CN101062041B - Novel medical function of cucurbitacin - Google Patents
Novel medical function of cucurbitacin Download PDFInfo
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- CN101062041B CN101062041B CN2007100115151A CN200710011515A CN101062041B CN 101062041 B CN101062041 B CN 101062041B CN 2007100115151 A CN2007100115151 A CN 2007100115151A CN 200710011515 A CN200710011515 A CN 200710011515A CN 101062041 B CN101062041 B CN 101062041B
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- CVKKIVYBGGDJCR-SXDZHWHFSA-N Cucurbitacin B Natural products CC(=O)OC(C)(C)C=CC(=O)[C@@](C)(O)[C@@H]1[C@@H](O)C[C@]2(C)C3=CC[C@@H]4C(C)(C)C(=O)[C@H](O)C[C@@]4(C)[C@@H]3CC(=O)[C@@]12C CVKKIVYBGGDJCR-SXDZHWHFSA-N 0.000 title claims abstract description 56
- LNSXRXFBSDRILE-UHFFFAOYSA-N Cucurbitacin Natural products CC(=O)OC(C)(C)C=CC(=O)C(C)(O)C1C(O)CC2(C)C3CC=C4C(C)(C)C(O)C(O)CC4(C)C3(C)C(=O)CC12C LNSXRXFBSDRILE-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 150000001904 cucurbitacins Chemical class 0.000 title claims abstract description 44
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Images
Abstract
The invention discloses a new usage of cucurbitacin (Cucurbitacins) in medicinal technique domain, which is characterized by the following: using cucurbitacin and medicinal component to treat laryngocarcinoma and increase quantity of leukocyte; preparing to multiple agent type such as tablet, powder medicine, capsule, granula, oral liquid, injection and so on with the cucurbitacin or medicinal component; proceeding independent give drug or combined treatment; using to leucopenia because of radiotheraphy of tumor patient; counting the give drug dosage of cucurbitacin with total cucurbitacin; giving the drug to mouse with 0. 001mg/kg-1mg/kg; giving to adult with 0. 1mg-5mg/day.
Description
Technical field:
The invention belongs to medical technical field, relate to the new purposes of known substance cucurbitacin (Cucurbitacins).Specifically, mean cucurbitacin and pharmaceutical compositions thereof the new purposes in the white blood cell count medicine of treatment laryngeal carcinoma, raising radiation therapy subject.
Background technology:
Cucurbitacin (Cucurbitacins) belongs to the 19-methyl and appears at a class tetracyclic triterpenoids compound on the C-9 position, mainly be distributed in the cucurbitaceous plant, in high plants such as Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae and some macro fungis, discovery arranged also.The researcher Qiu Minghua of Kunming plant institute of the Chinese Academy of Sciences leads scientific and technical personnel on the basis of a series of novel cucurbitacins of finding, 229 nearly all cucurbitacine chemical compounds have been studied, new textural classification pattern has been proposed, Qian 5 class formation types are divided into 12 classes again thus, have obtained the approval of international academic community.At present, the cucurbitacin that China's approval is produced is Cucurbitacine again, and (another name: Pedicellus Melo) extract mainly contains compositions such as Cucurbitacin B, E for the Chinese medicine muskmelon pedicel, Cucurbitacin B content is more than 60% in the existing extract, and its quality standard records in China's ministry standard.The cucurbitacin sheet is used for the treatment of chronic hepatitis, and (cucurbitacin sheet pharmacy circular 1986,21 (6): 357), through Shanghai, ground 13 tame hospital clinicals such as Beijing, Chongqing, its effective percentage is 75.2%, and obvious effective rate is 44.6%.Observe the cucurbitacin sheet clinically and can improve chronic hepatitis common sympton and main physical signs more all sidedly, and have and significantly fall enzyme (S-GPT), the turbid descending (TTT, ZnTT) and fall the red matter effect of gallbladder, do not cause the S-GPT knock-on after the drug withdrawal, albumen inversion and hyperglobulinemia also there is tangible role of correcting, can also improve the non-specific cell immunocompetence of chronic hepatitis patient, no obvious toxic-side effects.With the exception of this, the cucurbitacin sheet can also be used for the treatment of primary hepatocarcinoma, through Shanghai, ground such as Beijing, Guangxi six tame hospital clinicals observe, and add up 169 examples, effective percentage 69%, obvious effective rate 39%.Clinical observation shows, this medicine and 5-fluorouracil are relatively, it improves symptom, eliminate liver pain, dwindle the tumor body, prolong life cycle, regain one's strength etc., all be better than matched group, and the toxic and side effects of chemotherapeutics as none (treatment hepatitis, hepatocarcinoma new drug cucurbitacin sheet, Chinese herbal medicine, 1987,18 (10): 21; The 50 routine clinical observations of cucurbitacin treatment primary hepatocarcinoma, new drug and clinical, 1984,3 (2): 21-22; The pharmacology of cucurbitacin and clinical practice, Chinese herbal medicine, 1992,23 (11): 605～608).The author is arranged recently with cucurbitacin sheet and chemotherapeutic associating, the treatment mid and late liver cancer, median survival interval was by 6.1 ± 7.12 months of single chemotherapeutic, (the cucurbitacin sheet adds the clinical observation on the therapeutic effect of chemotherapeutic treatment advanced primary liver cancer to bring up to 12.5 ± 7.54 months, cancer, 1989,8 (6): 434～436); Other has literary composition to find Cucurbitacin B, and E has stronger lethal effect to nasopharyngeal carcinoma cell; Have document to point out, the long medication course of treatment (6 week) can obviously suppress the liver proliferation of fibrous tissue, prevents fatty degeneration of liver and cirrhotic formation and development.Existing patent mostly is the patent relevant with dosage form, a new use patent " 200610046738.7 " is disclosed recently as " nano medicine ' Hulusu ' and preparation method thereof; application number: 01103658.3 ", " cucurbitacin cyclodextrin clathrate and preparation thereof; application number: 02153647.3 ", " cucurbitacin liposome prescription and preparation thereof; application number: 02144633.4 ", " drop pills of cucurbitacine and preparation method thereof; application number: 200310100943.3 ", cucurbitacin is used for liter treats in vain and with chemotherapy drugs in combination, reverse the white effect of falling of chemotherapeutics.But do not see that about " cucurbitacin ", " Cucurbitacin P.E Elaterin " being used for the treatment of laryngeal carcinoma and using it for radiotherapy combined and improve curative effect reduce toxic and side effects, the leukocytic report of patients undergoing chemotherapy particularly raises.
Laryngeal carcinoma (carcinoma of larynx) sickness rate accounts for 1～5% of general tumour, is only second to nasopharyngeal carcinoma and nasal cavity in the department of otorhinolaryngology field, and nasal sinus cancer occupies the 3rd.Sending out the age well is 50～70 years old.The male sees than the women more, is about 8: 1, and is the highest with northeast, North China and East China sickness rate.The Therapeutic Method of laryngeal carcinoma is mainly radiotherapy or operative treatment, and operative treatment usually causes the patient to lose language function, and radiotherapy can cause leukopenia; In addition, if when the scope of tumor is very big, pulmonary can occurs and shift and wait focus at a distance, must use chemotherapy this moment, do not possess therapeutical effect simultaneously and improve leukocytic medicine and have as yet at present.
Summary of the invention:
The invention provides and a kind ofly possess treatment laryngeal carcinoma effect simultaneously and improve leukocytic medicine, promptly usually treat laryngeal carcinoma, improve the white blood cell count of radiation therapy subject and contain being used for the treatment of laryngeal carcinoma and improving the pharmaceutical compositions of radiation therapy subject white blood cell count of cucurbitacin with calabash.Cucurbitacin is a class tetracyclic triterpenoids compound of extracting in cucurbitaceous plant, Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae plant and some macro fungis; Also comprise crude extract-Cucurbitacin P.E Elaterin.
The cucurbitacin main component is a Cucurbitacin B, still can comprise cucurbatacin E, isocucurbitacin B, two hydrogen Cucurbitacin B, cucurbitacin I, cucurbitacin Q one or more compositions wherein; Cucurbitacin B content is greater than 30%.
Can be prepared into multiple dosage form with cucurbitacin or its Pharmaceutical composition as the medicine of main component, as tablet, powder, capsule, granule, suspensoid, syrup, oral liquid, ointment, patch, injection.Route of administration comprises external, oral and injection.Can individually dosed or therapeutic alliance, be used for tumor patient because the low leukocyte counts disease that chemotherapy, radiotherapy cause.The cucurbitacin dosage calculates according to total cucurbitacin, and mice is with 0.001mg/ kilogram～1mg/ kg body weight administration, and health adult is 0.1mg～5mg/ day with dosage; Optimal dose is respectively mice 0.01mg/ kilogram～0.5mg/ kg body weight administration, and health adult is 0.3mg～3mg/ day with dosage, divides 1 time～4 times administrations.
Description of drawings:
Fig. 1 is the influence of the external propagation to laryngeal cancer cell Hep-2 of Cucurbitacin B among the embodiment 1
Fig. 2 be among the embodiment 2 Cucurbitacin B to the influence of nude mice laryngeal carcinoma transplanted tumor
Fig. 3 is a nude mice body weight situation of change among the embodiment 2
The specific embodiment:
Detailed component of the present invention is provided by the following example, but protection scope of the present invention not only is confined to this.
Embodiment 1:
The external anti-people's laryngeal cancer cell research of Cucurbitacin B (CuB, the purity that the HPLC area normalization method is measured is greater than 99%)
Experiment in vitro (MTT)
Method:
1. people's laryngeal cancer cell Hep-2 is cultivated with the RPMI1640 culture fluid that contains 10% hyclone, put 37 ℃, 5%CO
2In the incubator, went down to posterity 1 time in per 3～4 days.Select the cell of exponential phase to be used for experiment.
2. attached cell is suspended in the culture fluid after digesting with 0.25% pancreatin (containing EDTA1mM/L), and transferring cell concentration is 2.5 * 10
4/ mL is inoculated on 96 orifice plates by every hole 100 μ L, and 3 multiple holes are established in every hole.(blank) only adds culture fluid in the blank hole.
3. after cultivation 18-24h treated cell attachment, grouping added variable concentrations medicine (0.5 μ L), and another group is matched group (not dosing).
4. continue to cultivate 24,48 or 72 hours, every hole adds 5mg/mL MTT reagent 10 μ L, continues to cultivate 4 hours, and every hole adds 10%SDS (containing 10mM/L hydrochloric acid) 100 μ L, spends the night in the incubator.
5. survey the OD value in every hole with microplate reader (570nm wavelength).Obtain the Hep-2 cell inhibitory rate according to the OD value, computing formula be suppression ratio (inhibit rate, IR)=[(matched group OD value mean-blank group OD value mean)-(experimental group OD value mean-blank organizes OD value mean)]/(matched group OD value mean-blank organizes OD value mean).
That is: 1-(OD
Experiment-OD
Blank)/(O
The D contrast-OD
Blank)
The results are shown in accompanying drawing 1.
Embodiment 2:
Anti-people's laryngeal carcinoma pharmacodynamic study in Cucurbitacin B (CuB, the purity that the HPLC area normalization method is measured is greater than the 99%) body
Method:
1. people's laryngeal cancer cell Hep-2 is cultivated with the RPMI1640 culture fluid that contains 10% hyclone, put 37 ℃, 5%CO
2In the incubator, went down to posterity 1 time in per 3～4 days.Select the cell of exponential phase to be used for experiment.
2. attached cell is suspended in the normal saline after digesting with 0.25% pancreatin (containing EDTA1mM/L), and transferring cell concentration is 2.5 * 10
7/ mL.
3.18-20 40 of gram nude mices (BALB/C, 5-6 week is female, available from China Concord Medical Science University of Chinese Academy of Medical Sciences institute of lab animals), oxter, right side inoculating cell 5 * 10
6/ only, treat that the tumor piece grows into greater than 100mm
3The time, be divided into 4 groups at random, be respectively negative control group (0.9% sodium chloride, 0.2ml/ is the sky only), CucB low dose group (25 μ g/kg days), middle dosage group (50 μ g/kg days), high dose group (100 μ g/kg days), successive administration 14 days.
4. claim that Mus is heavy every day, measure the tumor size, calculate gross tumor volume and tumour inhibiting rate.
5. put to death animal in 24 hours after the last administration, get tumor and weigh.
The results are shown in accompanying drawing 2,3.
As seen from the figure, adopt this product treatment, compare with matched group, administration group mice body weight does not obviously descend, and this is the not available characteristics of conventional chemotherapy medicine, significantly is better than existing chemotherapeutics.
In addition, the leukocyte count (* 10 of all test group
9L
-1) be respectively: 7.3 ± 0.7,6.6 ± 0.6,6.2 ± 0.6,7.1 ± 0.7, promptly this product does not cause that murine interleukin descends when the treatment tumor, is the existing not available characteristics of antitumor drug.
Embodiment 3:
Crude extract-Cucurbitacin P.E Elaterin and cucurbatacin E (purity of HPLC area normalization method mensuration is greater than 95%)
Anti-people's laryngeal carcinoma pharmacodynamic study in the body
Method referring to " embodiment 2 "
18 of 18-20 gram nude mices, oxter, right side inoculating cell 5 * 10
6/ only, treat that the tumor piece grows into greater than 100mm
3The time, be divided into 3 groups at random, be respectively negative control group (0.9% sodium chloride, 0.2ml/ is the sky only), Cucurbitacin P.E Elaterin group (calculating dosage, gastric infusion, 300 μ g/kg days), cucurbatacin E group (Emulsion according to crude extract weight, intravenous administration, 200 μ g/kg days), successive administration 14 days.Put to death animal in 24 hours after the last administration, get tumor and weigh, calculate tumour inhibiting rate.The tumour inhibiting rate of Cucurbitacin P.E Elaterin group and cucurbatacin E group is respectively 39.2% and 51.6% as a result; Compare with the normal control group, body weight of treatment group mice and leukocyte all obviously do not change.
Embodiment 4:
The therapeutic alliance effect of cucurbitacin and radiotherapy
(wherein Cucurbitacin B content is 62.6% to Cucurbitacine, remaining composition is mainly cucurbatacin E, adopt marketable material, Tianjin Medicine Research Academy Pharmaceutical Co., Ltd) liposome (preparation method is seen patent " 200610046738.7 ") associating radiotherapy raising curative effect.Test divides three groups, and first group is the radiotherapy alone group, the irradiation of 500 rads; Second group is simple Emulsion group, and high, medium and low dosage is respectively 100 μ g/kg, 50 μ g/kg, 25 μ g/kg; The 3rd group for uniting group.Route of administration: intravenous injection; Dosage regimen: once a day, treated altogether 10 days; The result: first group tumour inhibiting rate is 21%; Second group tumour inhibiting rate is respectively 48%, 37%, 28%; The 3rd group of therapeutic alliance, tumour inhibiting rate rises to 71%, 62%, 51% respectively; Leukocyte (* 10
9L
-1) be respectively: first group, 2.6; Second group, 7.1,6.6,7.3; The 3rd group, 6.3,6.7,5.8; Normal group 6.9.
Embodiment 5:
The clinical patients use-case
4 patients (age is respectively 55,61,46 for 3 male, a women, 53 years old) oral Cucurbitacine soft capsule after carrying out radiotherapy (adopts marketable material, Tianjin Medicine Research Academy Pharmaceutical Co., Ltd, 0.3mg/ ball, self-control.
Its self-control method is Cucurbitacine 1g, MCT 1000g, and vitamin E 100g with MCT and vitamin E mix homogeneously, adds the cucurbitacin of recipe quantity, and 60 ℃ of heating for dissolving promptly get the solution of clear.This solution can continue to prepare soft capsule according to conventional method.
The result shows that its appetite/body weight/vital signs such as sleep all have clear improvement, and tumor is controlled, leukocyte count particularly, and after radiotherapy finishes, 4 patients' leukocyte (* 10
3) be respectively 3.2,3.8,3.1,3.6, use after 4 days leukocyte (* 10
3) rise to 4.6,4.3,5.1,4.2 respectively, continue to take reached for 2 weeks after, leukocyte (* 10
3) rise to 6.7,5.7,6.2,5.5 respectively, have very significantly leukogenic effect.
Claims (6)
1. the application of cucurbitacin in the medicine of preparation treatment laryngeal carcinoma.
2. application according to claim 1, it is characterized in that: cucurbitacin or its Pharmaceutical composition and pharmaceutically acceptable carrier are made tablet, powder, capsule, granule, suspensoid, syrup, oral liquid, ointment, patch, injection, are used for external, oral and injection.
3. application according to claim 1 is characterized in that: described cucurbitacin is a class tetracyclic triterpenoids compound, cucurbitacin crude extract, the Cucurbitacin P.E Elaterin that extracts in cucurbitaceous plant, Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae plant and the macro fungi.
4. application according to claim 3, it is characterized in that: described cucurbitacin, be the Cucurbitacin B monomer or be main component, still comprise one or more the mixture among cucurbatacin E, cucurbitacin I, the cucurbitacin Q, and Cucurbitacin B content is greater than 30% with the Cucurbitacin B.
5. application according to claim 1 is characterized in that: described cucurbitacin dosage calculates according to cucurbitacin, and health adult is 0.1mg～5mg/ day with dosage.
6. application according to claim 1 is characterized in that: described cucurbitacin dosage is that health adult is 0.3mg～3mg/ day with dosage, divides 1 time～4 times administrations.
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| CN102038689B (en) * | 2009-10-26 | 2014-04-09 | 沈阳药科大学 | Application of cucurbitacin in preparation of medicaments for treating cough |
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| CN1723906A (en) * | 2004-07-19 | 2006-01-25 | 胡才忠 | Cucurbitacine liposome and its prepn. method |
| CN1883484A (en) * | 2006-05-30 | 2006-12-27 | 沈阳药科大学 | Novel pharmacological use of cucurbitacine |
| CN1919339A (en) * | 2006-06-13 | 2007-02-28 | 沈阳药科大学 | Cucurbitacin nano preparation comprising protein, preparation method and use thereof |
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| CN1883484A (en) * | 2006-05-30 | 2006-12-27 | 沈阳药科大学 | Novel pharmacological use of cucurbitacine |
| CN1919339A (en) * | 2006-06-13 | 2007-02-28 | 沈阳药科大学 | Cucurbitacin nano preparation comprising protein, preparation method and use thereof |
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