CN104586835B - The medical usage of andrographolide - Google Patents
The medical usage of andrographolide Download PDFInfo
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- CN104586835B CN104586835B CN201510052029.9A CN201510052029A CN104586835B CN 104586835 B CN104586835 B CN 104586835B CN 201510052029 A CN201510052029 A CN 201510052029A CN 104586835 B CN104586835 B CN 104586835B
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- Prior art keywords
- andrographolide
- paracetamol
- groups
- apap
- present
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 73
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 64
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 96
- 229960005489 paracetamol Drugs 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 30
- 230000036541 health Effects 0.000 claims abstract description 11
- 230000000202 analgesic effect Effects 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 18
- 231100000334 hepatotoxic Toxicity 0.000 claims description 8
- 230000003082 hepatotoxic effect Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- 241000699666 Mus <mouse, genus> Species 0.000 description 27
- 241001465754 Metazoa Species 0.000 description 18
- 208000002193 Pain Diseases 0.000 description 17
- 230000036407 pain Effects 0.000 description 17
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- 239000000651 prodrug Substances 0.000 description 14
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
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- 241001529936 Murinae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
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- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to medicine, the medical usage and its pharmaceutical composition of more particularly to a kind of andrographolide.The andrographolide of the present invention can be used for preparing the medicine or health products to paracetamol Synergy and attenuation.
Description
Technical field
The present invention relates to Medicines and Health Product field, the medical usage and its drug regimen of more particularly to a kind of Herba Andrographitis
Thing.
Background technology
Pain is a kind of common clinical disease, brings considerable distress to patient, or even can influence quality of life.For treating
The medicine of pain is a lot, most commonly non-steroid anti-inflammatory drug.But such medicine can cause many adverse reactions, such as alimentary canal
Reaction, hepatotoxicity wind agitation, renal toxicity, cardiovascular risk etc..
Paracetamol is one kind in NSAIDs, belongs to phenyl amines.Because its antipyretic effect is strong, often
For having a headache, having a toothache, the chronic dull pain and cold, fever etc. such as courbature, cramp, arthralgia.But it is if heavy dose of or long
Phase uses, and can cause serious hepatotoxicity wind agitation, especially most common with hepatonecrosis.Because compound preparation of the country containing paracetamol is more
Up to twenty or thirty kind, such as SUXIAO GANMAO JIAONANG, Xiaoersuxiaoganmao Granules, sense health, Bufferin, QIANGLI YINQIAO PIAN, 999 cold drugs
Deng, and its non-prescribed medicine mass selling, using extensive, therefore the hepatic lesion as caused by paracetamol should cause the weight of height
Depending on.Find that hepatic lesion occurs for 30% patient to the analysiss of cases of 150 poisoning by paracetamol, general mortality rate 1%~
2%.Clinical examination is most commonly that transaminase is raised.Hepatic injury caused by paracetamol is always domestic and foreign scholars research
Focus.
Andrographolide is extraction in acanthaceous plant Herba Andrographitis Andrographispaniculata (Burm.f) Nees
Obtained diterpene ginkgolide.Modern pharmacological research shows, andrographolide have anti-inflammatory, antibacterial, it is antiviral, antitumor,
The effects such as immunological regulation, treatment cardiovascular and cerebrovascular disease, hepatic cholagogic.
The content of the invention
The purpose of the present invention aims to provide the new medical usage and its pharmaceutical composition of a kind of andrographolide.
Specifically, the first aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydration
The application of thing or prodrug in the analgesic activity for improving paracetamol, the application is not for the purpose for the treatment of.
The second aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Prepare the application in the medicine or health products for the analgesic activity for improving paracetamol.
The third aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
The application in the hepatotoxicity wind agitation of paracetamol is reduced, the application is not for the purpose for the treatment of.
The fourth aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Prepare the application in the hepatotoxic medicine or health products of reduction paracetamol.
The fifth aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Improve the analgesic activity of paracetamol and reduce the application in its hepatotoxicity wind agitation, the application is not for the purpose for the treatment of.
The sixth aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Prepare the analgesic activity for improving paracetamol and reduce the application in its hepatotoxic medicine or health products.
Present invention also offers a kind of analgesic composition, its andrographolide comprising therapeutically effective amount and to acetyl
Amino phenols, the weight ratio of the andrographolide and paracetamol is 13.5:1~13.5:3.
The details of various aspects of the present invention will be able to detailed description in subsequent chapters and sections.By hereafter and claim
Description, the features of the present invention, purpose and advantage will become apparent from.
Brief description of the drawings
Fig. 1 acetic acid writhing tests investigate influence of the andrographolide combination paracetamol to mouse writhing number of times,
Note：The * P compared with acetic acid model group<0.05,**P<0.01,***P<0.001；Compared with APAP groups#P<0.05；
Fig. 2 each group animal's livers HE is dyed,
Note：Multiplication factor 200 ×；
Fig. 3 each group animal blood serum ALT, AST levels.
Embodiment
The appearance part of the present invention is had been surprisingly found that based on such a：By classical analgesic experiment method, (acetic acid is turned round
Body method and hot plate method) and Cancer pain models experimentally find both andrographolide and paracetamol combination after, punching
Lotus lactone can improve the analgesic activity of paracetamol；At the same time, the present inventor is also surprising that：Andrographolide
ALT, AST caused by paracetamol can also be reduced to raise.The studies above result is proved：Andrographolide is except that can increase
The analgesia effect of strong paracetamol, moreover it is possible to the hepatotoxicity wind agitation of paracetamol is reduced, so as to play its medicine to greatest extent
With value.
And then, the first aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or
Application of the prodrug in the analgesic activity for improving paracetamol, the application is not for the purpose for the treatment of.
The second aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Prepare the application in the medicine or health products for the analgesic activity for improving paracetamol.
The third aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
The application in the hepatotoxicity wind agitation of paracetamol is reduced, the application is not for the purpose for the treatment of.
The fourth aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Prepare the application in the hepatotoxic medicine or health products of reduction paracetamol.
The fifth aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Improve the analgesic activity of paracetamol and reduce the application in its hepatotoxicity wind agitation, the application is not for the purpose for the treatment of.
The sixth aspect of the present invention there is provided andrographolide or its pharmaceutically acceptable salt, hydrate or prodrug exist
Prepare the analgesic activity for improving paracetamol and reduce the application in its hepatotoxic medicine or health products.
Present invention also offers a kind of analgesic composition, its andrographolide comprising therapeutically effective amount and to acetyl
Amino phenols, the weight ratio of the andrographolide and paracetamol is 13.5:1~13.5:3.
As it is known to those skilled in the art, the andrographolide (Andrographolide, Andro) of the present invention has
Following general structure：
Molecular formula：C20H30O5Molecular weight：350.44
Present invention additionally comprises corresponding all pharmaceutically acceptable salt, hydrate or the prodrug of above-claimed cpd.This
A little salt can be by part (for example, amido) positively charged in compound with having the negatively charged (for example, trifluoro of opposite-sign
Acetic acid) formed；Or by part (for example, carboxyl) negatively charged in compound and positive charge (for example, sodium, potassium, calcium, magnesium) shape
Into.Compound can be containing a nonaromatic double bond, with one or more asymmetric centers.So, these compounds
It can be mixed as racemic mixture, single enantiomter, single diastereoisomer, diastereoisomer
Thing, cis or trans isomers are present.All these isomers are all expected.Described " prodrug of andrographolide " leads to
Often refer to a kind of material, after being applied with appropriate method, can be metabolized or be chemically reacted in subject's body and be transformed into and wear
Heart lotus lactone or its salt.
The andrographolide of the present invention can be separated from the herb or leaf of acanthaceous plant Herba Andrographitis to be prepared；Or it is logical
Commercial sources purchase acquisition is crossed, its purity meets medicinal standard；Or marketable material is utilized, by traditional in the prior art
The synthesis of compound synthesis method is obtained.One of ordinary skill in the art can synthesize the change of the present invention according to existing known technology
Compound.The compound of synthesis can be further purified with further by modes such as column chromatography, high performance liquid chromatography or crystallizations.
It is helpful to synthesis application compound to synthesize chemical improvement, protection functional group methodology (protection is deprotected)
, and it is well known in the prior art technology, such as R.Larock, Comprehensive Organic
Transformations,VCH Publishers(1989)；T.W.Greene and P.G.M.Wuts,Protective
Groups in Organic Synthesis,3rdEd.,John Wiley and Sons(1999)；L.Fieser and
M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and
Sons(1994)；and L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,
There is disclosure in John Wiley and Sons (1995).
Exemplified by the andrographolide of the present invention is made into medicine.The present invention andrographolide can be used alone or with
The form of pharmaceutical composition is used.Pharmaceutical composition includes the andrographolide of the invention and pharmaceutically acceptable load as active component
Body.It is preferred that the present invention pharmaceutical composition contain 0.1~99.9% percentage by weight as the of the invention of active component
Andrographolide." pharmaceutical acceptable carrier " will not destroy the pharmaceutical active of the andrographolide of the present invention, while its effective dose, i.e.,
Consumption when can play pharmaceutical carrier effect is nontoxic to human body.
Described pharmaceutical acceptable carrier includes but is not limited to：Soft phosphatide, aluminum stearate, aluminum oxide, ion exchange material, self-emulsifying
Drug delivery system, tween or other surfaces activator, haemocyanin, buffer substance for example phosphate, amion acetic acid, sorbic acid,
Water, salt, electrolyte such as sulfate protamine, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, magnesium silicate, saturated fatty acid
Partial glyceride mixtures etc..
Other conventional excipient substance such as adhesives (such as microcrystalline cellulose), filler (such as starch, glucose, anhydrous lactitol
Sugar and lactose bead), disintegrant (such as cross-linked pvp, crosslinked carboxymethyl fecula sodium, Ac-Di-Sol, low-substituted hydroxypropyl
Base cellulose), lubricant (such as magnesium stearate) and sorbefacient, absorption carrier, flavouring agent, sweetener, excipient, dilution
Agent, wetting agent etc..
One of ordinary skill in the art should be known how by the ordinary skill in the art, according to weight disclosed by the invention
Than the andrographolide and paracetamol of the present invention being mixed, prepare the present invention has synergic antalgic effect
Low hepatotoxic pharmaceutical composition.
The andrographolide and its pharmaceutical composition of the present invention can be prepared by this area conventional method and can pass through intestines
Road or non-bowel or topical routes.Oral formulations include capsule, tablet, oral liquid, granule, pill, powder, pellet
Agent, paste etc.；Non-intestinal drug delivery agent is including parenteral solution etc.；Local administration preparation includes creme, patch, ointment, spray
Deng.Preferably oral formulations.
The andrographolide of the present invention and the method for administration of its pharmaceutical composition can for it is oral, sublingual, through muscle or
Subcutaneously, vein, urethra, vagina etc..
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.
Unless otherwise defined, all specialties used in text known to scientific words and one skilled in the art with anticipating
Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Wen Zhong
Described preferable implementation only presents a demonstration with material to be used.
The features described above that the present invention is mentioned, or the feature that embodiment is mentioned can be in any combination.Patent specification is taken off
All features shown can be used in combination with any combinations thing form, and each feature disclosed in specification can provide phase with any
The alternative characteristics substitution of same, impartial or similar purpose.Therefore except there is special instruction, disclosed feature is only impartial or similar
The general example of feature.
The andrographolide of embodiment one is combined the analgesic activity of paracetamol
The present invention using acetic acid twisting and hot-plate investigate andrographolide, paracetamol and andrographolide and
Paracetamol is combined the analgesic activity to mouse.
1 experiment material
1.1 animal subjects
ICR mouse, ♀ (acetic acid writhing test) or ♂ (hot plate method), 18~22g of body weight, purchased from Shanghai Si Laike experimental animals
Co., Ltd, animal quality certification number：SCXK (Shanghai 2007-0005).Mouse feeder temperature (22 ± 1) DEG C, relative humidity (65
± 10) %, the daily 12h of lighting hours.
1.2 test medicines and its preparation
Paracetamol (APAP)：Paracetamol powder 108mg accurately is weighed, (65 DEG C) lifes of 18ml heat are dissolved in
Manage in salt solution, mix, be made into 6mg/ml solution for mouse stomach.
Andrographolide (Andro)：Accurately weigh andrographolide powder 15mg to be dissolved in 0.75mlDMSO, be made into
20mg/ml mother liquor, takes 0.5ml mother liquors plus 4.5ml physiological saline, is made into 2mg/ml solution for 20mg/kg groups.Separately take
0.15ml mother liquors add 2.85ml physiological saline, are made into 1mg/ml solution for 10mg/kg groups.Administering mode：Inject in abdominal cavity.
Aspirin (AS)：Aspirin enteric coated tablet (100mg aspirin/piece) 2 is taken, mortar is fully crushed, plus
6.67ml CMC-Na solution is fully suspended, and is made into 30mg/ml suspensions for mouse stomach.
2 experimental methods
2.1 acetic acid writhing tests
2.1.1 animal packet and administration
Mouse is grouped at random by body weight, packet and drug-treated situation such as table 1：
The acetic acid writhing test mice group of table 1 and drug-treated situation
2.1.2 handle
Using the paracetamol dosage 60mg/kg with smaller analgesic activity as andrographolide, combination is to acetyl ammonia
The dosage of base phenol analgesic activities research, using 300mg/kg aspirin as positive control, investigates andrographolide combination to acetyl
Influence of the amino phenols to mouse writhing number of times.
0min gives relative medicine, and 55min pneumoretroperitoneums inject 0.75% acetic acid, and dosage is 0.1ml/10g, observation
The writhing number of times of mouse in 15min.Writhing show as belly indent, abdomen antetheca be close to that cage bottom, buttocks be twisted/raised or trunk after
Limb is upheld.
2.2 hot plate methods
2.2.1 it is grouped
Mouse is grouped at random by body weight, situation such as table 2 below is grouped：
The animal packet of table 2 and administrations table
2.2.2 animal pre-sifted
Mouse is singly only successively placed on 55 DEG C of hot-plate instrument, observation from mouse metapedes touch hot plate to occur adding metapedes or
Time required for jump is used as its pain threshold.Mouse of the screening pain threshold more than 5s and less than 30s is standby in advance.
2.2.3 handle
The agent of paracetamol analgesic activities research is combined using 135mg/kg paracetamol as andrographolide
Amount, using 300mg/kg aspirin as positive control, investigates andrographolide and is combined paracetamol to mouse pain threshold
Influence.
The measure of pain threshold before administration：Survey 2 times, surveyed once every 5min.60s still nonresponders, are calculated by 60s.Give phase
30min after medicine, 60min are answered, 120min respectively surveys a pain threshold, and calculate the threshold of pain and improve percentage.Improve percentage in the threshold of pain
Pain threshold before=(pain threshold before pain threshold-administration after administration)/administration.It is effective more than or equal to 50% that percentage is improved in the threshold of pain.
2.3 andrographolides are combined influence of the paracetamol to cancer pain
2.3.1 material
ICR Mouse Weights (18 scholar 2) g, female, purchased from Shanghai Slac Experimental Animal Co., Ltd., animal is qualified
Card number：SCXK (Shanghai 2007-0005).The strain of mice lung cancer (Lwis) knurl is carried by Chinese Academy of Medical Sciences's Experimental Animal Center breeding field
For.
2.3.2 mouse bone cancer pain model is set up in modeling
After Animal Anesthesia (etherization), lie on the back, left rear limb cropping, with skin at 75% alcohol disinfecting femur and shin bone
Skin, a skin incision for being about 0.5-1cm is cut at knee joint along rectus femoris tendon direction, carefully, exposure kneecap, first with one
The secondary sterile 1mL syringe needles of property are punctured along femur long axis direction in kneecap and punched, and are then changed 10uL syringes and are entered femur
Ossis, is slowly injected into 10u murine lung cancer cells containing Lwis (3 × 105L-) to femur.Injection seals pin hole after finishing with bone wax.
Aseptic cotton carrier dips in physiological saline cleaning wound, skin suture.The isometric physiological saline of kneecap section injection on the left of naive animals,
Remaining operation is with other each groups.
2.3.3 it is grouped and is administered, such as table 3 below：
The experimental animal of table 3 is grouped and administrations table
2.3.4 pain behavior measure
Pain behavior measure is carried out before modeling each group medication in the 10th day and after each group medication in the 14th day respectively, treatment group, mould
Type group and blank group are in 5h after last dose, and control group measures pain behavior in 30min after administration with mechanical stimulus method.Use mouse
The paw withdrawal that vola is stimulated 2g von Frey fibers reacts percentage to reflect Mechanical allodynia.
Specific method：2g Von Frey fibers stimulate mid-plantar on the left of mouse to continue 5-6s, and observation mouse paw withdrawal is anti-
Should.Every animal experiment 5 times, 2min is at least spaced between 2 experiments.The paw withdrawal reaction hundred that animal is stimulated Von Frey fibers
Point rate is：(paw withdrawal number of times+5) × l00%.
3 experimental results
3.1 acetic acid writhing test results are as shown in Figure 1
Compared with acetic acid model group, APAP groups, APAP+Andro10mg/kg groups, APAP+Andro 20mg/kg groups, APAP
+ Andro 30mg/kg groups, Andro10mg/kg groups, Andro20mg/kg groups, Andro 30mg/kg and AS group can significantly subtract
Mouse writhing number of times caused by few acetic acid；Compared with APAP groups, the writhing number of times of APAP+Andro10mg/kg group mouse significantly subtracts
It is few, and the statistically significant (#P of difference<0.05).This explanation is combined after Paracetamol to andrographolide, can be improved
The analgesic activities of paracetamol.
3.2 hot plate method results are as shown in table 4
The hot plate method of table 4 investigates influence of the andrographolide combination paracetamol to mouse pain threshold
Note：Compared with control#P<0.05,##p<0.01。
As shown in table 4,0.5h, APAP groups, APAP+Andro10 groups, APAP+Andro20 groups, APAP+ upon administration
Andro30 groups and AS groups have analgesic activity (threshold of pain increase rate>50%).Compared with control groups, APAP groups, APAP+
There were significant differences for Andro10 groups and AS groups.In addition, 30 groups of threshold of pains than APAP groups of APAP+Andro10 groups and APAP+Andro
Improve percentage high, but indifference between group；1h, APAP+Andro10 groups, APAP+Andro20, APAP+Andro30 upon administration
Group and AS groups have analgesic activity (threshold of pain increase rate>50%), and with control groups compared, there were significant differences.With APAP groups
Compare, the threshold of pain increase rate ratio APAP groups of 30 groups of APAP+Andro10 groups, APAP+Andro20 and APAP+Andro are high, but nothing
Statistical significance；2h upon administration, in addition to APAP group analgesic activities, remaining 7 groups have analgesic activity.And with control group phases
Than in addition to APAP groups are without significant difference, remaining 7 groups there were significant differences.Compared with APAP groups, APAP+Andro10 groups, APAP+
Andro20 groups and tri- groups of APAP+Andro30 threshold of pain increase rate are improved, but no statistical significance.
Andrographolide is combined paracetamol it can be seen from upper table result, has upon administration during 1h and 2h aobvious
The analgesic activity of work, and compared with APAP groups, percentage is improved in the threshold of pain certain potential rise.Illustrate that andrographolide may
There is certain synergistic effect to the analgesic activities of paracetamol.
The influence of 3.3 pairs of cancer pain mouse pain behaviors
The paw withdrawal that allodynia reaction is stimulated 2gVon Frey fibers with mouse reacts to measure Mechanical hyperalgesia.
It the results are shown in Table 5 and table 6.
Paw withdrawal reacts percentage before the modeling of table 5 each group medication in the 10th day
Note：Compared * P with blank group<0.01
Paw withdrawal reacts percentage after the modeling of table 6 each group medication in the 14th day
Note：Compared #P with model group<0.05,*P<0.01, with APAP groups than $ P<0.05.
Table 5 illustrates before modeling each group medication in the 10th day that model group, control group and treatment group's paw withdrawal react percentage compared with blank
Group increases (P<0.01), prompting mouse produces Mechanical allodynia behavior.
Modeling the 14th day as can be seen from Table 6, treatment group's paw withdrawal reaction percentage is reduced, less than control group and close to blank
Group, with model group comparing difference significantly (P<0.05 or P<0.0l), illustrate that medicine generates analgesic activity.And APAP+Andro
Group compares P with APAP groups<0.05, illustrate that andrographolide combination paracetamol can strengthen the analgesia of paracetamol
Effect, serves the effect of Synergistic.
The andrographolide of embodiment two mitigates the hepatotoxic research of paracetamol
After it specify that andrographolide can strengthen the analgesic activity of paracetamol, the present invention is further investigated
Andrographolide is on the hepatotoxic influence of paracetamol.
2.1 experiment materials
2.1.1 animal C57BL/6 mouse, ♂, 18~22g of body weight are public purchased from Shanghai Si Laike experimental animals Limited Liability
Department, animal credit number：SCXK (Shanghai) 2012-0002.Mouse feeder temperature (22 ± 1) DEG C, relative humidity (65 ± 10) % shines
Bright time daily 12h.Animal adaptability is fed 4 days, is freely taken food, is drunk water.
2.1.2 medicine andrographolide (SIGMA companies), paracetamol (SIGMA companies).
2.1.3 instrument ELIASA (company：Gene Company Limited, model：SynergyH4)
2.2 experimental methods
Animal is randomly divided into blank control group (CONT), APAP groups, APAP+Andro groups and Andro groups.Animal before experiment
Water 12h is can't help in fasting, in addition to CONT groups (giving isometric physiological saline), and remaining each group mouse 0.2ml/10g gavage is to acetyl
Amino phenols, 1h pneumoretroperitoneums injection andrographolide 0.1ml/10g gives 6h after paracetamol and puts to death animal, takes blood and liver
It is dirty.
2.3 experimental results
2.3.1 hepatic pathology section HE is dyed
As shown in Fig. 2 comparing with CONT groups, APAP groups occur around obvious hepatic injury, liver bleeding, central veins of liver
Hepatic tissue water sample becomes, a small number of lymphocytic infiltrations, and liver cell vacuole sample becomes, and karyon disappears.APAP+Andro group hepatic injuries are notable
Improve, damaged area is greatly reduced.Andro groups are unchanged.
2.3.2 Serum ALT, AST detections
As shown in figure 3, being compared with APAP groups, APAP+Andro groups ALT, AST are significantly reduced.Show that andrographolide can drop
ALT, AST rise caused by low paracetamol.
It these results suggest that：Andrographolide can mitigate hepatic injury caused by paracetamol, improve liver function.From
And mitigate the hepatotoxicity wind agitation of paracetamol.
Many aspects involved in the present invention have been explained as above.However, it should be understood that without departing from spirit of the invention
Under the premise of, those skilled in the art can carry out equivalent change and modification to it, and the change and modification equally fall into the application
Claim coverage.
Claims (3)
1. andrographolide or its pharmaceutically acceptable salt prepare the medicine for the analgesic activity for improving paracetamol or
Application in health products.
2. andrographolide or its pharmaceutically acceptable salt are preparing the analgesic activity for improving paracetamol and are reducing it
Application in hepatotoxic medicine or health products.
3. a kind of analgesic composition, it is characterised in that it includes the andrographolide and acetparaminosalol of therapeutically effective amount
Phenol, the weight ratio of the andrographolide and paracetamol is 13.5:1~13.5:3.
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| 穿心莲的药理作用及应用的研究进展;方桂友等;《福建畜牧兽医》;20071231;第29卷(第6期);22至25 * |
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