanol and mix thoroughly, granulate through 16 order ferrum silk screen nets, dry below 60 ℃, granulate adds an amount of magnesium stearate mixing, tabletting behind the analysis content.Can be made into 1000 every tablet tablet that contains the 100mg naringin.
The preparation of embodiment 19, naringenin and derivant capsule thereof
(1) prescription
Naringenin and derivant 1000.0g thereof
Microcrystalline Cellulose 1000g
Carboxymethyl starch sodium 140g
Dehydrated alcohol is an amount of
Pulvis Talci 80g
Make 10000 capsules altogether
(2) preparation technology gets in crude drug naringenin and derivant thereof and the prescription other adjuvant respectively by above prescription and crosses 100 mesh sieves respectively, put 60 ℃ of oven dry, take by weighing recipe quantity naringenin and derivant thereof and microcrystalline cellulose rope, the carboxymethyl starch sodium equivalent method mix homogeneously that progressively increases, with an amount of dehydrated alcohol system soft material, 30 mesh sieves are granulated, 50～60 ℃ of dryings 2 hours with 30 mesh sieve granulate, add the Pulvis Talci and the carboxymethyl starch sodium mix homogeneously of recipe quantity.
The preparation of embodiment 20, naringenin capsule
Prescription:
Naringenin 50g
Starch 140g
Micropowder silica gel 10g
Make 1000
Technology:
Get the recipe quantity naringenin, pulverized 100 mesh sieves, in the starch of adding recipe quantity, the micropowder silica gel, mixing directly incapsulates, and can be made into 1000 every capsule that contains the 50mg naringenin.
The preparation of embodiment 21, hesperetin capsule
Prescription:
Hesperetin 50g
Starch 140g
Micropowder silica gel 10g
Make 1000
Technology:
Get the recipe quantity hesperetin, pulverized 100 mesh sieves, in the starch of adding recipe quantity, the micropowder silica gel, mixing directly incapsulates, and can be made into 1000 every capsule that contains the 50mg hesperetin.
Claims (15)
1. naringenin and derivant thereof the application in the anti-cardiac-cerebral vascular diseases product of preparation.
2. the application of the compositions of naringenin and derivant thereof in the anti-cardiac-cerebral vascular diseases product of preparation.
3. the application of naringenin according to claim 1 and 2 and derivant thereof is characterized in that, described anti-cardiac-cerebral vascular diseases product is meant the product that is used to prevent, diagnose, detect, protect, treat and study cardiac-cerebral vascular diseases.
4. the application of naringenin according to claim 3 and derivant thereof is characterized in that, described anti-cardiac-cerebral vascular diseases product is to comprise in medicine, the Foods or drinks field product one or more.
5. the application of naringenin according to claim 4 and derivant thereof is characterized in that, described anti-cardiac-cerebral vascular diseases product is to comprise in medicine, reagent, food, health food, additive or the beverage one or more.
6. the application of naringenin according to claim 1 and 2 and derivant thereof is characterized in that, described cardiac-cerebral vascular diseases is to comprise cardiovascular and cerebrovascular disease and relevant disease, Alzheimer's disease and relevant disease thereof;
In reperfusion injury that described cardiovascular and cerebrovascular disease and relevant disease thereof are to comprise cerebral infarction, myocardial infarction, cerebral ischemia---reperfusion injury, myocardial ischemia---, apoplexy sequela, the vascular dementia one or more;
Described Alzheimer's disease and relevant disease thereof are to comprise in the Alzheimer's disease one or more.
7. the application of naringenin according to claim 1 and 2 and derivant thereof; it is characterized in that described naringenin and derivant thereof are to comprise in monomer naringenin and derivant, hesperetin and derivant thereof, isosakuranetin and derivant thereof or eriodictyol and the derivant thereof one or more.
8. the application of naringenin according to claim 7 and derivant thereof; it is characterized in that described naringenin and derivant thereof are to comprise the monomer naringenin; naringin; naringenin-7-O-β-rutinoside; naringenin-7-O-glucoside; naringenin-7-O-rhamnoside; hesperetin; Hesperidin; neohesperidin; hesperetin-7-O-glucoside; hesperetin-7-O-rhamnoside; isosakuranetin; sakuranetin; poncirin; isosakuranetin-7-O-β-rutinoside; isosakuranetin-7-O-glucoside; isosakuranetin-7-O-rhamnoside; eriodictyol; eriocitrin; new eriocitrin; in eriodictyol-7-O-glucoside or eriodictyol-7-O-rhamnoside one or more.
9. the application of naringenin according to claim 1 and 2 and derivant thereof is characterized in that, the chemical structure of general formula of described naringenin and derivant thereof is as follows:
Wherein, R
1Be to comprise in the hydrogen or alkyl one or more; R
2Be to comprise in hydrogen, hydroxyl or the alkoxyl one or more; R
3Be to comprise in hydrogen, alkyl or the glycosyl one or more;
Described alkyl is to comprise in straight chained alkyl, branched alkyl or the cyclic alkyl with 1～6 carbon atom one or more;
Alkyl in the described alkoxyl is to comprise in straight chained alkyl, branched alkyl or the cyclic alkyl with 1～6 carbon atom one or more.
10. the application of naringenin according to claim 9 and derivant thereof is characterized in that, described R
1Be to comprise in hydrogen, methyl or the ethyl one or more; R
2Be to comprise in hydrogen, hydroxyl, the methoxy or ethoxy one or more; R
3Be to comprise hydrogen, have the alkyl of 1～6 carbon atom or contain in the glycosyl of 1～6 monosaccharide one or more.
11. the application of naringenin according to claim 10 and derivant thereof is characterized in that, described R
3Be to comprise hydrogen, methyl, ethyl or contain in the glycosyl of 3 monosaccharide one or more;
Described monosaccharide is meant Glucopyranose., xylopyranose, arabopyranose, pyrans rhamnose, and sugar chain can be straight or branched, and connected mode can be (1-2), (1-3), (1-4) or (1-6) connection.
12. the application of naringenin according to claim 9 and derivant thereof, it is characterized in that described alkyl is to comprise in methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, tertiary pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopenta or the cyclohexyl one or more;
Alkyl in the described alkoxyl is to comprise in methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, tertiary pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopenta or the cyclohexyl one or more.
13. the application of naringenin according to claim 12 and derivant thereof is characterized in that, described alkyl is to comprise in the alkyl with 1～3 carbon atom one or more;
Alkyl in the described alkoxyl is to comprise in the alkyl with 1～3 carbon atom one or more.
14. the application of naringenin according to claim 13 and derivant thereof is characterized in that, described alkyl is to comprise in methyl or the ethyl one or more;
Alkyl in the described alkoxyl is to comprise in methyl or the ethyl one or more.
15. the application of naringenin according to claim 9 and derivant thereof is characterized in that, described naringenin and derivant thereof are to comprise in the following chemical compound one or more:
Work as R
1Be hydrogen and R
2During for hydrogen, expression monomer naringenin and derivant thereof;
Work as R
1Be methyl and R
2During for hydroxyl, expression hesperetin and derivant thereof;
Work as R
1Be methyl and R
2During for hydrogen, expression isosakuranetin and derivant thereof;
Work as R
1Be hydrogen and R
2During for hydroxyl, expression eriodictyol and derivant thereof.
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