CN100553629C - The application of paeonol in preparation anti esophageal cancer medicine - Google Patents
The application of paeonol in preparation anti esophageal cancer medicine Download PDFInfo
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- CN100553629C CN100553629C CNB200610096653XA CN200610096653A CN100553629C CN 100553629 C CN100553629 C CN 100553629C CN B200610096653X A CNB200610096653X A CN B200610096653XA CN 200610096653 A CN200610096653 A CN 200610096653A CN 100553629 C CN100553629 C CN 100553629C
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Abstract
The application of paeonol in preparation anti esophageal cancer medicine, be to be active component, comprise that paeonol-Benexate Hydrochloride and pharmaceutical carrier are prepared into the application of pharmaceutically acceptable dosage forms such as dry suspension, powder, tablet, capsule, granule, soft capsule, injection, injection lyophilized powder, suppository, drop pill, syrup, oral solution with the paeonol.The toxic and side effects that its medicine is used for the treatment of the esophageal carcinoma is little, and prolonged application has no adverse reaction, treating both the principal and secondary aspects of a disease.
Description
Technical field:
The present invention relates to medical technical field, more particularly relate to the application of paeonol in the treatment esophageal carcinoma.
Background technology:
The esophageal carcinoma is the malignant tumor that betides the epithelium of esophagus tissue, accounts for 2% of all malignant tumor.Up-to-date statistics shows, the annual new cases in the whole world are nearly 400,000, and dead up to 340,000 examples.China is the highest country of esophageal carcinoma sickness rate, accounts for more than 50% of world's esophageal carcinoma, and its mortality rate comes the 4th in all tumors.Our province is the province occurred frequently of the esophageal carcinoma, reports that according to the sampling survey of the 1990-1992 of Anhui Province tumor mortality reason the esophageal carcinoma occupies second of our province tumor mortality reason, the first place of the male tumor cause of death.The local infringement or metastasis taken place at least 80% patient when patient with esophageal carcinoma was made a definite diagnosis, can't surgical radical treatment.Age of onset is many, and the male is more than the women more than 40 years old, but patient below 40 years old has growth trend in recent years, day by day becomes the main killer of our province labour force population.
At present, operation remains the primary means of the treatment esophageal carcinoma, but after the Resection of Esophageal Carcinoma 3 years survival rates only 30%～35%, 5 years survival rates less than 20%.Radiotherapy also is a kind of important Therapeutic Method for inoperable esophageal carcinoma.Often symptom is not obvious for the early stage esophageal carcinoma, and many cases one have belonged to late period after diagnosing, and prognosis is very poor, and survival rate was no more than 10% in 5 years.The local infringement or metastasis taken place at least 80% patient when making a definite diagnosis, can't surgical radical treatment.Postmortem shows, clinical 70% had metastasis when symptom occurring, and wherein lymphatic metastasis is 73%～74.5%, and it is 50%～75% that other internal organs shift.Thereby surgery alone, radiotherapy or operation+radiotherapy is also difficult to reach satisfied radical cure effect, and main failure cause is that metastasis and local tumor are not controlled and recurred.For preventing and treat whole body and shift that chemotherapy is present unique definite effective method, so chemotherapy progressively becomes the important component part of esophageal carcinoma Comprehensive Treatment.As for late esophagus cancer, because tumor tissues and the feed of following that inflammatory edema caused are blocked and local pain, seriously influence survival time of patients and quality of life, it is generally acknowledged, appeasing property chemotherapy can be improved patient's quality of life significantly, its life span of proper extension.
At present, with cisplatin (cisplatin, CDDP) adjuvant chemotherapy for the basis is the important means of the treatment esophageal carcinoma, its effective percentage is only about 50%, but chemotherapy has bigger toxic and side effects, part patient is difficult to tolerance.Especially CDDP drug resistance fashion occurring does not have ideal chemotherapeutics and substitutes.Therefore the chemotherapeutics of actively seeking a kind of low toxicity becomes the current problem of needing solution badly.The chemotherapy of the esophageal carcinoma mainly adopts the combined chemotherapy based on PDD, and therefore, at the characteristics that our province esophageal carcinoma sickness rate height, stadium evening, operation can not be effected a radical cure, the medicine of actively seeking high-efficiency low-toxicity is a difficult problem that needs to be resolved hurrily that faces at present.
Paeonol (Paeonol) claim paeonol again, is the main effective ingredient of ranunculaceae peony Paeonia Suffruticosa Andr. root bark and Asclepiadaceae plant Radix Cynanchi Paniculati Pycnostelma Paniculatum (Bunge) K.Schum dry root or herb.Paeonol is a kind of micromolecular phenolic compound, and the acicular crystal that is white in color has the characteristic of fusing point low (mp51 ℃ ± 1 ℃), volatile and poorly water-soluble, and its molecular weight (Mr) is 166.18, and molecular formula is C
9H
10O
3, chemical constitution is 2-hydroxyl-4-methoxyacetophenone:
Paeonol has anti-calmness, hypnosis, analgesic, analgesia, antiinflammatory, pharmacological action such as antibiotic.Modern study shows that paeonol also has certain anti-tumor activity, and experiment in vitro finds that it has inhibited proliferation to various tumor cell strains, and gastric infusion has anti-Mouse Liver function of tumor.But do not see the report of paeonol so far to the esophageal carcinoma.
Summary of the invention:
The present invention is for avoiding above-mentioned existing in prior technology weak point, provide a kind of toxic and side effects little, and prolonged application has no adverse reaction, the application of the paeonol for the treatment of both the principal and secondary aspects of a disease in preparation anti esophageal cancer medicine.
The inventor draws as drawing a conclusion through systematic study:
Paeonol is at 0.047～1.504mmolL
-1Under the concentration human esophagus cancer cell Eca-109 is had the obvious growth inhibitory action, drug level is high more, and inhibitory action is strong more, has significant concentration dependence (r:0.964, P＜0.01), IC
50Be 0.342mmolL
-1Show that paeonol has good antineoplastic activity and wide characteristics of antitumor spectra external.Paeonol 50mg.kg
-1The continuous irrigation stomach is 14 days under the dosage, can suppress the growth that nude mice is transplanted human esophagus cancer Eca-109, and its suppression ratio reaches 23.54%, along with the increase antitumor action enhancing of dosage.Especially, the paeonol (100mgkg under the doses
-1) and cisplatin (5mgkg
-1) tumour inhibiting rate is up to 77.91% during use in conjunction, the difference of the tumour inhibiting rate of using separately than paeonol, cisplatin has significance, and prompting paeonol and cisplatin have synergism.Each group does not all have nude mice death in the experimentation.Experimental result prompting paeonol may have a good application prospect in the treatment of the esophageal carcinoma.
The application of paeonol of the present invention in preparation anti esophageal cancer medicine can be that paeonol and pharmaceutical carrier combine Pharmaceutical composition, and the dosage form of prepared one-tenth comprises pharmaceutically acceptable dosage forms such as dry suspension, powder, tablet, capsule, granule, soft capsule, injection, injection lyophilized powder, suppository, drop pill, syrup, oral solution.
The Pharmaceutical composition that paeonol of the present invention and pharmaceutical carrier are combined into is prepared into pharmaceutical preparation, and its consumption usage is medication every day 1～5 time, and each consumption is counted 50～250mg with paeonol.
The dosage form of paeonol Pharmaceutical composition the best of the present invention is to be the dry suspension of pharmaceutical carrier with mannitol etc.
Paeonol Pharmaceutical composition of the present invention is made the dry suspension of anti esophageal cancer, and its pharmaceutical carrier comprises mannitol, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, Ka Baimu, polyvidone, sucrose, xylitol etc.
Compared with the prior art, beneficial effect of the present invention is embodied in its medicine, and to be used for the treatment of the toxic and side effects of the esophageal carcinoma little, and prolonged application has no adverse reaction, treating both the principal and secondary aspects of a disease.
Following animal experiment is described further beneficial effect of the present invention:
Medicine and reagent: Paeonal injection liquid: available from Shanghai first (the specification 5mgml of pharmaceutical factory
-1).The paeonol raw material is provided by Inst., of Clinical Pharmacology, Anhui Medical Univ. plant chamber; Cisplatin injection: (the specification 1mgml of Nanjing Pharmaceutical Factory Co., Ltd.
-1); RPMI1640 cultivates powder and purchases the Gibco company in the U.S.; Tetrazolium bromide is purchased the Sigma company in the U.S..Breach end labelling (TUNEL) test kit of terminal deoxynucleotidyl transferase mediation is available from U.S. promega company.
Cell strain and laboratory animal: human esophagus cancer cell strain Eca-109 is available from Chinese Academy of Sciences's Shanghai cell bank.Ages in BALB/c nude mice 6～8 week, the SPF level, the male and female dual-purpose, Medical University Of Anhui's animal center provides.
Statistical procedures: experimental data represents that with x ± s significance test adopts variance analysis between group.
1, paeonol is in external inhibitory action to human esophagus cancer cell Eca-109 growth
1.1 experimental technique
Adopt mtt assay, paeonol group, cell matched group and the blank group of establishing variable concentrations, the cell of the trophophase of taking the logarithm (1～5) * 10
7L
-1Be inoculated on 96 orifice plates, establish 6 multiple holes for every group, 100 μ l are inoculated in every hole, put 37 ℃, 5%CO
2Incubator cultivated 24 hours, abandon supernatant, the every hole of paeonol group adds the paeonol of 200 μ l variable concentrations respectively, and (final concentration of Pae is 0.047,0.094,0.188,0.376,0.752,1.504mmolL
-1); Cell matched group and blank group only add the equivalent culture fluid, continue to cultivate 48h, and 4h paeonol group and the every hole of matched group add 20 μ lMTT (5gL before stopping cultivation
-1), cultivate 4h again after, the careful suction abandoned supernatant, and adds 150 μ l DMSO dissolving MTT precipitation, behind the agitator mixing, measures light absorption value (A) in microplate reader with 490nm, obtains growth inhibition ratio by following formula.Growth inhibition ratio=(1-medication group A value/control group A value) * 100%.With the drug level is transverse axis, and suppression ratio is made the longitudinal axis, draws growth curve.Logarithm and suppression ratio with drug level carry out rectilinear regression and obtain IC
50
1.2 experimental result
Paeonol 0.047～1.504mmolL
-1Growth to human esophagus cancer cell Eca-109 has inhibitory action, and suppression ratio raises along with drug concentrations and raises Pae 0.047,0.094,0.188,0.376,0.752,1.504mmolL
-1Eca-109 cell inhibiting rate is followed successively by 5.44%, 12.28%, 27.99%, 39.53%, 84.41%, 89.98%.Logarithm and suppression ratio with concentration carry out rectilinear correlation analysis: Pae:r=0.964, P＜0.01.IC
50Be 0.342mmolL
-1See Table 1.
Table 1 paeonol is in external inhibitory action to human esophagus cancer cell Eca-109 growth
*P＜0.05,
*(paeonol=0) is compared with matched group in P＜0.01
2, paeonol is transplanted the inhibitory action of human esophagus cancer cell Eca-109 to nude mice
2.1 experimental technique
The human esophagus cancer cell Eca-109 of trophophase makes cell suspension 2.1.1 the interior inhibition test of body is taken the logarithm, and the adding culture medium is made cell concentration and is about 1 * 10
7Ml
-1, it is subcutaneous to be inoculated in every nude mice left side axillary fossa, at random nude mice is divided into matched group at random, cisplatin 5mgkg
-1Group, paeonol various dose group, paeonol 100mgkg
-1+ cisplatin 5mgkg
-1Group.Every group of 6 nude mices, paeonol gastric infusion behind the inoculation 24h, every day 1 time, logotype 14 days.The cisplatin lumbar injection, 1 week 2 times, totally 2 weeks.Put to death nude mice when experiment finishes and weigh, peel off the tumor body and claim tumor heavy.Calculate tumour inhibiting rate by following formula.Tumour inhibiting rate=(matched group tumor weight-medication group tumor is heavy)/matched group tumor heavy * 100%.
2.1.2 two medicine synergy evaluations adopt two medicine interaction indexes (CDI) to estimate two medicine interactive properties, and CDI=AB/ (A * B).Heavily calculate according to tumor, AB is two medicine coupling groups and the heavy ratio of matched group tumor; A or B are each medicine use group separately and the heavy ratio of matched group tumor.Two medicine interaction properties are for collaborative when CDI＜1; When CDI＜0.7, the synergism highly significant.
2.1.3HE stained preparation prepares the fresh tumor tissues of 4% formaldehyde fixed, conventional dehydration, and specimens paraffin embedding slices dewaxes to water HE dyeing mounting, and the light microscopic high power field is observed the tumor cell form down.
2.1.4 1mm is got in the sample for use in transmitted electron microscope preparation
3Tumor tissues, fixing before method 2.5% glutaraldehyde routinely, fixing behind the osmic acid of reuse 1%, dehydration, the continuous ultrathin section of 70nm after the embedding, the dyeing of lead acetate uranium, the ultrastructure of the H-800 of Hitachi type transmission electron microscope observing tumor cell is also taken the photograph sheet.
2.1.5 the original position apoptosis detects TdT (terminal deoxynucleotidyl transferase) the mediated dUTP nick end labeling breach end-labelling-TUNEL method that adopts.The tissue slice routine dewaxes to water, 20 μ gml
-1Protease K digesting 30 minutes, room temperature; 100 μ l level pads 5～10 minutes; 100 μ lTdT reactant liquor effects 60 minutes, 37 ℃; 0.3% hydrogen peroxide sealing endogenous peroxidase activity; Streptavidin-horseradish peroxidase (SP-HRP) effect 30 minutes, room temperature; Diaminobenzidine (DAB) colour developing, haematoxylin is redyed, dehydration, transparent, mounting.The positive contrast that adds DNase I is established in experiment, adds the negative contrast that does not contain the TdT reactant liquor.Ordinary optical microscope is chosen 5 high power fields (* 400), counts wherein apoptosis cell, and calculates the percent value that apoptotic cell accounts for tumor cell, i.e. apoptotic index AI (apoptosis index).
2.2 experimental result
2.2.1 paeonol is transplanted the inhibitory action of human esophagus cancer cell Eca-109 to nude mice
Paeonol is at 25mgkg
-1During dosage nude mice being transplanted the Eca-109 tumour inhibiting rate is 10.67%, compares there was no significant difference with matched group.Paeonol is at 50mgkg
-1, 100mgkg
-1And 200mgkg
-1Tumour inhibiting rate to nude mice transplanting Eca-109 during dosage is respectively 23.54%, 27.91% and 34.46%; Cisplatin 5mgkg
-1The group tumour inhibiting rate is 58.71%; Paeonol 100mgkg
-1+ cisplatin 5mgkg
-1The tumour inhibiting rate of group is respectively 77.91%.Compare P＜0.05 with matched group for these 5 groups.Paeonol 100mgkg
-1+ cisplatin 5mgkg
-1The group respectively with cisplatin 5mgkg
-1Group and paeonol 100mgkg
-1Compared significant difference (P＜0.05), and calculated CDI=0.74, pointed out two medicines to share and have synergism.Each group does not all have nude mice death in the experimentation.See Table 2.
Table 2 paeonol is transplanted the inhibitory action of human esophagus cancer cell Eca-109 to nude mice
*Compare with matched group P＜0.05;
ΔCompare with paeonol+cisplatin group P＜0.05
2.2.2 light microscopic morphological observation
The matched group growth of tumour cell is vigorous, the cell density height; Paeonol various dose group, cisplatin group and two medicines associating (paeonol 100mgkg
-1+ cisplatin 5mgkg
-1) minimizing of function cells density and visible more apoptotic cell, show as cell volume and dwindle, karyopycnosis, cracked, engrain, part forms apoptotic body.
2.2.3 transmission electron microscope morphological observation
Detect medication group tumor tissues under the Electronic Speculum, the tumor cell of visible more apoptosis.Show the obvious apoptosis morphological change under the Electronic Speculum, the cancerous cell after birth is more complete, and organelle is intact substantially, and the nuclei dyeing chromaticness concentrates that the limit is poly-, endochylema concentrates, karyorrhexis and a large amount of apoptotic body form.
2.2.4TUNEL detection apoptosis
See under the light microscopic, the obvious pyknosis of apoptotic cell, nuclear is fine and close, is sepia, and multi-blade or crescent granule often accumulate in the nuclear periphery, and it is blue that the nuclear of non-apoptotic cell is.It is tan apoptotic cell that matched group has a little nucleus engrain, at paeonol various dose group, cisplatin 5mgkg
-1Group and paeonol 100mgkg
-1+ cisplatin 5mgkg
-1Group, apoptotic cell is obviously more than the matched group (see figure 3).Medication group apoptotic index has been compared significant difference with matched group
(P＜0.05 or P＜0.01).See Table 3.
The detection of table 3 pair cell apoptotic index (n=5, x ± s)
*P＜0.05，
**P＜0.01?vs?control?group
The specific embodiment:
Paeonol, comprise with pharmaceutical carrier and be combined as pharmaceutically acceptable dosage form, comprise dry suspension, powder, tablet, capsule, granule, soft capsule, injection, injection lyophilized powder, suppository, drop pill, syrup, oral solution, in esophageal carcinoma therapy, use.
Its consumption usage is medication every day 1～5 time, and each consumption is counted 50～250mg with paeonol.
Specifically can make various pharmaceutical preparatioies, but protection scope of the present invention is not limited to this by following component and method.
Embodiment 1:
Group component (mg/ bag)
Paeonol-Benexate Hydrochloride 1850 (being equivalent to paeonol 150mg)
Mannitol 2800
Sodium carboxymethyl cellulose 250
Microcrystalline Cellulose 100
Preparation method:
(1) take by weighing paeonol 1g, add an amount of dehydrated alcohol, heating in water bath makes dissolving; Other takes by weighing 10 times of amount beta-schardinger dextrin-s and puts in the three-neck flask, is dissolved in water at a certain temperature and makes saturated solution; The speed of paeonol anhydrous alcohol solution with 2/min is slowly dropped in the beta-schardinger dextrin-saturated solution, treat after dehydrated alcohol volatilizes three-neck flask to be sealed.The continuation heating in water bath also stirs a period of time, take out, put cold preservation 24h crystallize in the refrigerator, filter clathrate, use a small amount of distilled water wash, put in the vacuum drying oven below 50 ℃ dry, get white loose shape clathrate powder, the an amount of petroleum ether of reuse is flung to petroleum ether, makes paeonol-Benexate Hydrochloride;
(2), after above-mentioned paeonol-Benexate Hydrochloride and adjuvant be mixed in proportion, be distributed into the dry suspension of every bag of 5g in the GMP cleaning shop.It is 150mg that every bag of dry suspension contains the paeonol amount, uses mixing in water for oral taking, takes 1 bag at every turn, and take 1-5 every day.
Embodiment 2:
Group component (mg/ sheet)
Paeonol 50
Mannitol 175
Cross-linking sodium carboxymethyl cellulose 23
Magnesium stearate 2
PVP K
30Ethanol liquid is an amount of
Preparation method:
In the GMP cleaning shop, after paeonol and above-mentioned adjuvant be mixed in proportion, according to a preparation of Chinese Pharmacopoeia version in 2005 tablet standard, granulate, use the automatic tableting press tabletting, make tablet, it is 50mg that every tablet contains the paeonol amount, and the patient takes 3 at every turn, and take 1-5 every day.
Embodiment 3:
Group component (mg/ ball)
Paeonol 50
Vegetable oil 200
Preparation method:
In the GMP cleaning shop, paeonol is mixed with vegetable oil, grind well with colloid mill; Other joins gelatin solution (100 parts in gelatin, 55 parts of glycerol, 120 parts in water), and is standby; With automatic pellet press pill, make soft capsule, it is 50mg that every ball contains the paeonol amount, and the patient takes 3 balls at every turn, and take 1-5 every day.
Claims (1)
1, the application of paeonol in preparation anti esophageal cancer medicine.
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| CN101708169A (en) * | 2009-12-18 | 2010-05-19 | 苏州大学 | Colonic targeting administration preparation containing active substance of paeonol and preparation method thereof |
| CN103861120B (en) * | 2012-08-16 | 2015-12-09 | 湖北天圣康迪制药有限公司 | A kind of preparation method of enclose medicament |
| CN110437156B (en) * | 2019-08-26 | 2022-07-19 | 桂林医学院 | Paeonol dihydropyrimidinone derivative, preparation method and application thereof |
| CN110590852B (en) * | 2019-08-29 | 2022-12-09 | 合肥学院 | Platinum complex with antitumor activity and preparation method thereof |
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Non-Patent Citations (4)
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| 丹皮及其有效成分丹皮酚抗肿瘤作用研究进展. 黄远洁等.福建中医学院学报，第15 增刊卷. 2005 |
| 丹皮及其有效成分丹皮酚抗肿瘤作用研究进展. 黄远洁等.福建中医学院学报，第15 增刊卷. 2005 * |
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