CN102091064A - Use of furanodiene - Google Patents
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- CN102091064A CN102091064A CN 201010604051 CN201010604051A CN102091064A CN 102091064 A CN102091064 A CN 102091064A CN 201010604051 CN201010604051 CN 201010604051 CN 201010604051 A CN201010604051 A CN 201010604051A CN 102091064 A CN102091064 A CN 102091064A
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Abstract
The invention belongs to the technical field of medicines and discloses new use of furanodiene, namely the use of furanodiene in the preparation of medicines for treating human papillomavirus (HPV) infection. Tests and researches show that furanodiene has remarkable treatment effect on cervical carcinoma caused by HPV infection among various factors causing cervical carcinoma.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of new purposes of middle pharmaceutically active ingredient.
HPV of the present invention is meant the human papillomavirus.
Background technology
Middle pharmaceutically active ingredient is material base of its performance drug action, the comprehensive quality control of clear and system of active substance is the key and the core of the modernization of Chinese medicine, the curative effect material pesticide effect research of Chinese medicine is clear, thereby replace effective ingredient in Chinese or extract, could ensure its quality homogeneous, stable curative effect, safety is controlled, become standard active ingredient, be prepared into medicine as crude drug, therefore, carry out deep research in the centering pharmaceutically active ingredient, have profound significance, help the modernization of Chinese medicine, help Chinese medicine to go to the world, help the healthy of the mankind more.
Furanodiene is one of effective ingredient in the Chinese medicine Rhizoma Curcumae, and the open furanodiene of Chinese patent (application number is 200710169718.3) is used for treating laryngeal carcinoma, leukemia, cerebral glioma, ehrlich ascites carcinoma etc.Furanodiene can be treated cervical cancer.
The paathogenic factor of cervical cancer is not studied clear now, now studies more its pathogenesis of thinking and comprises that mainly (virus causes the cervical cancer Research Progress in Pathogenesis for human papillomavirus, herpesvirus, HIV (human immunodeficiency virus); Yang Lili, Tong Xiuqin; 2009 the 41st the 8th phases of volume of Inner Mongol medical journal Inner Mongolia Med J), (correlation analysiss of reproductive tract infection and precancerous lesions of uterine cervix and cervical cancer such as chlamydia, bacterial infection, infusorian; Yang Jie; The practical medicine of China the 5th the 27th phase of volume of JIUYUE in 2010), therefore, cause in the cervical cancer factor numerous, it is most important that the proof furanodiene causes cervical cancer to have a therapeutical effect to what reason, and this deep research can well be proved conclusively furanodiene and be can be good at treating this disease of cervical cancer, is the announcement of furanodiene control effect and mechanism, for furanodiene in the new drug development process, definite, deep theoretical basis is provided.
Summary of the invention
For these reasons, the scientific research personnel of our company studies by experiment, from the paathogenic factor of numerous cervical cancers, study and proved that furanodiene infects HPV and has good therapeutical effect, illustrate that the furanodiene cervical cancer that infection causes to HPV has good therapeutical effect; Particularly content is more than or equal to 50% furanodiene, with commercially available Oleum Curcumae relatively, have better pharmacological action; Compare less than 50% furanodiene with content, also have better pharmacological action.
The present invention is achieved through the following technical solutions.
The application of furanodiene in preparation treatment HPV infection medicine.
The application of furanodiene in the cervical disease medicine that preparation treatment HPV infects
The application of furanodiene in the cervical cancer medicine that preparation treatment HPV infects
Furanodiene content more than or equal to 50% less than 100%.
Wherein HPV is high-risk human mammilla papillomavirus hypotype or low risk human papillomavirus hypotype.
Wherein the HPV type is one or more in 16,18,26,31,33,35,39,45,51,52,53,56,58,66,59,68,73 and 82 types.
Wherein the HPV type be 6,11,40,42,43,44,54,61,70,72,81,83 and 89 types one or more.
Wherein the furanodiene site of action includes but not limited to E6 and E7 albumen among the HPV.
Wherein furanodiene is the pharmaceutical preparation of active component.
Wherein pharmaceutical preparation is oral formulations, ejection preparation, vagina preparation or rectal formulation.
Wherein oral formulations is tablet, granule, capsule, drop pill or oral liquid; Wherein ejection preparation is injectable emulsion or lyophilized injectable powder; Wherein vagina preparation is suppository, soft capsule, effervescent tablet, gel, ointment, vaginal tablet, membrane or foam; Wherein rectal formulation is suppository or soft capsule.
HPV of the present invention is meant the human papillomavirus.
Pharmacology test
Test the effect of 1 anti-human papilloma virus (anti-HPV)
Test reagent: HPV nucleic acid amplification (PCR) fluorescence detection reagent kit (comprising DNA extraction liquid 1, DNA extraction liquid 2, PCR reactant liquor, Taq enzyme, UNG).Other reagent are analytical pure.
Trial drug:
Test 1 group: commercially available Oleum Curcumae.
Test 2 groups: content is 49.3% furanodiene.
Test 3 groups: content is 90.1% furanodiene.
Test method:
Sample preparation: above-mentioned test 1 assembly is set to 500 μ g/ml solution; Test 2 assembly and be set to 0.8 μ g/ml solution; To test 3 and be configured to 10 μ g/ml solution; Test 3 assembly and be set to 5 μ g/ml; Test 3 assembly and be set to 1 μ g/ml; Test 3 assembly and be set to 0.8 μ g/ml; Test 3 assembly and be set to 0.4 μ g/ml;
The preparation of HPV infected specimen: be diagnosed as HPV from hospital outpatient and infect the isolated preparation of taking (the HPV type is 16,52,58 mixed types), focus in 1 centrifuge tube, 30mg weighs, use glass homogenizer homogenate, add the 5mL normal saline again, be made into the stripped suspension of 6mg/mL, standby.
The method of sample treatment: draw 25 μ L sample liquid and 25 μ L specimen suspensions to the 15mL centrifuge tube with liquid-transfering gun, jolting is even, and sample and specimen can fully be acted on, and puts 37 ℃ of water baths and cultivates, behind sample treatment specimen 1d, 3d, 5d, 7d, respectively get 1 group and carry out following test.
The extraction of HPV-DNA: from warm bath cabinet, take out specimen suspension through sample treatment, extract DNA by the test kit step: add 50 μ L normal saline, add 100 μ LDNA extracting solution behind the mixing again, jolting is even, the centrifugal 10min of 1200r/min, abandoning supernatant, add 25 μ LDNA extracting solution 2 again, abundant mixing, 100 ℃ of boiling water boil 10min, the centrifugal 10min of 1200r/min, supernatant is the HPV-DNA template.
DNA cloning: get the PCR reactant liquor 37.6 μ L in the detection kit, Taq archaeal dna polymerase 0.4 μ L, UNG0.03 μ L add HPV-DNA template 2 μ L again in the PCR reaction tube, and button strict control lid places quantitative PCR instrument cocycle amplification.HPV-DNA carries out cyclic amplification through high-temperature denatured, process annealing and extension, and cyclic program is set to: 37 ℃, and 5min; 94 ℃, 1min; 95 ℃, 5sec; 60 ℃, 30sec circulates 40 times.
Amount standard curve: detect quantitatively with fluorescent probe,, set up the quantitative positive criteria product of HPV-DNA of 4 series concentration, be followed successively by 5 * 10 according to the detection kit requirement
7/ mL, 5 * 10
6/ mL, 5 * 10
5/ mL, 5 * 10
4/ mL, (its detection sensitivity is 1 * 10 through the PCR detection
3/ mL, the result is judged to be feminine gender less than this concentration person).Natural logrithm with initial copy number is an abscissa, and cycle threshold is a vertical coordinate, and the regression straight line that obtains is a standard curve, in view of the above the amplification times of sample is carried out quantitatively.
Result of the test: see Table 1.
The DNA exercising result that table 1 different tests medicine infects HPV
Annotate :-represent negative.
The HPV infected specimen changed into be diagnosed as HPV from hospital outpatient and infect the isolated preparation (HPV is 18 types) take, test according to the method described above, test 1 day, 3 days, 5 days, 7 days result of 3 groups of (0.8-10 μ g/ml) (content is 50.2% furanodiene) cultivations and be all feminine gender; 5 days results are negative to test 2 groups of (content is 17.3% furanodiene) incubation times, and incubation time 7 days is feminine gender as a result; It is negative to test 7 days results of 1 group of cultivation.
The HPV infected specimen changed into be diagnosed as HPV from hospital outpatient and infect the isolated preparation (the HPV type is 53 and 66 types) take, test according to the method described above, test 1 day, 3 days, 5 days, 7 days result of 3 groups of (0.8-10 μ g/ml) (content is 66.9% furanodiene) cultivations and be all feminine gender; 5 days results are negative to test 2 groups of (content is 24.7% furanodiene) incubation times, and incubation time 7 days is feminine gender as a result; It is negative to test 7 days results of 1 group of cultivation.
The HPV infected specimen changed into be diagnosed as HPV from hospital outpatient and infect the isolated preparation (the HPV type is 6,43,44,54,61,70,72,81,83 and 89 types) take, test according to the method described above, test 1 day, 3 days, 5 days, 7 days result of 3 groups of (0.8-10 μ g/ml) (content is 83.2% furanodiene) cultivations and be all feminine gender; 5 days results are negative to test 2 groups of (content is 32.6% furanodiene) incubation times, and incubation time 7 days is feminine gender as a result; It is negative to test 7 days results of 1 group of cultivation.
Conclusion (of pressure testing): above-mentioned test data shows that the DNA that in 3 groups of the tests HPV is infected has the good restraining effect.
Test 2
Influence to the effect of HPV E6 E7 gene inhibition
Test material:
Cervical cancer tumer line: human cervical carcinoma CaSKi cell line (the HPV16 positive, the HPV53 positive, the HPV83 positive); People's cervix uteri squamous epithelial cancer immortalized cell line H8 (the HPV-56 positive, the HPV66 positive, the HPV42 positive).
Primer: by Shanghai Sangon Biological Engineering Technology And Service Co., Ltd, it is synthetic to use U.S. PE company 391 type automatic dna synthesizers, purification mode: PAGE.
Culture medium and serum: Dulbecco ' s Modified Eagle Medium (DMEM) culture medium (GIBCOBRL), hyclone (river, Tianjin page or leaf biochemical product company limited); Toolenzyme: Taq archaeal dna polymerase (Promega), reverse transcriptase (AMV Reverse Transcriptase) (Promega).
Trial drug:
Test 1 group: commercially available Oleum Curcumae.
Test 2 groups: content is 40.9% furanodiene.
Test 3 groups: content is 93.1% furanodiene.
Experimental technique
The cultivation of cervical cancer tumer line: human cervical carcinoma CaSKi cell is in the DMEM of 5% hyclone culture medium, and the H8 cell is in containing the DMEM culture medium of 2% hyclone, and 37 ℃, 5%CO2 saturated humidity environment is cultivated down.
Drug level is selected: different experiments group drug level 5 μ g/ml.
Cellular morphology is observed: living cells is taken a picture: with the cell inoculation of exponential phase in 6 orifice plate culture plates, every hole 10 * 10
4Individual cell, a slice coverslip is placed in every hole in 6 well culture plates of each experimental group, forms the cover plate with cell, is replaced by the pastille culture medium behind second day cell attachment, cultivates after three days observation of cell form and photograph under inverted microscope.
The blue colorimetry of tetramethyl azo azoles detects different pharmaceutical to CaSKi cell and H8 cell growth inhibited situation: with cell inoculation in 96 porocyte culture plates, 3000 cells in every hole, added different medicinal liquids in second day, parallel 5 holes of each concentration, 37 ℃, 5%CO2 cultivates every hole adding 5mg/ml tetramethyl azo azoles indigo plant (MTT) 20 μ l after 24 hours, continue to cultivate 4 hours, abandoning supernatant, every hole adds dimethyl sulfoxide 150 μ l, cultivates microplate reader 492nm mensuration OD value after 20 minutes.
Cell cycle detects: the same method in six well culture plates with the culture medium culturing that contains the variable concentrations medicine five days, parallel 3 holes of each drug level, collecting cell, the preparation single cell suspension, PBS cleans 2 times, pre-cooling 70% ethanol is fixed, 4 ℃ of preservations are to be checked.Handle endochylema RNA, 50mg/L iodate third ingot (popidium iodide through the 0.01%RNA enzyme, PI) behind the DNA dyeing 30min, remove by filter agglomerating cell through 300 mesh sieves, use COULTER EPICS XL flow cytometer and detect in the cell cycle not the natural death of cerebral cells rate of phase simultaneously.Every part of specimen is measured 5000 cells, phase when distinguishing cell cell cycle of living in according to dna content.
The mDNA detection of expression: collect to cultivate the 5th day cell, TRIZOL handles the back and extracts RNA, and reverse transcription is cDNA, and amplification HPVE6, E7, the β-action that increases simultaneously be as internal reference, HPV E6, E7 primer (616bp):
Upstream 5`-TGACTTTGCTTTTCGGGGATT-3`,
Downstream 5`-GAGAACAGATGGGGCACAC-3`.
β-action (552bp) primer sequence: upstream: 5`-ATCATGTTTGAGACCTTCAACACC-3`, downstream 5`-CATGGTGGTGCCGCCGCCAGACAG-3`.
The amplification parameter is: 94 ℃ of pre-degeneration 5min; 94 ℃ of degeneration 45s, 50 ℃ of renaturation 45s, 72 ℃ are extended lmin, 30 circulations of increasing; 72 ℃ are extended added-time 5min; 4 ℃ of preservations of PCR product; 2% agarose gel electrophoresis observed result, voltage 40V.Use the semi-quantitative analysis that Scion Image 4.0 (NIH) software carries out electrophoretic band image ash value.Testing gene electrophoretic band gray level ratio=band gray value to be measured/with a specimen internal reference β-action band gray value.
Use SPSS 13.0.0 statistical software, carry out one factor analysis of variance (ANOVA), t check etc.
The growth inhibited effect of table 2 pair CaSki cell (OD, n=5) absorbance (OD)
Annotate: compare #P＜0.05, ##P＜0.01 with the control group; Compare * P＜0.05 for 1 group with test; Compare △ P＜0.05 for 2 groups with test.
The growth inhibited effect of table 3 pair H8 cell (OD, n=5) absorbance (OD)
Annotate: compare #P＜0.05, ##P＜0.01 with the control group; Compare * P＜0.05 for 1 group with test; Compare △ P＜0.05 for 2 groups with test.
The influence of table 4 couple HPVE6, E7 gene expression (CaSKi cell cycle distribution and apoptosis rate)
Annotate: compare #P＜0.05, ##P＜0.01 with the control group.
The influence of table 5 couple HPVE6, E7 gene expression (H8 cell cycle distribution and apoptosis rate)
Annotate: compare #P＜0.05, ##P＜0.01 with the control group.
Table 6RT-PCR product electrophoretic band gray value
Annotate: compare #P＜0.05, ##P＜0.01 with the control group.
Conclusion (of pressure testing): above-mentioned test 1 has proved furanodiene with test 2, and infection has fine inhibitory action to HPV, the HPV different subtype is infected have the good restraining effect, mainly acts on its E6, E7 albumen; Relatively has better pharmacological action with Oleum Curcumae; Be lower than 50% furanodiene with content and relatively have better pharmacological action.
Preparation embodiment
Embodiment 1
Furanodiene is the tablet of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 90.1%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 2
Furanodiene is the capsule of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 44.3%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 3
Furanodiene is the injectable emulsion of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 59.7%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 4
Furanodiene is the lyophilized injectable powder of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 67.8%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 5
Furanodiene is the vaginal suppository of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 98.9%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 6
Furanodiene is the vaginal foam agent of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 86.8%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 7
Furanodiene is the vagina effervescence of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 72.7%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 8
Furanodiene is the rectal suppository of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 90.0%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 9
Furanodiene is the vagina gel of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 77.5%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 10
Furanodiene is the vagina ointment of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 93.6%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 11
Furanodiene is the vagina membrane of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 68.3%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 12
Furanodiene is the vagina soft capsule of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 74.7%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 13
Furanodiene is the rectum soft capsule of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 92.6%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 14
Furanodiene is the granule of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 58.7%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 15
Furanodiene is the rectal suppository of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 62.2%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
Embodiment 16
Furanodiene is the rectum soft capsule of active component preparation, and said preparation is used for the treatment of HPV and infects the disease that causes, and includes but not limited to cervical disease or cervical cancer.
Wherein furanodiene content 77.4%.Wherein HPV infects and includes but not limited to high-risk-type human nipple virus hypotype or low risk human papillomavirus hypotype.
The foregoing description includes but not limited to described.
Claims (9)
1. the application of furanodiene in preparation treatment HPV infection medicine.
2. application according to claim 1, wherein furanodiene content more than or equal to 50% less than 100%.
3. application according to claim 1, wherein HPV is high-risk human mammilla papillomavirus hypotype or low risk human papillomavirus hypotype.
4. application according to claim 1, wherein the HPV type is one or more in 16,18,26,31,33,35,39,45,51,52,53,56,58,66,59,68,73 and 82 types.
5. application according to claim 1, wherein the HPV type be 6,11,40,42,43,44,54,61,70,72,81,83 and 89 types one or more.
6. according to each described application of claim 4-5, wherein the furanodiene site of action comprises E6 and E7 albumen among the HPV.
7. according to each described application of claim 1-2, wherein furanodiene is the pharmaceutical preparation of active component.
8. application according to claim 7, wherein pharmaceutical preparation is oral formulations, ejection preparation, vagina preparation or rectal formulation.
9. application according to claim 8, wherein oral formulations is tablet, granule, capsule, drop pill or oral liquid; Wherein ejection preparation is injectable emulsion or lyophilized injectable powder; Wherein vagina preparation is suppository, soft capsule, effervescent tablet, gel, ointment, vaginal tablet, membrane or foam; Wherein rectal formulation is suppository or soft capsule.
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| 《实用癌症杂志》 20100228 梁东霞等 宫颈癌与hpv关系的研究进展 202-205 1-9 第25卷, 第2期 2 * |
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