CN107095870B - A kind of compound medicament composition and application thereof with anti-lymphadenoma effect - Google Patents
A kind of compound medicament composition and application thereof with anti-lymphadenoma effect Download PDFInfo
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- VABYUUZNAVQNPG-UHFFFAOYSA-N Piperlongumine Natural products COC1=C(OC)C(OC)=CC(C=CC(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-UHFFFAOYSA-N 0.000 claims abstract description 39
- VABYUUZNAVQNPG-BQYQJAHWSA-N Piplartine Chemical compound COC1=C(OC)C(OC)=CC(\C=C\C(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-BQYQJAHWSA-N 0.000 claims abstract description 39
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- GGOVLAUMYLPYAZ-UHFFFAOYSA-N puberulumine Natural products COC1=C(OC)C(OC)=CC(C=CC(=O)N2CCCCC2)=C1 GGOVLAUMYLPYAZ-UHFFFAOYSA-N 0.000 description 1
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPPWMWCITPGPKK-UHFFFAOYSA-M sodium;1-hydroxy-3-oxododecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCC(=O)CC(O)S([O-])(=O)=O HPPWMWCITPGPKK-UHFFFAOYSA-M 0.000 description 1
- UAJTZZNRJCKXJN-UHFFFAOYSA-M sodium;2-dodecoxy-2-oxoethanesulfonate Chemical compound [Na+].CCCCCCCCCCCCOC(=O)CS([O-])(=O)=O UAJTZZNRJCKXJN-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/121—Ketones acyclic
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to natural medicine fields, disclose a kind of compound medicament composition and application thereof with anti-lymphadenoma effect containing piperlongumine and decanoy acetaldehyde.The active constituent of the compound medicament composition is made of the piperlongumine that molar ratio is 1:1~1:20 and decanoy acetaldehyde.The two drug combination has the purposes of stronger synergistic treatment lymthoma.
Description
Technical field
It is the invention belongs to natural medicine field, in particular to a kind of that there is anti-lymphadenoma containing piperlongumine and decanoy acetaldehyde
Compound medicament composition of effect and application thereof.
Background technique
Cancer is to seriously endanger a big chronic disease of human health, has become the second largest killer for being only second to cardiovascular disease.
Since the 21th century, due to the quick process of modern industrialization, the factors such as environmental pollution cause lymphocyte system to be exempted from
Epidemic disease is destroyed and lymthoma disease incidence is caused to show an increasing trend year by year, and makes we are aware that developing one kind can be used in preventing and treating
The drug system of lymthoma seems very urgent.
Piperlongumine (piperlongumine, PLM) is also known as piplartine (piplOMAine), belongs to alkaloids chemical combination
Object.Initial separation is from the root of Piperaceae plant fructus piperis longi Piper longum Linn., in long handle pepper P.sylvaticum
Roxb. and tumor dash forward pepper P.tuberculatumJacq. etc. root in also have and get.As that studies piperlongumine gos deep into,
It was found that piperlongumine has a variety of pharmacotoxicological effects, wherein there is significant cytotoxicity to tumour cell, it is adjusted high in fat
The blood lipid metabolism of mass formed by blood stasis rat, and show many pharmacological activity such as anti-platelet aggregation, analgesia, antimycotic.Current research table
It is bright it there is the cytotoxicity of specificity to kinds of tumor cells, and it is very small to the toxicity of normal cell
(Nature.2011Jul 13；475(7355):231-4.；ACS Chem Biol.2013May 17；8 (5): 923-9.), because
This piperlongumine is a kind of traditional Chinese medicine monomer that can selectively kill tumour of great potential.
Cordate houttuynia is on the fresh herb or dry ground of saururaceae plant houttuynia cordata Houttuynia cordata Thunb.
Part, first recorded in " Mingyi Bielu ", history tree document is all on the books thereafter " is good at, to control wanting for lung harmony with removing summer-heat lung heat
Medicine ".Cordate houttuynia acrid flavour, it is slightly cold, it is distributed in lung channel, have the function of clearing heat and detoxicating, the carbuncle that disappears apocenosis, inducing diuresis for treating strangurtia, is mainly used for pulmonary abscess
Pyemesis, phlegm heat panting cough etc..Modern study proves that cordate houttuynia has preferable anti-inflammatory activity, clinically for treating respiratory tract sense
Dye, such as conjunctivitis, keratitis, acute and chronic rhinitis, nasosinusitis diseases associated with inflammation.As traditional heat-clearing and detoxifying herb, fish raw meat
Grass is because of its significant anti-inflammatory, refrigeration function, in the Ministry of Public Health in 2003 from the 8 kinds of anti-SARS Chinese medicines recommended in up to ten thousand kinds of Chinese medicines,
Houttuynia cordata injection comes the 2nd.Decanoy acetaldehyde is effective component decanoyl acetaldehyde in Herba Houttuyniae volatile oil
(decanoylacetaldehyde, DLH also known as decanoyl acetaldehyde, sodium hydrogensulfite addition product are known as sodium houttuyfonate or fish
The plain sodium of raw meat grass), modern pharmacological research discovery cordate houttuynia is known as antibacterial, anti-inflammatory effect, and there is not been reported for the research of its anticancer.
Early-stage study at us finds that DLH has good anticarcinogenic effect, especially combination PLM.These give for compound DLH and PLM
Medicine treatment malignant tumour lymthoma provides completely new chance.The superior anticancer therapeutic of decanoy acetaldehyde is lived with having high anti-cancer
Property the natural drug combination and cooperation treatment malignant tumours such as lymthoma, be one and merit attention and very promising antitumor multiple
Composite medicine direction.It combines decanoy acetaldehyde and natural drug piperlongumine is used for the preventive and therapeutic action of malignant tumour lymthoma still
Have no pertinent literature report almost without.
Summary of the invention
In order to overcome shortcoming and defect existing in the prior art, the primary purpose of the present invention is that providing a kind of with anti-
The compound medicament composition of function of tumor；The active constituent of the compound medicament composition is by piperlongumine and decanoy acetaldehyde group
At.
Another object of the present invention is to provide a kind of purposes of above-mentioned compound medicament composition with antitumor action；
Pharmacological testing proves that the compound medicament composition has collaboration anti-lymphadenoma effect.
The purpose of the invention is achieved by the following technical solution:
A kind of compound medicament composition with anti-lymphadenoma effect, the active constituent of the compound medicament composition are by Bi
Roots of grass amide and decanoy acetaldehyde composition.
Preferably, the molar ratio of the piperlongumine and decanoy acetaldehyde is 1:1~1:20.
More preferred, the molar ratio of the piperlongumine and decanoy acetaldehyde is 1:1~1:10.
The compound medicament composition also contains pharmaceutically acceptable carrier.
A kind of above-mentioned compound medicament composition with anti-lymphadenoma effect is preparing the purposes in anti-lymphadenoma drug.
The anti-lymphadenoma drug can be used for the treatment of the lymthoma of mammal including people.
The present invention have the advantages that compared with prior art as follows protrude and the utility model has the advantages that
Inventor has found in piperlongumine (PLM) and the active research of decanoy acetaldehyde (DLH) compatibility pharmacology, by fish raw meat
Careless element and piperlongumine combination medicine-feeding, the especially association with fine inhibiting tumor cell when the two molar ratio is 1:1-1:20 compatibility
Same-action.Inventor is respectively that model carries out external DLHT screening to Daudi, Raji and BC-3, finds it with very strong anti-
Proliferation activity and be in good timeliness and dose-effect relationship, in conjunction with classics be administered in combination analysis principle (Median-effect
Principle it) and statisticallys analyze, the results showed that it has synergistic effect, and collaboration effect especially can be obviously generated in fa < 0.5
It should inhibit three kinds of cancer cell multiplications, this illustrates that piperlongumine (PLM) and decanoy acetaldehyde (DLH) composition can be in low dosage compatibilities
The biological effect of the mono- medicine high dose of DLH or PLM is generated, generates, has good so as to substantially reduce the toxic side effect of drug
Good clinical application development prospect.Meanwhile etc. effects dose evaluation show combination drug to the toxicity of normal liver cell L-O2 still
Do not increase.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, and embodiments of the present invention are not limited thereto.
Embodiment 1:Daudi, Raji and BC-3 cell screening optimizes piperlongumine (PLM) and decanoy acetaldehyde (DLH) compound
Pharmaceutical composition.
The cell of logarithmic growth phase is inoculated with 3 × 10 respectively4A cells/well is on 96 orifice plates, after 6 hours to be grown, from
The heart abandons supernatant, and be then administered by following grouping: tumour cell sets not dosing group and dosing group, and wherein dosing group sets DLH and PLM is mono-
Medicine group, DLH and PLM drug combination different mol ratio example group, every group sets 4-6 multiple holes, cultivates 24 hours, abandons supernatant, is added 100
100 μ l DMSO (dimethyl sulfoxide) are added in DLHT (tetrazolium) serum-free medium of the μ l containing 5mg/ml culture 4 hours, place
In vibrating 10min on micro-oscillating instrument, then detection OD value at 570nm is placed in microplate reader.As a result according to following inhibiting rate formula
The inhibiting rate of growth of tumour cell in each case is calculated, concrete outcome is shown in Table 1.
Inhibiting rate=(1- dosing group OD value/control group OD value)
Table 1 be DLH and PLM individually and be administered in combination function cells 72 hours after various concentration IC50Inhibiting rate.
Inhibition situation when 1:1 and 1:20 compatibility combines in molar ratio by DLH and PLM.From wherein we can obtain with
The increase of compatibility concentration, inhibiting rate be in concentration dependent.Wherein we have found that with compatibility concentration increase, inhibiting rate
In concentration dependent.
The mono- medicine of table 1 PLM and DLH acts on 72 hours IC50(μg/mL)
Embodiment 2:DLH and PLM are administered in combination effect analysis
It is evaluation base with Median-effect Principle (median-effect principle or Chou-Talalay association index method)
Plinth, drawing the Combination index curve under dose-effect curve and different effect using CombiDrug statistical software, (fa-C is bent
Line), be between the effect shared from two medicines and two medicine of relationship quantitative assessment of Combination index cooperate with, antagonism or be added relationship.Tool
Steps are as follows for body:
(the test group OD570 value/tumour cell blank control group that is averaged is average for drug effect effect, that is, inhibiting rate (fa)=1-
OD570) the efficacious prescriptions formula fa/fu=(D/Dm) inm, both sides take logarithm logfa/fu=mlogD-mlogDm, if a=-
MlogDm, b=m, x=logD, y=logfa/fu, efficacious prescriptions formula obtains y=bx-a in substitution；Wherein fa is drug effect effect,
Fu=1-fa, D are drug concentration, and m is slope, and Dm is middle effect concentration, i.e. drug concentration when 50% effect.According to above-mentioned formula,
Respective middle effect concentration Dm (logDm=-a/m) when two kinds of anticarcinogens are applied alone and share is calculated, then calculates and is applied alone and two medicines
When sharing in various effects required drug concentration (D=Dm (fa/f u) 1/m), can calculate when two medicines share in various effects
When Combination index (when CI=D1/DX1+D2/DX2+ α (D1D2)/(DX1DX2), D1, D2 are that two medicines generate X effect when sharing
Two medicines respectively needed for concentration, DX1, DX2 are two medicines respective concentration when generating X effect when two medicines are used alone).α=0 is two kinds of phases
Mutual repellency drug, α=1 are two kinds of mutual nonexclusion drugs.Because DLH is different from piperlongumine mechanism of action, therefore this experiment
In take α=0.As CI < 1, two medicines share effect as collaboration；CI=1, two medicines share effect addition；CI > 1, it is short of money that two medicines share effect
It is anti-.
It is analyzed by software, compound medicament composition of the invention has good synergistic effect, and specific effect is shown in Table 2,
There is very strong synergistic effect when evaluating the principle of effect, i.e. CI index < 0.1 according to Median-effect Principle
(Very strong synergism)；CI index is 0.1-0.3 Shi Weiqiang synergistic effect (Strong synergism)；CI refers to
Number has synergistic effect (Synergism) for 0.3-0.7；CI index is 0.7-0.85 with moderate synergistic effect (Moderate
synergism)；There is weak synergistic effect (Slight synergism) when CI index is 0.85-0.90 section；CI index is
There is nearly synergistic effect (Nearly additive) when 0.90-1.10 section；There is antagonism effect when index > 1.10 CI or more
It answers.
Table 2 is as it can be seen that PLM and DLH compatibility has synergistic effect；Especially have when the two molar ratio is 1-1:20 compatibility
Good synergistic effect, when the two molar ratio is 1:10, synergistic effect is most strong.
2 compound action 72 hours association index CI of PLM with DLH difference compatibility of table compare
Embodiment 3: piece is made according to following prescription in piperlongumine (PLM) and decanoy acetaldehyde (DLH) compound medicament composition
Agent:
Prescription is as follows:
Preparation process is as follows:
Drug and auxiliary material are crossed into 80 meshes respectively, by piperlongumine and 48 grams of microcrystalline celluloses and 12 grams of sodium carboxymethyl starches
It is sufficiently mixed, 10% starch slurry softwood, the granulation of 18 meshes, it is dry at 60 DEG C, obtain particle 1.By decanoy acetaldehyde and 24 grams of crystallites
Cellulose, 15 grams of starch and 8 grams of sodium carboxymethyl starches are sufficiently mixed, 10% starch slurry softwood, the granulation of 18 meshes, are done at 60 DEG C
It is dry, obtain particle 2.By equal increments principle, particle 1 and particle 2 are sufficiently mixed, 16 mesh sieves, magnesium stearate is added, mixed
It is even, tabletting, slice weight 500mg.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (5)
1. a kind of compound medicament composition with anti-lymphadenoma effect, it is characterised in that: the activity of the compound medicament composition
Ingredient is made of piperlongumine and decanoy acetaldehyde.
2. a kind of compound medicament composition with anti-lymphadenoma effect according to claim 1, it is characterised in that: described
The molar ratio of piperlongumine and decanoy acetaldehyde is 1:1~1:20.
3. a kind of compound medicament composition with anti-lymphadenoma effect according to claim 1, it is characterised in that: described
The molar ratio of piperlongumine and decanoy acetaldehyde is 1:1~1:10.
4. a kind of compound medicament composition with anti-lymphadenoma effect according to claim 1, it is characterised in that: this is multiple
Recipe compositions also contain pharmaceutically acceptable carrier.
5. prepared by a kind of compound medicament composition with anti-lymphadenoma effect according to any one of claims 1 to 4
Purposes in anti-lymphadenoma drug.
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| CN109602744A (en) * | 2018-12-13 | 2019-04-12 | 中国人民解放军总医院 | Piperlongumine is preparing the application in antibacterial-anti-inflammatory drug |
| CN109620836B (en) * | 2018-12-24 | 2021-05-18 | 陕西科技大学 | Compound pharmaceutical composition with breast cancer resistance, application thereof and medicine based on composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002041828A2 (en) * | 2000-11-17 | 2002-05-30 | Dajun Yang | Houttuyninum compositions and methods for inhibiting the activity of erbb-2 based thereon |
| CN102125552A (en) * | 2010-01-20 | 2011-07-20 | 李绍路 | Use of piperlongumine derivatives in preparation of medicines for treating cancers and medicinal compositions thereof |
| CN102146054A (en) * | 2010-02-10 | 2011-08-10 | 新昌县来益科技开发有限公司 | Piperlongumine derivatives and medicinal composition and application to preparation of medicament for inhibiting tumor growth thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002041828A2 (en) * | 2000-11-17 | 2002-05-30 | Dajun Yang | Houttuyninum compositions and methods for inhibiting the activity of erbb-2 based thereon |
| CN102125552A (en) * | 2010-01-20 | 2011-07-20 | 李绍路 | Use of piperlongumine derivatives in preparation of medicines for treating cancers and medicinal compositions thereof |
| CN102146054A (en) * | 2010-02-10 | 2011-08-10 | 新昌县来益科技开发有限公司 | Piperlongumine derivatives and medicinal composition and application to preparation of medicament for inhibiting tumor growth thereof |
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