CN109568587A - Pharmaceutical combination preparations and radix aucklandiae, Radix Aucklandiae extract are preparing the application in chemotherapeutics Synergy and attenuation agent - Google Patents
Pharmaceutical combination preparations and radix aucklandiae, Radix Aucklandiae extract are preparing the application in chemotherapeutics Synergy and attenuation agent Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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Abstract
The present invention provides a kind of pharmaceutical combination preparations and radix aucklandiae, Radix Aucklandiae extract to prepare the application in chemotherapeutics Synergy and attenuation agent, is related to pharmaceutical technology field, pharmaceutical combination preparations provided by the invention, including chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract.The pharmaceutical combination preparations are compared with being used alone chemotherapeutics, on the basis of being had no significant effect to tumour inhibiting rate, the problems such as Anorectic effect Alcohol, the state of mind difference and weight loss that cancer patient easily occurs in chemotherapy process can be effectively improved.Meanwhile the pharmaceutical combination preparations can also effectively enhance the oxyradical removing power of body, to ensure that oxidation/peroxidating balance, reduction oxidative stress avoids body cell damage aggravation.Also, pharmaceutical combination preparations, additionally it is possible to improve stimulation and damage of the chemotherapeutics to alimentary canal mucous membrane, especially intestinal mucosa, have the function of protecting alimentary canal mucous membrane, reduce intestinal mucosa cells apoptosis caused by chemotherapeutics.
Description
Technical field
The present invention relates to pharmaceutical technology fields, exist more particularly, to a kind of pharmaceutical combination preparations and radix aucklandiae, Radix Aucklandiae extract
Prepare the application in chemotherapeutics Synergy and attenuation agent.
Background technique
Cancer is that often regulation is lost only due to body cell, disease caused by hyper-proliferative.The cell of hyper-proliferative claims
Cancer cell, cancer cell can often invade surrounding tissue, in addition can be transferred to through body-internal-circulation system and/or lymphatic system body other
Part.There are many types for cancer, and whether the severity of illness depends on cancer cell place position, grade malignancy and occur to turn
It moves.
Currently, malignant tumour seriously endangers people's health, and increase trend is presented in number of the infected.With new antitumor
The research and development and clinical application of drug, oneself has significant progress to chemotherapy of tumors, but the side reaction of chemotherapeutics is still that limitation chemotherapy is answered
Principal element.Therefore, some drugs are taken before radiotherapy or chemotherapy reaches normal tissue to protect normal tissue, becomes swollen
The supplementary means of tumor treatment.It is reported that taking Amifostine (thyol) when chemotherapy can reduce the renal toxicity of chemotherapeutics, blood poison
Property, neurotoxicity, ototoxicity, generally speaking tolerance is good；After Mei Sina (mesna) intravenous injection, drug is focused primarily upon
Kidney has in conjunction with the metabolite of renal toxicity with ring phosphorus phthalein amine (CTX) and different ring phosphorus phthalein amine (IFO), generates non-toxic compound,
It is discharged rapidly by urine.In addition, since mucosal tissue is also to divide faster tissue, and anti-tumor drug is to faster group of division
It knits with cytotoxicity, therefore gastrointestinal mucosal inflammation is also to limit one of the critical issue of tumor chemotherapeutic drug dosage,
After cancer patient takes chemotherapeutics, chemotherapeutics generally has significant destruction to alimentary canal Mucosal system.But day
Before there is no fully effective prevention and treatment to the drug or method of the chemotherapy mucosa injury caused and inflammation.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first purpose of this invention is to provide a kind of pharmaceutical combination preparations, existing in the prior art at least to alleviate
One of technical problem.
Second object of the present invention is to provide said medicine combination formulations answering in the product of preparation treatment tumour
With.
Third object of the present invention is that providing radix aucklandiae and/or Radix Aucklandiae extract is preparing chemotherapeutics Synergy and attenuation agent
In application, generally there is significant destroy to make alimentary canal Mucosal system to alleviate chemotherapeutics existing in the prior art
With, and there is no effective the technical issues of preventing and treating method.
The present invention provides a kind of pharmaceutical combination preparations, including chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract.
Further, the chemotherapeutics includes alkylating agent, antimetabolite, antitumor antibiotic, plant, steroids or miscellaneous
One of class is a variety of；
Preferably, the chemotherapeutics includes one or both of plant or miscellany；
Preferably, the chemotherapeutics includes one or both of Irinotecan or oxaliplatin.
Further, the Radix Aucklandiae extract includes one of terpene, alkaloid, anthraquinone or flavones or a variety of, preferably
For terpene；
Preferably, the Radix Aucklandiae extract includes costunolide, dihydro costene lactones, 12- melonia radix aucklandiae
Hydrocarbon lactone, dihydrocostulactone, dehydro-α-curcumene, Alpha-hydroxy dehydro-α-curcumene, beta-hydroxy dehydro-α-curcumene, white birch ester
Acid, betulinic acid methyl esters, river perfume (or spice) lactone, cynaropicrin, santamarine, α-ring costunolide, alantolactone, different building
Fragrant lactone, different dihydro costene ester, β-one of ring costunolide or radix aucklandiae terpene aldehyde or a variety of, preferably costunolide
And/or dehydro-α-curcumene.
Further, the weight ratio of the chemotherapeutics and the radix aucklandiae and/or Radix Aucklandiae extract is 5-75:10-
800；
Preferably, effective dosage of the pharmaceutical combination preparations is 10-875mg/kg/ days.
Further, the pharmaceutical combination preparations further include pharmaceutically acceptable auxiliary material.
Further, the pharmaceutical combination preparations include oral preparation or ejection preparation.
The present invention also provides application of the above-mentioned pharmaceutical combination preparations in the product of preparation treatment tumour.
In addition, the present invention also provides radix aucklandiaes and/or Radix Aucklandiae extract to prepare answering in chemotherapeutics Synergy and attenuation agent
With.
Further, the synergy includes improving immunity of organisms.
Further, the attenuation includes following (a)-(d):
(a) improve intestinal tract injury；
(b) intestinal mucosa is protected；
(c) injured intestinal mucosa is repaired；
(d) inhibit oxidative stress effect.
Pharmaceutical combination preparations provided by the invention, including chemotherapeutics and radix aucklandiae and/or radix aucklandiae extract
Object.The pharmaceutical combination preparations are compared with being used alone chemotherapeutics, on the basis of being had no significant effect to tumour inhibiting rate, Neng Gouyou
Effect improves the problems such as Anorectic effect Alcohol, state of mind difference and weight loss that cancer patient easily occurs in chemotherapy process.Meanwhile it should
The oxyradical that pharmaceutical combination preparations can also effectively enhance body removes power, thus ensure that oxidation/peroxidating balance,
Oxidative stress is reduced, body cell damage aggravation is avoided.Also, pharmaceutical combination preparations, additionally it is possible to improve chemotherapeutics
Stimulation and damage to alimentary canal mucous membrane, especially intestinal mucosa have the function of protecting alimentary canal mucous membrane, reduce chemotherapeutics and lead
The intestinal mucosa cells apoptosis of cause.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, is also possible to obtain other drawings based on these drawings.
Figure 1A is the practical growing state of tumour that each group dosage regimen that the embodiment of the present invention 1 provides treats colon cancer；
Figure 1B is the line for the mouse weight situation of change that each group dosage regimen that the embodiment of the present invention 1 provides treats colon cancer
Property result figure；
Fig. 2A is the duodenal HE coloration result that each group dosage regimen that the embodiment of the present invention 1 provides treats colon cancer
Figure；
Fig. 2 B is the HE coloration result figure for the jejunum that each group dosage regimen that the embodiment of the present invention 1 provides treats colon cancer；
Fig. 2 C is the HE coloration result figure for the ileum that each group dosage regimen that the embodiment of the present invention 1 provides treats colon cancer；
Fig. 2 D is the HE coloration result figure for the colon that each group dosage regimen that the embodiment of the present invention 1 provides treats colon cancer；
Fig. 3 A is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of SOD content in serum；
Fig. 3 B is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of MDA content in serum；
Fig. 3 C is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of NF-kB content in serum；
Fig. 3 D is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of iNOS content in serum；
Fig. 3 E is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of IL-6 content in serum；
Fig. 3 F is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of TNF-α content in serum；
Fig. 3 G is result figure of each group dosage regimen that provides of the embodiment of the present invention 1 to the influence of COX-2 content in serum；
Fig. 4 is the gross tumor volume growth pattern result that each group dosage regimen that the embodiment of the present invention 2 provides treats colon cancer
Figure；
Fig. 5 A is the duodenal HE coloration result that each group dosage regimen that the embodiment of the present invention 2 provides treats colon cancer
Figure；
Fig. 5 B is the HE coloration result figure for the jejunum that each group dosage regimen that the embodiment of the present invention 2 provides treats colon cancer；
Fig. 5 C is the HE coloration result figure for the ileum that each group dosage regimen that the embodiment of the present invention 2 provides treats colon cancer；
Fig. 5 D is the HE coloration result figure for the colon that each group dosage regimen that the embodiment of the present invention 2 provides treats colon cancer；
Fig. 6 A is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of SOD content in serum；
Fig. 6 B is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of MDA content in serum；
Fig. 6 C is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of NF-kB content in serum；
Fig. 6 D is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of iNOS content in serum；
Fig. 6 E is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of IL-6 content in serum；
Fig. 6 F is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of TNF-α content in serum；
Fig. 6 G is result figure of each group dosage regimen that provides of the embodiment of the present invention 2 to the influence of COX-2 content in serum.
Specific embodiment
Technical solution of the present invention is clearly and completely described below in conjunction with embodiment, it is clear that described reality
Applying example is a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
According to an aspect of the invention, there is provided a kind of pharmaceutical combination preparations, including chemotherapeutics and radix aucklandiae and/or wood
Fragrant extract.
Radix aucklandiae is domestic and international medicinal herbs most in use, and raw material is easy to get extensively, low in cost.There is the function of promoting qi circulation and relieving pain, warming middle-JIAO for easing the stomach
Effect, is usually used in the diseases such as chest and abdomen swelling and pain, vomiting, diarrhea, dysentery, tenesmus, dyspepsia.Radix Aucklandiae extract is the effective of radix aucklandiae
Ingredient.
Pharmaceutical combination preparations provided by the invention are compared with being used alone chemotherapeutics, to tumour inhibiting rate
On the basis of having no significant effect, Anorectic effect Alcohol, the spiritual shape that cancer patient easily occurs in chemotherapy process can be effectively improved
The problems such as state difference and weight loss.Meanwhile the pharmaceutical combination preparations can also effectively enhance the oxyradical removing power of body,
To ensure that oxidation/peroxidating balance, oxidative stress is reduced, avoids body cell damage aggravation.Also, the drug
Combination formulations, additionally it is possible to improve stimulation and damage of the chemotherapeutics to alimentary canal mucous membrane, especially intestinal mucosa, there is protection digestion
The effect of mucous membrane reduces intestinal mucosa cells apoptosis caused by chemotherapeutics.
In the various embodiments of the present invention, chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract can be in a preparations
In, such as pharmaceutical combination preparations of the invention can make comprising chemotherapeutics, radix aucklandiae and/or Radix Aucklandiae extract and pharmaceutically acceptable
Carrier composition (mixture).Chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract are also possible to individual preparation, for example,
They can be respectively commercially available preparation.
In one preferred embodiment, pharmaceutical combination preparations of the present invention be chemotherapeutics and radix aucklandiae and/or
The combination of Radix Aucklandiae extract.
In the various embodiments of the present invention, chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract can be connect with any
The sequence application received.In one embodiment, chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract can be applied simultaneously.Another
In one embodiment, chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract, which can also separate, to be applied, for example, in treatment with chemotherapy medicine
Radix aucklandiae and/or Radix Aucklandiae extract are applied before or after object.
In some preferred embodiments, the chemotherapeutics includes alkylating agent, antimetabolite, antitumor antibiotic, plant
One of species, steroids or miscellany are a variety of；
Preferably, the chemotherapeutics includes one or both of plant or miscellany；
Preferably, the chemotherapeutics includes one or both of Irinotecan or oxaliplatin.
Irinotecan belongs to the camptothecin in cell toxicant kind anti-cancer drugs object, is a kind of potent DNA topoisomerase I inhibition
Agent is cell cycle specific drugs, mainly acts on the S phase, can also cause the death of other cycling cells.Its adverse reaction is
Dosage correlation toxicity-late-onset diarrhea can lead to weak, de- water and rock-soil coupling, hypovolemia, shock, both affect
Curative effect of medication reduces the life quality or even threat to life of patient again.Irinotecan can also cause intestines structure and function
Change, lead to serious colonic damage, such as epithelial cell necrosis, the increase of Apoptosis, crypts hypoplasia and expansion.It is difficult to understand husky
Sharp platinum (Oxaliplatin) is the 3rd generation platinum class anticarcinogen, is the platinum-like compounds of diamino hexamethylene, i.e., with 1,2- diamino hexamethylene
Groups replace the amino of cis-platinum.Existing oxidative damage and the death that can induce enteric nervous member researches show that oxaliplatin, may be used also
Lead to serious colonic motor dysfunction.
One or both of Irinotecan or oxaliplatin and radix aucklandiae and/or Radix Aucklandiae extract are combined, it can be not
On the basis of influencing tumour inhibiting rate, the toxic side effect of Irinotecan or oxaliplatin is effectively reduced.
In some preferred embodiments, the Radix Aucklandiae extract includes one in terpene, alkaloid, anthraquinone or flavones
Kind is a variety of, preferably terpene；
Preferably, the Radix Aucklandiae extract includes costunolide, dihydro costene lactones, 12- melonia radix aucklandiae
Hydrocarbon lactone, dihydrocostulactone, dehydro-α-curcumene, Alpha-hydroxy dehydro-α-curcumene, beta-hydroxy dehydro-α-curcumene, white birch ester
Acid, betulinic acid methyl esters, river perfume (or spice) lactone, cynaropicrin, santamarine, α-ring costunolide, alantolactone, different building
Fragrant lactone, different dihydro costene ester, β-one of ring costunolide or radix aucklandiae terpene aldehyde or a variety of, preferably costunolide
And/or dehydro-α-curcumene.
Costunolide is sesquiterpenoids, and molecular formula is C15H20O2.Costunolide generates and NF- kB activation except inhibition NO
Outside, activation and the DNA binding activity of AP-1 albumen that can also reduce MAPKs protein kinase, to inhibit the table of IL-1 β gene
It reaches.
Decahydro-3,6,9-tris(methylene)azuleno[4,5-b molecular formula is C15H18O2, nuclear factor (NF- κ B) can be made to inactivate and inhibit induction type
The expression of nitricoxide synthase (iNOS) gene, and then NO is made to generate reduction, it can also reduce the TNF-α of lipopolysaccharides (LPS) induction
It is horizontal.
In some preferred embodiments, the weight of the chemotherapeutics and the radix aucklandiae and/or Radix Aucklandiae extract
Than for 5-75:10-800；Such as can be, but be not limited to 5:10,5:20,5:30,5:50,5:100,5:200,5:300,5:
400、5:500、5:600、5:700、5:800、75:10、75:20、75:50、75:100、75:200、75:300、75:400、75:
500,75:600,75:700 or 75:800.Chemotherapeutics and Chinese traditional medicine composition Internet of Things are adjusted according to applied chemotherapeutics difference
The weight ratio of used time, and/or, according to associated be radix aucklandiae, Radix Aucklandiae extract or radix aucklandiae and Radix Aucklandiae extract difference, and
Weight ratio when the type difference adjustment chemotherapeutics and Chinese medicine composition of Radix Aucklandiae extract are combined.
Preferably, effective dosage of the pharmaceutical combination preparations is 10-850mg/kg/ days.
Chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract can be with any effective quantity applications, such as can be, but be not limited to
10mg/kg/ days, 15mg/kg/ days, 20mg/kg/ days, 50mg/kg/ days, 100mg/kg/ days, 200mg/kg/ days, 300mg/kg/
It, 400mg/kg/ days, 500mg/kg/ days, 600mg/kg/ days, 700mg/kg/ days, 800mg/kg/ days or 875mg/kg/ days.
In view of the weight of object, age, general state and the severity of disease and administration route and dosage form, drug effectively at
The difference divided, implementer can change the effective quantity.
In some preferred embodiments, the pharmaceutical combination preparations further include pharmaceutically acceptable auxiliary material.
When pharmaceutically acceptable auxiliary material refers to production drug and prescription being dispensed, the excipient and additives used refers to
In addition to the active ingredient (s, reasonable assessment is had been carried out in terms of safety, and includes the substance in pharmaceutical preparation.Same medicine
It can be used for the pharmaceutical preparation of different way of administration with auxiliary material, and play the role of different and purposes.In drug provided by the invention
The pharmaceutically acceptable auxiliary material of addition can play the role of excipient, serve as carrier or improve stability, in addition, also having
The critical functions such as solubilising, hydrotropy or slow controlled release.
Typical but non-limiting pharmaceutically acceptable auxiliary material includes: solvent, propellant, solubilizer, cosolvent, emulsification
Agent, colorant, binder, disintegrating agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, flavoring
Agent, preservative, suspending agent, coating material, aromatic, anti stickness agent, antioxidant, chelating agent, penetration enhancer, pH adjusting agent,
Buffer, plasticizer, surfactant, foaming agent, defoaming agent, thickener, inclusion agents, moisturizer, absorbent, diluent, wadding
One of solidifying agent and deflocculant, filter aid or release retarding agent are a variety of.
In some preferred embodiments, the pharmaceutical combination preparations include oral preparation or ejection preparation.
When oral medication, said medicine can be made into and arbitrarily take orally acceptable dosage form, such as can be, but unlimited
In tablet, capsule, granule, pill, syrup, oral solution, oral suspensions or Orally taken emulsion.
Wherein, the carrier that tablet uses generally comprises lactose and cornstarch, and lubricant such as stearic acid in addition can also be added
Magnesium.The diluent that capsule uses generally comprises lactose and dried corn starch.Oral suspensions are then usually by active constituent
It is used in mixed way with suitable emulsifier and suspending agent.
Optionally, some sweeteners, aromatic or colorant can also be added in the above oral dosage form.
When being administered in the form of injection, said medicine can be made into the acceptable dosage form of any injection, such as can be with
For, but it is not limited to injection or powder-injection.
Wherein, workable carrier and solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing
Fixed oil also is used as solvent or suspension media, such as monoglyceride or two glyceride.
The present invention also provides application of the above-mentioned pharmaceutical combination preparations in the product of preparation treatment tumour.
In addition, the present invention also provides radix aucklandiaes and/or Radix Aucklandiae extract to prepare answering in chemotherapeutics Synergy and attenuation agent
With.
In some preferred embodiments, the synergy includes improving immunity of organisms.
In some preferred embodiments, the attenuation includes following (a)-(d):
(a) improve intestinal tract injury；
(b) intestinal mucosa is protected；
(c) injured intestinal mucosa is repaired；
(d) inhibit oxidative stress effect.
In order to facilitate it is clearer understand the contents of the present invention, be described in detail as follows now in conjunction with specific embodiment.
Unless otherwise instructed, experimental animal, drug used in the embodiment of the present invention and the equal source of reagent are regular and easy
Purchase channel:
Costunolide (20mg/ bottles), dehydro-α-curcumene (20mg/ bottles) are purchased from the limited public affairs of Dalian U.S. logical sequence science and technology
Department；Radix aucklandiae is purchased from the careless Co., Ltd of Tianjin flourishing age hundred, is accredited as certified products through University Of Tianjin professor Gao Wenyuan；Oxaliplatin (50mg/
Bottle) (Hengrui Medicine Co., Ltd., Jiangsu Prov.)；(Jiangsu Hengrui Medicine share has hydrochloride for injection Irinotecan (40mg/ bottles)
Limit company)；Loperamide hydrochloride capsules (Loper) (Xian-Janssen Pharmaceutical Ltd.)；Haematoxylin is purchased from Shanghai profit into biology
Science and Technology Ltd.；Yihong is purchased from magnificent biotech firm；Analysis level ethyl alcohol, anhydrous potassium dihydrogenphosphate (KH2PO4), disodium hydrogen phosphate
(Na2HPO4·12H2O), sodium dihydrogen phosphate (NaH2PO4·2H2O), sodium chloride (NaCl) and formaldehyde are purchased from Tianjin sky over the river chemical industry
Technology Co., Ltd.；Picric acid is purchased from Beijing chemical reagent Co., Ltd；It is limited at medicine company share that physiological saline is purchased from Hebei day
Company；MDA detection kit, SOD detection kit are purchased from Nanjing and build up Biotechnology Co., Ltd；NF- κ B Elisa reagent
(Wuhan is rich for box, iNOS Elisa kit, IL-6Elisa kit, TNF-α Elisa kit, COX-2Elisa kit
Shi De bioengineering Co., Ltd).
Assay balance (German Sartorius company)；Micropipettor (DRAGONLAB company, the U.S.)；Dewaterer
(Leica TP 1020, Germany)；Cycle type slicer (Leica RM2016, Germany).
Balb/c mouse (22-25g) is purchased from Military Medical Science Institute's Experimental Animal Center (Beijing), animal credit number
SCXH (army) 2012-0004, quality certification number: 0042643.Experiment mice is raised in Chinese Academy of Medical Sciences's radiation medicine research
Institute's Experimental Animal Center.Laboratory mice adaptability under conditions of 25 ± 1 DEG C of temperature, daytime 12h circulation, free water food is raised
It is tested after supporting seven days.
1 oxaliplatin of embodiment and radix aucklandiae or Radix Aucklandiae extract are combined
1.1, dosage regimen
(1) Balc/c mouse is divided into 7 groups, picric acid label:
| Grouping | Dosage |
| Blank group (Control health mouse) | - |
| Model group (Model mice with tumor) | - |
| Oxaliplatin group (OLP) | 5mg/kg |
| Oxaliplatin+radix aucklandiae group (OLP+MX) | 5mg/kg+800mg/kg |
| Oxaliplatin+costene lactones group (OLP+CO) | 5mg/kg+21.6mg/kg |
| Oxaliplatin+dehydrogenation costene lactones group (OLP+DE) | 5mg/kg+21.6mg/kg |
| Oxaliplatin+positive drug Loperamide (OLP+LOP) | 5mg/kg+8mg/kg |
Each administration group is administered 7 times by weight 0.2mL/20g, and blank group and model group give same amount of distilled water.Last
For 24 hours, mouse materials, observe radix aucklandiae or Radix Aucklandiae extract cooperates with the synergistic effect of chemotherapeutic oxaliplatin for fasting before being administered.
(2) Balc/c mouse is divided into 7 groups, picric acid label:
Each administration group is administered 7 times by weight 0.2mL/20g, and blank group gives same amount of distilled water.Prohibit before last dose
For 24 hours, mouse materials, observe radix aucklandiae to food or Radix Aucklandiae extract cooperates with chemotherapeutic oxaliplatin attenuation.
1.2, Testing index
(1) overview: including weight, feed, water, diarrhea, appearance hair color, activity condition etc..
(2) histotomy is observed: the damage and reparation situation at the observation each position of small intestine.
1.3, statistical procedures
Using SPSS17.0 statistically analyze processing software, to each group experimental data carry out statistical analysis, experimental data with
(x ± s) is indicated, is compared using sided t inspection, and * indicates there is significant difference p < 0.05, and * * indicates there is extremely significant property
Difference p < 0.01.
1.4, result
Tumour inhibiting rate is not apparent from after experimental result display radix aucklandiae and monomer collaborative treatment medicine oxaliplatin treatment colon cancer
It influences (Figure 1A, table 2), between tumour inhibiting rate and there was no significant difference.Mouse customary physiological index is further improved after drug combination, is made
The drinking water diet amount and the state of mind of mouse have apparent improvement, and improve mouse caused weight in therapeutic process and subtract
Gently (Figure 1B)；Spleen index and thymus index (table 1) are improved, prompts radix aucklandiae and monomer that body can be improved in tumor-bearing mice
Immunity.
The organ index of 1 oxaliplatin radix aucklandiae of table and its monomer in treating colon cancer
The tumour inhibiting rate of 2 oxaliplatin radix aucklandiae of table and its monomer in treating colon cancer
The HE dyeing of each intestinal segment of Fig. 2A, 2B, 2C and 2D small intestine site is observed that blank group intestinal villi is longer, arrangement
Closely, brush border is clear, and after giving chemotherapeutic, and length shortens, and density is reduced, the deformation of villus abscess, gland structure by
It destroys, blur margin is clear, and with serious inflammatory cell infiltration, small intestine major function is nutrient absorption, its damage
It can cause the absorption of moisture, so as to cause diarrhea；And after combining with radix aucklandiae and costene lactones, dehydro-α-curcumene, it controls
The villus arrangement for the treatment of group is more neat, and edge becomes clear cashmere density and increases compared with model group conspicuousness, and gland structure is complete, respectively
Position is able to maintain preferable form, and effect is most preferably at ileum position.In colon, blank group crypt orientations are neat, knot
Structure is complete, and in oxaliplatin list administration group, pathological change is obvious, torsional deformation serious with the vacuolation of crypts position, form
Structure is seriously damaged, and the damage of large intestine, causes its defecation dyskinesia, and with radix aucklandiae and costene lactones, go
After hydrogen constuslactone combination therapy, colon structure is significantly improved.
Passing through the survey to peroxidation horizontal (MDA) (Fig. 3 B) and oxyradical Scavenging activity (SOD) (Fig. 3 A)
It is fixed, evaluate the oxidative stress of body, by Fig. 3 B and Fig. 3 A statistics indicate that, after giving Chemotherapeutic treatments, the mistake of body
Oxidation level significantly increases, and resistance to oxidation (SOD) significantly reduces, and shows during Chemotherapeutic treatments, lipid peroxidation
Horizontal to increase, the oxyradical of body is removed power and is reduced, and causes oxidation/anti-oxidant unbalance, activation oxidative stress approach, so that
The cell degree that is damaged is big, and after combining with radix aucklandiae and/or Radix Aucklandiae extract, it can significantly improve this state, show
It writes and enhances the oxyradical removing power of body, thus ensure that oxidation/peroxidating balance, reduction oxidative stress.
Oxidative stress can directly cause tissue damage and trigger a series of inflammatory reactions, and NF-kB exists in inflammatory reaction
This stage plays a crucial role.Once this stage is activated by chemotherapeutic and ROS, NF-kB causes gene expression and proinflammatory
The generation of inflammation factor such as TNF-α, IL-1 β and IL-6, these proinflammatory inflammation factors will lead to tissue damage and apoptosis again in turn.
NF-kB also causes the expression of adhesion molecule and COX-2 gene, and leads to angiogenesis.A series of pro-inflammatory mediators pass through positive feedback
Approach amplifies entire inflammatory process, and then aggravates tissue damage.This process occurs mainly in submucosa and epithelium substrate, stomach
Intestinal mucosa ulcer and its atrophic variation are characterized, this is because the climax stage of tissue damage and stem cell death is in this mistake
Journey.The integrality and function of mucous epithelium are destroyed.The bacterium at mucosal ulcer position passes through stimulation hyperemia and activating macrophage
Further result in inflammation.Decahydro-3,6,9-tris(methylene)azuleno[4,5-b can make nuclear factor (NF- κ B) to inactivate and inducible nitric oxide is inhibited to close
The expression of enzyme (iNOS) gene, and then NO is made to generate reduction, it can also reduce TNF-α level.Costunolide is generated except inhibition NO
It is outer with NF- κ activation, activation and the DNA binding activity of AP-1 albumen of MAPKs protein kinase can be also reduced, to inhibit white Jie
The expression of plain gene.Compared to the blank group, the significant up-regulation of NF-kB (Fig. 3 C) and iNOS's is aobvious for experimental result display model group
The increase of work property causes the increase of the IL-6 (Fig. 3 D) and NO of the inflammatory factor in downstream, and the result of study of structure-activity relationship shows Δ 11
(13) exocyclic double bond is structure necessary to sesquiterpenoids ingredient inhibits NO to generate.The inflammatory reaction that NO is generated may be with super oxygen
Object anion O2- reaction generates peroxynitrite (ONOO-).Peroxynitrite is the cytotoxic oxidant of tool, and
After radix aucklandiae and costene lactones, dehydro-α-curcumene treatment, the expression of the NF-kB of upstream is reduced, to make the proinflammatory of downstream
Factor TNF-α (Fig. 3 F), IL-1 β and IL-6 (Fig. 3 E) and inflammatory factor COX-2 (Fig. 3 G) are substantially reduced, and reduce iNOS's
It expresses (Fig. 3 D), intracorporal NO level is made to tend to normally, cytotoxicity be reduced, to play the protective effect to stomach and intestine.
Show the work that Synergy and attenuation is played after radix aucklandiae cooperates with chemotherapeutic oxaliplatin treatment colon cancer through this embodiment
With.It has no adverse effects after the two joint to tumour inhibiting rate, but from the point of view of organ index, the immunity energy of body can be enhanced to a certain degree
Power, to play the role of synergy after illustrating medicine radix aucklandiae collaboration chemotherapeutic oxaliplatin；Energy after radix aucklandiae and monomer administration
Gastrointestinal toxicity caused by oxaliplatin is reversed, as a result confirms that radix aucklandiae and monomer can inhibit level of inflammation caused by chemotherapeutic, keeps away
Exempt from body cell damage aggravation, intestinal mucosa is protected, to play the role of attenuation.As a result after also showing drug combination
Mouse customary physiological index is improved, the drinking water diet amount of mouse and the state of mind is made to have apparent improvement.
2 Irinotecan of embodiment and radix aucklandiae or Radix Aucklandiae extract are combined
2.1, dosage regimen
(1) Balc/c mouse is divided into 7 groups, picric acid label:
| Grouping | Dosage |
| Blank group (Control health mouse) | - |
| Model group (Model mice with tumor) | - |
| Irinotecan group (CPT) | 75mg/kg |
| Irinotecan+radix aucklandiae group (CPT+MX) | 75mg/kg+800mg/kg |
| Irinotecan+costene lactones group (CPT+CO) | 75mg/kg+21.6mg/kg |
| Irinotecan+dehydrogenation costene lactones group (CPT+DE) | 75mg/kg+21.6mg/kg |
| Irinotecan+positive drug Loperamide (CPT+LOP) | 75mg/kg+20mg/kg |
Each administration group is administered 7 times by weight 0.2mL/20g, and blank group and model group give same amount of distilled water.Last
For 24 hours, mouse materials, observe radix aucklandiae or Radix Aucklandiae extract cooperates with the synergistic effect of chemotherapeutic Irinotecan for fasting before being administered.
(2) Balc/c mouse is divided into 6 groups, picric acid label:
| Grouping | Dosage |
| Blank group (Control health mouse) | - |
| Model group (Model CPT) | 75mg/kg |
| Irinotecan+radix aucklandiae group (CPT+MX) | 75mg/kg+800mg/kg |
| Irinotecan+costene lactones group (CPT+CO) | 75mg/kg+21.6mg/kg |
| Irinotecan+dehydrogenation costene lactones group (CPT+DE) | 75mg/kg+21.6mg/kg |
| Irinotecan+positive drug Loperamide (CPT+LOP) | 75mg/kg+20mg/kg |
Each administration group is administered 7 times by weight 0.2mL/20g, and blank group gives same amount of distilled water.Prohibit before last dose
For 24 hours, mouse materials, observe radix aucklandiae to food or Radix Aucklandiae extract cooperates with chemotherapeutic Irinotecan attenuation.
2.2, Testing index
(1) overview: including weight, feed, water, diarrhea, appearance hair color, activity condition etc..
(2) histotomy is observed: the damage and reparation situation at the observation each position of small intestine.
2.3, statistical procedures
Using SPSS17.0 statistically analyze processing software, to each group experimental data carry out statistical analysis, experimental data with
(x ± s) is indicated, is compared using sided t inspection, and * indicates there is significant difference p < 0.05, and * * indicates there is extremely significant property
P < 0.001 difference p < 0.01, * * *.
2.4, result
Radix aucklandiae and monomer and Irinotecan are administered in combination, and do not influence the drug effect (Fig. 4, table 3) of Irinotecan inhibitor against colon carcinoma cells；
And the situation of weight loss caused by chemotherapeutic can be alleviated, spleen index and thymus index (table 4) are improved, effect is slightly stronger than Lip river
Piperazine butylamine.Confirm that radix aucklandiae and its monomer component reduce the enterotoxication curative effect of Irinotecan from the performance of mouse ordinary circumstance.
The effect of 3 radix aucklandiae of table and monomer joint irinotecan CT26 colon cancer
4 radix aucklandiae of table and monomer combine Irinotecan Synergy and attenuation-organ index
The histopathologic slide at each position of enteron aisle is observed, compared to the blank group, each position of small intestine has obviously model group
Damage (Fig. 5 A, 5B, 5C and 5D), intestinal villus quantity reduce, length shorten, intestinal crypts disappear etc., jejunum site tissue damage is the most
Seriously, and radix aucklandiae can reverse this damage, prompt radix aucklandiae that there is protective effect to small intestine site, and in radix aucklandiae monomer costene
Rouge and dehydro-α-curcumene also show the protective effect to small intestine.And in colon site, there are apparent crypts for model group
Vacuolation, disorganized, goblet cell has necrosis, apoptosis that can improve this phenomenon after radix aucklandiae prophylactic treatment, with maintenance
Intestinal mucosal barrier is complete.And damaged intestinal mucosal barrier, the endotoxin in enteric cavity can be made to enter submucosa, and then cause inflammation
Reaction.
Toxic reagent is exposed in mucomembranous cell and leads to DNA damage and cell death meeting induced oxidation stress pathways, this
One approach is to cause albumen peroxidating, lipid peroxy due to the anti-oxidant unbalance generation for making excessive O2- of body oxidant
Change, damaging cells structure and lead to tissue damage；By to peroxidation horizontal (MDA) and oxyradical Scavenging activity
(SOD) measurement is shown after giving Chemotherapeutic treatments by Fig. 6 A and Fig. 6 B data, and resistance to oxidation (SOD) significantly drops
It is low, show during Chemotherapeutic treatments, the horizontal of lipid peroxidation increases, and the oxyradical of body is removed power and reduced, and makes
At oxidation/anti-oxidant unbalance, so that cell is damaged, degree is big, and after combining with radix aucklandiae, significantly enhances the oxygen of body
Change radicals scavenging power and reduce cellular damage level, to ensure that oxidation/peroxidating balance.
The damage of DNA and the activation of ROS, cause the activation of NF-kB, and make the inflammatory factor expression in downstream, as TNF-α,
IL-6；And these inflammatory factors will lead to tissue damage and apoptosis.Under Irinotecan effect, the level of inflammation of body is significant
Rise, generates a series of proinflammatory factor, and these pro-inflammatory mediators amplify entire inflammatory process by positive feedback approach, thus plus
Play damage significantly reduces NF-kB by scheming (6C, 6D) result it is found that radix aucklandiae and monomer can treat inflammatory reaction caused by chemical drug
Level plays anti-inflammatory effect to inhibit downstream level of inflammation.
Show that Irinotecan causes intestinal mucosa to damage by analysis to the present embodiment result and summary, each portion of small intestine
The toxicity of position causes the absorption to nutriment and moisture, while having destruction to large intestine structure function, causes entire stomach
The dysfunction of enteron aisle.And radix aucklandiae and costunolide and dehydro-α-curcumene can be effectively reduced intestines caused by Irinotecan
The toxic side effect of mucositis.Mechanism Study discovery, costunolide and dehydro-α-curcumene are by repairing impaired intestinal mucosa, suppression
The generation of ROS processed increases the level for pressing down the scorching factor in vivo, the approach such as the release of inflammatory factor is inhibited to play protective effect.
Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Pipe present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: its according to
So be possible to modify the technical solutions described in the foregoing embodiments, or to some or all of the technical features into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The range of scheme.
Claims (10)
1. a kind of pharmaceutical combination preparations, which is characterized in that including chemotherapeutics and radix aucklandiae and/or Radix Aucklandiae extract.
2. pharmaceutical combination preparations according to claim 1, which is characterized in that the chemotherapeutics includes alkylating agent, anti-generation
Thank one of medicine, antitumor antibiotic, plant, steroids or miscellany or a variety of；
Preferably, the chemotherapeutics includes one or both of plant or miscellany；
Preferably, the chemotherapeutics includes one or both of Irinotecan or oxaliplatin.
3. pharmaceutical combination preparations according to claim 1, which is characterized in that the Radix Aucklandiae extract includes terpene, biology
One of alkali, anthraquinone or flavones are a variety of, preferably terpene；
Preferably, the Radix Aucklandiae extract includes costunolide, dihydro costene lactones, in 12- melonia costene
Ester, dihydrocostulactone, dehydro-α-curcumene, Alpha-hydroxy dehydro-α-curcumene, beta-hydroxy dehydro-α-curcumene, betulinic acid,
Betulinic acid methyl esters, river perfume (or spice) lactone, cynaropicrin, santamarine, α-ring costunolide, alantolactone, different elecampane
Lactone, different dihydro costene ester, β-one of ring costunolide or radix aucklandiae terpene aldehyde or a variety of, preferably costunolide
And/or dehydro-α-curcumene.
4. pharmaceutical combination preparations according to claim 1-3, which is characterized in that the chemotherapeutics and described
The weight ratio of radix aucklandiae and/or Radix Aucklandiae extract is 5-75:10-800；
Preferably, effective dosage of the pharmaceutical combination preparations is 10-875mg/kg/ days.
5. pharmaceutical combination preparations according to claim 1-3, which is characterized in that the pharmaceutical combination preparations also wrap
Include pharmaceutically acceptable auxiliary material.
6. pharmaceutical combination preparations according to claim 1-3, which is characterized in that the pharmaceutical combination preparations include
Oral preparation or ejection preparation.
7. application of the pharmaceutical combination preparations as claimed in any one of claims 1 to 6 in the product of preparation treatment tumour.
8. radix aucklandiae and/or Radix Aucklandiae extract are preparing the application in chemotherapeutics Synergy and attenuation agent.
9. application according to claim 8, which is characterized in that the synergy includes improving immunity of organisms.
10. application according to claim 8, which is characterized in that the attenuation includes following (a)-(d):
(a) improve intestinal tract injury；
(b) intestinal mucosa is protected；
(c) injured intestinal mucosa is repaired；
(d) inhibit oxidative stress effect.
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Cited By (2)
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| CN110742884A (en) * | 2019-11-22 | 2020-02-04 | 樊鹏程 | Application of costunolide, dehydrocostunolide and derivatives thereof in preparing medicines for preventing and treating anoxia and protecting myocardium |
| CN114081880A (en) * | 2021-08-27 | 2022-02-25 | 成都医学院第一附属医院 | Application of costunolide and derivatives thereof in preparation of medicines for preventing and/or treating intestinal injury |
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| CN110742884A (en) * | 2019-11-22 | 2020-02-04 | 樊鹏程 | Application of costunolide, dehydrocostunolide and derivatives thereof in preparing medicines for preventing and treating anoxia and protecting myocardium |
| CN114081880A (en) * | 2021-08-27 | 2022-02-25 | 成都医学院第一附属医院 | Application of costunolide and derivatives thereof in preparation of medicines for preventing and/or treating intestinal injury |
| CN114081880B (en) * | 2021-08-27 | 2023-09-15 | 成都医学院第一附属医院 | Use of costunolide and its derivatives in preparation of medicine for preventing and/or treating intestinal injury |
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