CN103622971B - A kind of medical composition and its use being used for the treatment of and/or preventing Alzheimer - Google Patents
A kind of medical composition and its use being used for the treatment of and/or preventing Alzheimer Download PDFInfo
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- CN103622971B CN103622971B CN201310691183.1A CN201310691183A CN103622971B CN 103622971 B CN103622971 B CN 103622971B CN 201310691183 A CN201310691183 A CN 201310691183A CN 103622971 B CN103622971 B CN 103622971B
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- galantamine
- oxylycorine
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- alzheimer
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Abstract
The invention discloses a kind of pharmaceutical composition being used for the treatment of and/or preventing Alzheimer, said composition is made up of galantamine and oxylycorine, the two coupling has the synergism of good acetylcholine esterase inhibition activity, can be used for treating Alzheimer.Said composition can greatly reduce the dosage of galantamine when treating and/or preventing Alzheimer, thus avoids side effects of pharmaceutical drugs, improves the compliance of administration.
Description
Technical field
The present invention relates to natural medicine field, be specifically related to a kind of medical composition and its use containing galantamine being used for the treatment of and/or preventing Alzheimer.
Background technology
Alzheimer (Alzheimer ' sDisease, AD) is the degenerative disease of a kind of central nervous system, and clinical manifestation is serious cognition, memory dysfunction and social adaptation decline.Its pathogenesis is complicated, the cause of disease is illustrated not yet completely, wherein acetylcholinesteraseinhibitors inhibitors (acetylcholinesteraseinhibitor, AChEI) be treat AD maturation and successful method the most at present, also be that a unique class is by U.S. FDA approval listing, also be the primary drug being used successfully to clinical AD treatment most the earliest, and be considered as the standard care of light moderate AD patient.AChEI mainly comprises donepezil (donepezil), bright (rivastigmine) of Li Fansi, tacrine (tacrine) and the alkaloid galantamine (galanthamine) extracted from plant, huperzine are first-class.
Galantamine has become one of choice drug for the treatment of AD by FDA approval exploitation, but the drug effect of this medicine is the same with other AChEI all there is certain effect time limit, there is bibliographical information, these medicines the longest effect duration is only 2 to three years [LauraA.Craiga, NancyS.Hong, RobertJ.McDonald.Revisitingthecholinergichypothesisinthe developmentofAlzheimer ' sdisease.NeuroscienceandBiobehavioralReviews.2011, 35:1397-1409], so, urgently exploitation can produce high effect in relative low dose situation at present, the new drug that action time is permanent.Be a kind of effective approach by AChEI and other combination therapies that can produce strong synergism, which can not only make pharmaceutically-active extension of validity, can also reduce the drug resistance of AChEI, side effect and toxicity etc., obtain paying close attention to more and more widely.But existingly do not find as in the research of the collaborative medication of acetylcholinesteraseinhibitors inhibitors the medicine that synergism is stronger about galantamine, involved compositions can not play low amounts when treating Alzheimer and act on efficiently.The reports such as such as Liu, although many maryllidaceous alkaloids all have anti-acetylcholinesterase activity, but close due to the mechanism of action, some are had to there is competitive inhibition relation between them, such as: galantamine and lycoramine, antagonism [YingLiu is there is between nor-galantamine, Jian-LiangZhou, PengLiu, ShiSun, PingLi.Chemicalmarkers ' fishingandknockoutforholisticactivityandinteractionevalu ationofthecomponentsinherbalmedicines.JournalofChromatog raphyA, 2010, 1217:5239-5245].
Oxylycorine another name lycobetaine, AT-1840, it is a kind of effective antitumour material, stronger to the fissional inhibitory action of early and middle portion, and untoward reaction is little, to immunologic function unrestraint phenomenon, mutagenic action is slight, is used for the treatment of digestive tract cancer, hepatocarcinoma, ovarian cancer, pulmonary carcinoma, incidence cancer, malignant lymphoma etc., wherein better to gastric cancer, ovarian cancer curative effect.
The molecular formula of galantamine and oxylycorine is respectively C
17h
21nO
3and C
16h
12nO
3.Molecular weight is 287.35 and 266.08.Structure is as follows:
Galantamine:
Oxylycorine:
Galantamine and oxylycorine are not carried out the report of drug combination in prior art.
Summary of the invention
The present invention is by a large amount of Experimental comparison screening, be surprised to find that galantamine and oxylycorine have beyond thought collaborative anti-acetylcholinesterase activity when drug combination, only need add a small amount of oxylycorine, greatly can reduce the effective dose of galantamine anti-acetylcholinesterase activity, this also means and adopts dosage galantamine being treated alzheimer disease greatly to reduce, thus make pharmaceutically-active extension of validity, the drug resistance of reduction, reduce the side effect such as bradycardia, Nausea and vomiting and toxicity; And after reducing dosage, toxic and side effects reduces, make originally to forbid a part of angina pectoris of galantamine, bradycardia, the resistance of mechanicalness intestinal patient also likely use said medicine.Inventor finds when suppressing AchE active to galantamine and oxylycorine compatibility, during by galantamine and oxylycorine combination medicine-feeding, has the synergism well suppressing AchE activity when particularly mass concentration ratio is 1:5-5:1.Inventor uses the Ellman method of improvement to carry out suppression ratio mensuration to the compositions of different proportion, and apply classical administering drug combinations analysis principle (Median-effectPrinciple) and statistical analysis, result shows that it has synergism, especially can produce when Fa>0.5 and obviously produce cooperative effect suppression AchE activity, this both explanations compositions can produce biological effect more better than monomer when low dosage compatibility, greatly can reduce the generation of the toxic and side effects of medicine, there is good clinical application DEVELOPMENT PROSPECT.
The present invention also provides a kind of method treating and/or preventing Alzheimer simultaneously, i.e. the galantamine of administering therapeutic effective dose and oxylycorine compositions, and this Therapeutic Method can be used for the mammal comprising people.
The invention provides a kind of pharmaceutical composition being used for the treatment of and/or preventing Alzheimer, it is characterized in that: active component is made up of galantamine and a kind of quinoline alkaloid.
Described quinoline alkaloid extracts in Bulbus Lycoridis Radiatae, and described quinoline alkaloid can be oxylycorine.
Preferably, in aforementioned pharmaceutical compositions, galantamine: the weight proportion of oxylycorine is 1:5-5:1.
More preferably, in aforementioned pharmaceutical compositions, galantamine: the weight proportion of oxylycorine is 5:1.
Present invention also offers above-mentioned composition and prepare the purposes treated and/or prevented in the medicine of Alzheimer.
Present invention also offers above-mentioned composition and prepare the purposes in acetylcholine esterase inhibition activity.
Said medicine can be prepared into various dosage form by adding pharmaceutically acceptable carrier, and described dosage form can be tablet, lozenge, pill, capsule, powder, granule, oral liquid, suspension, Emulsion or injection, suppository, patch.
Another object of the present invention there is provided a kind of method to the potentiation of galantamine acetylcholine esterase inhibition activity, and the method is by oxylycorine and galantamine drug combination.
Accompanying drawing explanation
Fig. 1 is galantamine and oxylycorine concentration ratio when being 5:1 pharmaceutical composition depression effect-drug combination exponential curve.
Fig. 2 is galantamine and oxylycorine concentration ratio when being 2:1 pharmaceutical composition depression effect-drug combination exponential curve.
Fig. 3 is galantamine and oxylycorine concentration ratio when being 1:1 pharmaceutical composition depression effect-drug combination exponential curve.
Fig. 4 is galantamine and oxylycorine concentration ratio when being 1:2 pharmaceutical composition depression effect-drug combination exponential curve.
Fig. 5 is galantamine and oxylycorine concentration ratio when being 1:5 pharmaceutical composition depression effect-drug combination exponential curve.
Detailed description of the invention
Be further elaborated below in conjunction with the synergism of embodiment to galantamine and oxylycorine, in following data, Gal refers to galantamine, and Ung refers to oxylycorine.
Embodiment 1
The Ellman method of improvement evaluates the activity of galantamine and oxylycorine acetylcholine esterase inhibition
Instrument and material
The multi-functional microplate reader of instrument: BioTekSynergy2 (BioTek company of the U.S.), high speed low temperature centrifugal machine (SovallEvolutionRC, Kendro company), turbula shaker (Vortex-Genie2, ScientificIndustries company of the U.S.).
Reagent: acetylcholinesterase (AchE, from electric eel, enzyme activity: 687U/mg albumen, Mr280kDa), acetyl cholinesterase iodide (Acetylthiocholineiodide, ATCh, AchE substrate, Mr289.2); 5,5 '-two sulfur-Lian (2-nitrobenzoic acid) (5,5-dithiobis (2-nitro) benzoicacid, DTNB) all purchased from Sigma – Aldrich(St.Louis, MO, USA); Ultra-pure water (Millipore, the U.S.), Tris Tris-base(Biosharp, Korea S), other reagent are all analytical pure.
The preparation of solution
Tris/HCl buffer: 20mMTris buffer is 7.5 containing 100mMNaCl, PH; AChE solution: get
aChE storing solution (1000U/mL) is used
buffer is diluted to 2U/mLAChE solution, and be placed in the preservation of 4 DEG C, refrigerator, the used time now joins, in order to avoid the loss of activity of enzyme; DTNB solution: get DTNB appropriate, be configured to 1mMDTNB solution with buffer solution; ATCh solution: get ATCh appropriate, be configured to 20mMATCh solution with buffer solution.
The preparation of sample
Precision takes standard substance galanthamine hydrobromide 0.12mg, is dissolved in 1mlTris/HCl buffer (containing 2%CH
3oH, v/v), obtain mother solution.Diluted by different multiples by mother solution: be respectively 1X, 5X, 10X, 20X, 40X, 80X, 160X, the concentration being converted into galantamine is 93.62,18.72,9.36,4.68,2.34,1.17,0.585, altogether 7 Concentraton gradient, and unit is μ g/ml.Same method, precision takes standard substance oxylycorine 0.1mg, is dissolved in 1mlTris/HCl buffer (containing 2%CH
3oH, v/v), obtain mother solution.Diluted by different multiples by mother solution: be respectively 1X, 20X, 100X, 500X, 1000X, 5000X, concentration is 100,5,1,0.2,0.1,0.02, altogether 6 Concentraton gradient, and unit is μ g/ml.Tris/HCl buffer is (containing 2%CH
3oH, v/v) be blank sample solution (negative control).
The galantamine of different proportion and the preparation of oxylycorine mixed solution: galantamine and oxylycorine are mixed with the mixed solution that concentration ratio is 1:5,1:2,1:1,2:1,5:1, dilute according to different multiples respectively: 1X, 5X, 10X, 50X, 100X, 200X, 500X.Take concentration ratio as 1:5 for example illustrates, galantamine and oxylycorine mother solution all being diluted respectively after namely converting is 80 μ g/ml, and galantamine is got
, oxylycorine is got
, mixing, is mother solution, and according to different multiples dilution, concentration is 80,16,8,1.6,0.8,0.4,0.16, and unit is μ g/ml.
Experimental technique
Acetyl cholinesterase iodide is the substrate of enzymatic reaction, and DTNB is developer.During active testing, 10 μ LTris/HCl buffer are added (containing 20mMTris in 96 orifice plates, pH7.5), 80 μ LDTNB(1mM), 4 μ L sample solutions, 4 μ LAChE solution (0.008U), after at room temperature hatching 10min, the acetyl cholinesterase iodide (20mM) adding 2 μ L starts enzymatic reaction, records absorbance at once under 412nm every 15 seconds, continuously record 20 minutes (multi-functional microplate reader of Synergy2, Biotek, USA).The solvent of all samples is that Tris/HCl buffer is (containing 2%CH
3oH, v/v), each sample replication 3 times, each 1 multiple hole.The same aforesaid operations of blank sample solution, obtains blank.Draw curve according to time and absorption value, choose linear point and draw reaction rate equation (R
2>0.99), wherein slope is reaction rate, and the AchE suppression ratio (Inhibitionratio) of sample solution uses following formulae discovery:
Inhibitionratio=(1-V/V
0)×100%
Wherein, V
0for blank control sample reaction rate, V is testing sample solution reaction rate.
Table 1,2 be respectively galantamine and oxylycorine individually dosed time suppression situation to AchE, find the increase along with concentration, suppression ratio presents concentration dependent, wherein the IC of galantamine
50be about 0.158ug/ml, the IC of oxylycorine
50be about 0.077ug/ml.
Table 3,4,5 is respectively galantamine and oxylycorine by suppression situation when 1:5 and 1:2,1:1 and 2:1 and 5:1 compatible combination, and as can be seen from wherein, along with the increase of compatibility concentration, its suppression ratio is concentration dependent.
The individually dosed IC of table 1 galantamine
50
The individually dosed IC of table 2 oxylycorine
50
Table 3 galantamine and oxylycorine press suppression situation during 1:5 and 1:2 compatible combination
Table 4 galantamine and oxylycorine press suppression situation during 1:1 and 2:1 compatible combination
Table 5 galantamine and oxylycorine press suppression situation during 5:1 compatible combination
Embodiment 2
Galantamine and oxylycorine administering drug combinations effect analysis
With Median-effectPrinciple(median-effect principle) for evaluating basis, Combination index curve (Fa-C curve) under dose-effect curve and different effect is drawn by application CombiDrug statistical software, from the relation chart of two medicine Combination indexes (see table 1,2,3,4,5 and Fig. 1,2,3,4,5) be collaborative between quantitative assessment two medicine, antagonism or the relation of addition.Concrete steps are as follows:
Drug effect benefit and suppression ratio (fa)=1-(testing sample solution reaction rate/blank control sample reaction rate) according in efficacious prescriptions formula fa/fu=(D/Dm)
m, take the logarithm logfa/fu=mlogD-mlogDm on both sides, if a=-mlogDm, b=m, x=logD, y=logfa/fu, in substitution, efficacious prescriptions formula obtains y=bx-a; Wherein fa is drug effect effect, and fu=1-fa, D are drug level, and m is slope, and Dm is middle effect concentration, the drug level namely during 50% effect.According to above-mentioned formula, calculate two kinds of prescriptions with and share time respective middle effect concentration Dm (logDm=-a/m), then calculate alone and two medicines share time when various effect required drug level [D=Dm (fa/fu)
1/m], the Combination index [CI=D when various effect when two medicines share can be calculated
1/ DX
1+ D
2/ DX
2+ α (D
1d
2)/(DX
1dX
2), D
1, D
2be two medicines, two medicines desired concns separately when producing X effect when share, DX
1, DX
2be two medicines, two medicines concentration separately when producing X effect when being used alone].α=0 is two kinds of mutual repellency medicines, and α=1 is two kinds of interaction nonexclusion medicines.Because Gal with Ung mechanism of action is different, therefore get α=0 in this experiment.Work as CI<1, it is collaborative that two medicines share effect; CI=1, two medicines share effect and are added; CI>1, two medicines share effect antagonism.
By analysis, pharmaceutical composition of the present invention has good synergism, and concrete effect is in table 6.Evaluate the principle of effect according to Median-effectPrinciple, namely there is during CI index <0.1 very strong synergism (Verystrongsynergism); It is strong cooperative effect (Strongsynergism) when CI index is 0.1-0.3; CI index is that 0.3-0.7 has cooperative effect (Synergism); CI index is that 0.7-0.85 has moderate cooperative effect (Moderatesynergism); CI index has weak cooperative effect (Slightsynergism) when being 0.85-0.90 interval; CI index has nearly synergistic effect (Nearlyadditive) when being 0.90-1.10 interval; CI index >1.10 and above time there is antagonistic effect.Table 6 is visible, and galantamine and oxylycorine compatibility have cooperative effect; Especially have good cooperative effect when both concentration ratios are 5:1-5:1 compatibility, when both concentration ratios are 5:1, cooperative effect is the strongest.
When table 6 galantamine and oxylycorine compatibility, association index CI compares:
Claims (5)
1. be used for the treatment of and/or prevent a pharmaceutical composition for Alzheimer, it is characterized in that: active component is galantamine: oxylycorine, weight proportion is 5:1.
2. the compositions of claim 1 is preparing the purposes treated and/or prevented in the medicine of Alzheimer.
3. the compositions of claim 1 is preparing the purposes in acetylcholine esterase inhibition activity.
4. be used for the treatment of and/or prevent a medicament for Alzheimer, it is characterized in that: the compositions of claim 1 is prepared into various dosage form by adding pharmaceutically acceptable carrier.
5. medicament according to claim 4, is characterized in that: described dosage form is tablet, lozenge, pill, capsule, powder, granule, oral liquid, suspension, Emulsion or injection, suppository, patch.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101703482A (en) * | 2009-11-20 | 2010-05-12 | 济南大学 | Galanthamine long-acting release injectable microsphere composite and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101703482A (en) * | 2009-11-20 | 2010-05-12 | 济南大学 | Galanthamine long-acting release injectable microsphere composite and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Isolation of narciprimine from cyrtanthus contractus(Amaryllidaceae) and evaluation of its acetylcholinesterase inhibitory activity;Jerald j. nair;《journal of ethnopharmacology》;20110723;第137卷;1102-1106 * |
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