CN101066263A - Use of baicalein as antifungal medicine synergist - Google Patents
Use of baicalein as antifungal medicine synergist Download PDFInfo
- Publication number
- CN101066263A CN101066263A CNA2007100416888A CN200710041688A CN101066263A CN 101066263 A CN101066263 A CN 101066263A CN A2007100416888 A CNA2007100416888 A CN A2007100416888A CN 200710041688 A CN200710041688 A CN 200710041688A CN 101066263 A CN101066263 A CN 101066263A
- Authority
- CN
- China
- Prior art keywords
- antifungal
- baicalin
- drug
- medicine
- baicalein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medicine technology and is especially new use of baicalein, which is one kind of effective components extracted from skullcap root and has been used in treating various kinds of inflammation, as antifungal medicine synergist. Baicalein is added into antifungal pyrrole medicine in the added amount of 4-16 mcg/ml. Experiments show that adding baicalein into antifungal medicine of fluconazole, ketocanazole, miconazole, etc can ensure the treating effect on fungal inflection and resist the drug tolerance of drug resisting fungi, so that baicalein may be used as the synergist of antifungal medicine.
Description
Technical field:
The present invention relates to medical technical field, is the new purposes of baicalin as antifungal medicine synergist.
Background technology:
(noroxylin, Baicalein BAI) are one of the active ingredient of extracting to baicalin from the dry root of labiate Radix Scutellariae, its structure is suc as formula shown in (I), be yellow acicular crystal, fusing point is 268 ℃-272 ℃ (methanol), the clinical various acute and chronic inflammation of treatment that are mainly used in.There is the report baicalin that Fusarium oxysporum and Candida albicans are had inhibitory action (Zhou Ligang etc., the antifungal activity of flavone and steroid compound, research and development of natural products, 1997,3:P24), but its antifungal activity a little less than, required active drug concentration is higher.
The pyroles antifungal drug comprises imidazoles group (imidazoles) and triazole group.Ketoconazole, clotrimazole, miconazole, econazole etc. are arranged in the imidazoles group.The domestic listing person of triazole group antifungal agent has fluconazol, itraconazole and voriconazole etc.At present, clinical antifungal drug commonly used is fluconazol, ketoconazole, miconazole, though they can effectively treat deep and shallow table portion fungal infection.But because clinical drug-resistant bacterial strain more and more general, cause that these antifungal drugs are invalid maybe need to strengthen dosage, and the increase of dosage must strengthen the generation of toxic and side effects.For example ketoconazole makes the treatment interruption thereby has limited its clinical practice because of its liver, cardiac toxicity.Therefore, do not increasing the antifungal drug consumption even reducing under the situation of dosage, utilize synergist effectively treat fungal infection particularly the drug resistance fungal infection have important clinical application value.
So far do not see the report of baicalin as yet as pyroles antifungal medicine synergists such as fluconazol, ketoconazole, miconazoles.
Summary of the invention:
The objective of the invention is is not increasing the antifungal drug consumption even is reducing under the situation of dosage, seeks new synergist with effective treatment fungal infection drug resistance fungal infection particularly.
The invention provides the new purposes of baicalin as antifungal medicine synergist, said antifungal drug is the pyroles antifungal drug, and baicalin addition in antifungal drug valid density is 4-16 mcg/ml or microgram/milligram.
Above-mentioned baicalin addition in antifungal drug valid density is preferably 8 mcg/ml or microgram/milligram, 16 mcg/ml or microgram/milligram.
Above-mentioned antifungal drug is imidazoles antifungal drug or antifungal drug in triazole class.
Above-mentioned antifungal drug is fluconazol, ketoconazole or miconazole.
In the above-mentioned application, add baicalin 4-16 microgram in every milliliters of liquid preparation (or every milligram of solid preparation), add fluconazol, ketoconazole or miconazole 0.125-0.5 microgram simultaneously.
The experiment proved that, baicalin has clear and definite potentiation when low concentration, endurance strain for clinical isolating endurance strain and laboratory-induced, when antifungal drug and baicalin share, can obviously reduce the dosage of antifungal drug, can not only under the situation that reduces dosage, guarantee its therapeutic effect equally, and can make the effect of antifungal drug recovery the drug resistance fungus to shallow table portion or deep fungal infection.Therefore can be used as the synergist of antifungal drug, be used for the treatment of different deeps and superficial fungal infection.
The present invention has opened up new purposes for baicalin, and also particularly fluconazol, ketoconazole, miconazole etc. provide a kind of effective synergist for the pyroles antifungal drug.
The specific embodiment:
The invention will be further described below in conjunction with embodiment, but enforcement of the present invention is not limited thereto.
Embodiment 1: baicalin and fluconazol share the effect to different clinical fungus strains.
Material and method
1. reagent:
Baicalin: available from Sigma company.
Fluconazol: Changzhou second pharmaceutical factory.
Dimethyl sulfoxine: China Medicine (Group) Shanghai Chemical Reagent Co..
Baicalin is made into the concentration of 32mg/ml with dimethyl sulfoxine, and the concentration of fluconazol is 2mg/ml, is subjected to the reagent thing in-20 ℃ of preservations.Before the experiment, 35 ℃ of incubators are put in the taking-up of medicine storage liquid melted, fully mixing carries out pharmacodynamics test respectively.
2. bacterial strain:
Candida albicans, gram Rou Shi candidiasis and microsporum canis clinical strain are provided by the Shanghai Changhai Hospital Mycology Lab, pick up from different section office of this hospital clinical sample respectively, and through morphology and biochemical evaluation.Also can select Candida albicans SC5314, ATCC76625 international standard bacterial strain for use.
All experiments are all drawn the plate activation in husky fort glucose agar medium (SDA) with bacterial strain, in 35 ℃ cultivated for 1 week after, the picking monoclonal is drawn the plate activation once more respectively, gets for the second time the gained monoclonal and puts the SDA inclined-plane, it is standby in 4 ℃ of preservations to cultivate the back with said method.
3. culture fluid:
RPMI RPMI-1640: RPMI 1640 (Gibco BRL company) 10.0g, NaHCO
32.0g morphine quinoline propane sulfonic acid (Sigma) 34.5g adds tri-distilled water 900ml dissolving, 1N NaOH transfers pH to 7.0, is settled to 1000ml, filters sterilization, 4 ℃ of preservations.
Husky fort agar glucose (SDA) culture medium: peptone 10g, glucose 40g, agar 18g adds tri-distilled water 900ml dissolving, adds 2mg/ml chloramphenicol solution 50ml, adjusts pH to 7.0, is settled to 1000ml, 4 ℃ of preservations behind the autoclaving.
The YEPD culture fluid: yeast extract 10g, peptone 20g, glucose 20g adds tri-distilled water 900ml dissolving, adds 2mg/ml chloramphenicol solution 50ml, is settled to 1000ml, 4 ℃ of preservations behind the autoclaving.
4. instrument:
Water isolation type electro-heating standing-temperature cultivator (Shanghai make a leapleap forward medical apparatus and instruments factory);
The desk-top constant temperature oscillator of THZ-82A (Shanghai make a leapleap forward medical apparatus and instruments factory);
511 type enzyme micro-plate readers (Shanghai the 3rd analytical tool factory);
5. bacterium liquid preparation:
(1) candidiasis bacterium liquid
The picking candidiasis is a small amount of on the SDA culture medium of 4 ℃ of preservations, is seeded to the 1mlYEPD culture fluid, in 30 ℃ with the activation of 200rpm shaken cultivation, make fungus be in later stage exponential phase of growth.Get this bacterium liquid to the 1mlYEPD culture fluid, activate 16 hours once more with said method after, with blood cell counting plate counting, adjust bacterial concentration to 3 * 10 with the RPMI RPMI-1640
3~5 * 10
3The concentration of individual/ml.
(2) microsporum canis bacterium liquid
The picking filamentous bacteria is seeded to the SDA inclined-plane on a small quantity on the SDA culture medium of 4 ℃ of preservations, in 35 ℃ cultivate a week after, picking is seeded to the SDA inclined-plane on a small quantity once more, cultivates weeks in 35 ℃.Add an amount of RPMI RPMI-1640 before the experiment in the SDA inclined-plane, blow and beat bacterium colony, fungal spore is free in the RPMI RPMI-1640, filter through four layers of sterile gauze then with suction pipe.Culture fluid adds the RPMI RPMI-1640 and adjusts spore concentration to 3 * 10 behind the blood cell counting plate counting
3~5 * 10
3The concentration of individual/ml.
6. drug sensitive plate preparation:
Get aseptic 96 orifice plates, add RPMI1640 culture fluid 100 μ l in No. 1 hole of every row and make blank; The 3-11 hole adds freshly prepared bacterium liquid 100 μ l; No. 2 holes add the fluconazol solution 2 μ l of bacterium liquid 196 μ l and 6.4mg/ml respectively.At the baicalin 2 μ l of No. 2 hole adding respective concentration, the 3-11 hole adds baicalin 1 μ l.
Doubling dilution is carried out in 2~No. 11 holes, make the final fluconazol concentration in 2~No. 11 holes be respectively 64,32,16,8,4,2,1,0.5,0.25 and 0.125 μ g/ml; No. 1 hole is for not containing the RPMI RPMI-1640 of medicine, and as negative control, No. 12 holes are for not containing the bacterium liquid of medicine, as positive control.Each drug sensitive plate is in 30 ℃ of cultivations.
7.MIC
80Value is judged:
Containing bacterium 96 orifice plates cultivated 24 hours respectively at 30 ℃ or after the week, surveys each hole OD value with enzyme micro-plate reader in 620nm.With the positive control boring ratio, be MIC with the drug level in the least concentration hole of OD value decline more than 80%
80(drug level when conk 80% is suppressed).
MIC when medicine
80Value surpasses when measuring concentration range, adds up by the following method: MIC
80When value is higher than maximum concentration 64 μ g/ml, count ">64 μ g/ml ".The equal operation repetitive of above-mentioned experiment 2 to 3 times is worked as MIC
80Value just is accepted in the time of accurately repeating; Work as MIC
80Value differs a concentration when above, then needs new experiment, till meeting the requirements.
Experimental result sees Table 1, table 2.
Table 1 baicalin and fluconazol share the MIC to the clinical Candida albicans of 5 strains
80Value
Bacterial strain | MIC 80Value (μ g/ml) is single to be used | MIC 80Value (μ g/ml) is share | ||
Flu | BAI | Flu | BAI | |
SC5314 ATCC76625 is white to be read 031105 and whitely reads 040421 and whitely read 040209 and whitely read 040732 and whitely read 040134 | 1 1 1 2 2 2 1 | 32 32 >64 >64 >64 >64 >64 | 0.125 0.125 0.125 0.125 0.25 0.25 0.5 | 4 4 4 4 8 4 4 |
Annotate: Flu represents fluconazol, and BAI represents baicalin (down together).
Table 2 baicalin and fluconazol share the MIC to 3 strains clinical gram Rou Shi candidiasis and microsporum canis
80Value
Bacterial strain | MIC 80Value (μ g/ml) is single to be used | MIC 80Value (μ g/ml) is share | ||
Flu | BAI | Flu | BAI | |
Gentle 031324 sheep of gentle 071005 gram of gram is little by 060321 | 32 >64 32 | >64 >64 >64 | 0.25 0.25 0.5 | 16 8 8 |
By table 1 and table 2 as seen, 8 μ g/ml baicalin can make the MIC of Candida albicans to fluconazol
80Value decline 2-8 doubly, 16 μ g/ml baicalin can make clinical gram Rou Shi candidiasis and microsporum canis MIC to fluconazol
80Value from 〉=32 reduce to≤0.5, illustrate that baicalin can obviously strengthen the antifungic action of fluconazol.
Embodiment 2: baicalin and fluconazol share the effect to different clinical and laboratory-induced persisters
Material and method
1. reagent:
Baicalin: available from Sigma company.
Fluconazol: Changzhou second pharmaceutical factory.
Dimethyl sulfoxine: China Medicine (Group) Shanghai Chemical Reagent Co..
Baicalin is made into the concentration of 32mg/ml with dimethyl sulfoxine, and the concentration of fluconazol is 2mg/ml, is subjected to the reagent thing in-20 ℃ of preservations.Before the experiment, 35 ℃ of incubators are put in the taking-up of medicine storage liquid melted, fully mixing carries out pharmacodynamics test respectively.
2. bacterial strain:
The clinical drug-resistant strain: Candida albicans provides by the Shanghai Changhai Hospital Mycology Lab, picks up from different section office of this hospital clinical sample respectively, and through morphology and biochemical evaluation.
The laboratory-induced persister: Candida albicans (SC5314-R, Y01-R) is induced the persister of formation for Candida albicans type strain SC5314, ATCC76625 through fluconazol, through morphology and biochemical evaluation.
Other experimental procedure and method are with embodiment 1.
Experimental result sees Table 3, table 4.
Table 3 baicalin and fluconazol share the MIC to 2 strain laboratory-induced Candida albicans persisters
80Value
Bacterial strain | MIC 80Value (μ g/ml) is single to be used | MIC 80Value (μ g/ml) is share | ||
Flu | BAI | Flu | BAI | |
Read SC5314-R in vain and read Y01-R in vain | >64 >64 | >64 >64 | 0.5 0.5 | 8 16 |
Table 4 baicalin and fluconazol share the MIC to the clinical Candida albicans persister of 5 strains
80Value
Bacterial strain | MIC 80Value (μ g/ml) is single to be used | MIC 80Value (μ g/ml) is share | ||
Flu | BAI | Flu | BAI | |
Thought 0501199 white thought 0601587 white thought 0601417 is read 0603115 in vain and is read 0601417 in vain in vain | >64 >64 64 64 >64 | >64 >64 >64 >64 >64 | 0.5 0.125 0.25 0.25 0.125 | 8 4 8 4 16 |
By table 3, table 4 as can be seen, originally to the drug-fast clinical Candida albicans MIC of fluconazol
80Be worth 〉=64, can make the MIC of fluconazol with the baicalin of 16 μ g/ml
80Value drops to 0.125-0.5 μ g/ml, to the Candida albicans of laboratory-induced, can make the MIC of fluconazol with the baicalin of 16 μ g/ml
80Value drops to 0.5 μ g/ml, shows that baicalin can make the sensitivity of bacterial strain recovery to medicine, strengthens the antibacterial efficacy of fluconazol greatly.
Embodiment 3: the drug combination of baicalin and miconazole, ketoconazole
Material and method
1. reagent:
Baicalin: available from Sigma company.
Miconazole: available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Ketoconazole: available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Dimethyl sulfoxine: China Medicine (Group) Shanghai Chemical Reagent Co..
Baicalin is made into the concentration of 32mg/ml with dimethyl sulfoxine, and miconazole and ketoconazole are made into the concentration of 6.4mg/ml respectively with dimethyl sulfoxine, be subjected to the reagent thing in-20 ℃ of preservations.Before the experiment, 35 ℃ of incubators are put in the taking-up of medicine storage liquid melted, fully mixing carries out pharmacodynamics test respectively.
Other experimental procedure and method are with embodiment 1.
Experimental result sees Table 5, table 6.
Table 5 baicalin and miconazole share the MIC to the clinical Candida albicans persister of 3 strains
80Value
Bacterial strain | MIC 80Value (μ g/ml) is single to be used | MIC 80Value (μ g/ml) is share | ||
Micon | BAI | Micon | BAI | |
The white 0601587 white thought 0501900 of reading reads 0501212 in vain | 32 32 16 | >64 >64 >64 | 0.5 0.125 0.125 | 4 8 4 |
Annotate: Micon represents miconazole, and BAI represents baicalin.
Table 6 baicalin and ketoconazole share the MIC to the clinical Candida albicans persister of 3 strains
80Value
Bacterial strain | MIC 80Value (μ g/ml) is single to be used | MIC 80Value (μ g/ml) is share | ||
Ketocon | BAI | Ketocon | BAI | |
The white 0601573 white thought 0603421 of reading reads 0603488 in vain | 16 32 16 | >64 >64 >64 | 0.125 0.125 0.125 | 4 8 4 |
Annotate: Ketocon represents ketoconazole, and BAI represents baicalin.
By table 5,6 as seen, baicalin not only can share the generation potentiation to fluconazol, and antifungal agent such as miconazole, ketoconazole are had antibiotic potentiation equally.Can make miconazole, ketoconazole MIC with the baicalin of 8 μ g/ml to the drug resistance Candida albicans
80Value drops to 0.5-0.125 μ g/ml from 16-32 μ g/ml.
Claims (6)
1, baicalin is characterized in that as the purposes of antifungal medicine synergist described antifungal drug is the pyroles antifungal drug, and baicalin addition in antifungal drug valid density is 4-16 mcg/ml or microgram/milligram.
2, baicalin according to claim 1 is characterized in that as the purposes of antifungal medicine synergist baicalin addition in antifungal drug valid density is 8 mcg/ml or microgram/milligram, 16 mcg/ml or microgram/milligram.
3, baicalin according to claim 1 and 2 is characterized in that as the purposes of antifungal medicine synergist described antifungal drug is the imidazoles antifungal drug.
4, baicalin according to claim 1 and 2 is characterized in that as the purposes of antifungal medicine synergist described antifungal drug is an antifungal drug in triazole class.
5, baicalin according to claim 3 is characterized in that as the purposes of antifungal medicine synergist described imidazoles antifungal drug is ketoconazole or miconazole.
6, baicalin according to claim 4 is characterized in that as the purposes of antifungal medicine synergist described antifungal drug in triazole class is a fluconazol.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200710041688A CN101066263B (en) | 2007-06-06 | 2007-06-06 | Use of baicalein as antifungal medicine synergist |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200710041688A CN101066263B (en) | 2007-06-06 | 2007-06-06 | Use of baicalein as antifungal medicine synergist |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101066263A true CN101066263A (en) | 2007-11-07 |
CN101066263B CN101066263B (en) | 2010-05-19 |
Family
ID=38879043
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200710041688A Expired - Fee Related CN101066263B (en) | 2007-06-06 | 2007-06-06 | Use of baicalein as antifungal medicine synergist |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101066263B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101961328A (en) * | 2010-09-17 | 2011-02-02 | 中国人民解放军第二军医大学 | Application of sodium houttuyfonate as synergist of antifungal medicament |
CN105669625A (en) * | 2016-01-28 | 2016-06-15 | 中国人民解放军第二军医大学 | 2-substituted benzopyran-4-one compounds and application thereof |
CN107412344A (en) * | 2017-05-10 | 2017-12-01 | 南京金盾动物药业有限责任公司 | Pharmaceutical composition for treating pet skin disease and preparation method thereof |
CN111057035A (en) * | 2019-11-05 | 2020-04-24 | 中国人民解放军第二军医大学 | Baicalein derivative and preparation method and application thereof |
CN112245566A (en) * | 2020-10-29 | 2021-01-22 | 河南农业大学 | New application of scutellaria flavonoid compound and/or metal ion complexing agent in synergism of polymyxin antibiotics antibacterial action |
-
2007
- 2007-06-06 CN CN200710041688A patent/CN101066263B/en not_active Expired - Fee Related
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101961328A (en) * | 2010-09-17 | 2011-02-02 | 中国人民解放军第二军医大学 | Application of sodium houttuyfonate as synergist of antifungal medicament |
CN101961328B (en) * | 2010-09-17 | 2011-12-21 | 中国人民解放军第二军医大学 | Application of sodium houttuyfonate as synergist of antifungal medicament |
CN105669625A (en) * | 2016-01-28 | 2016-06-15 | 中国人民解放军第二军医大学 | 2-substituted benzopyran-4-one compounds and application thereof |
CN105669625B (en) * | 2016-01-28 | 2018-05-25 | 中国人民解放军第二军医大学 | A kind of 2- substitution chromene -4- ketone compounds and its application |
CN107412344A (en) * | 2017-05-10 | 2017-12-01 | 南京金盾动物药业有限责任公司 | Pharmaceutical composition for treating pet skin disease and preparation method thereof |
CN107412344B (en) * | 2017-05-10 | 2021-02-26 | 南京金盾动物药业有限责任公司 | Pharmaceutical composition for treating pet skin diseases and preparation method thereof |
CN111057035A (en) * | 2019-11-05 | 2020-04-24 | 中国人民解放军第二军医大学 | Baicalein derivative and preparation method and application thereof |
CN111057035B (en) * | 2019-11-05 | 2021-10-26 | 中国人民解放军第二军医大学 | Baicalein derivative and preparation method and application thereof |
CN112245566A (en) * | 2020-10-29 | 2021-01-22 | 河南农业大学 | New application of scutellaria flavonoid compound and/or metal ion complexing agent in synergism of polymyxin antibiotics antibacterial action |
CN112245566B (en) * | 2020-10-29 | 2022-06-03 | 河南农业大学 | New use of Scutellariae radix flavonoid and/or metal ion complexing agent in synergistic polymyxin antibiotic antibacterial effect |
Also Published As
Publication number | Publication date |
---|---|
CN101066263B (en) | 2010-05-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102218052B (en) | Application of kaempferol as synergist of anti-fungal medicaments | |
Gomes et al. | Mucormycosis caused by unusual mucormycetes, non-Rhizopus,-Mucor, and-Lichtheimia species | |
Xiang et al. | Biocontrol potential of endophytic fungi in medicinal plants from Wuhan Botanical Garden in China | |
CN101066263A (en) | Use of baicalein as antifungal medicine synergist | |
CN115120602A (en) | Antifungal medicine synergist | |
CN102198130B (en) | Use of shikonin as antifungal medicine synergist | |
CN103520157B (en) | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs | |
CN101961328B (en) | Application of sodium houttuyfonate as synergist of antifungal medicament | |
Fondati et al. | A case of feline phaeohyphomycosis due to Fonsecaea pedrosoi | |
CN103040852B (en) | Application of lysine as synergist for preparing antifungal drug | |
CN102204909B (en) | Application of mangiferin as synergist of antifungal agents | |
CN111419829A (en) | Application of honokiol in inhibiting streptococcus suis or biofilm thereof | |
CN1235585C (en) | Use of berberine as anti fungus medicine synergist | |
CN103710418B (en) | Suppress the method for Aspergillus fumigatus biofilm formation | |
Naidu et al. | Onychomycosis caused by Scopulariopsis brumptii: A case report and sensitivity studies | |
CN104306477B (en) | Coptis water extract and monomer are preparing the purposes in suppressing Streptococcus suis or intervening streptococcus suis biofilm medicine | |
Daruliza et al. | Anti-Candida activity and brine shrimp toxicity assay of Ganoderma boninense | |
CN107412227A (en) | Application and antifungal composition of a kind of anthraquinone analog compound in antifungal drug is prepared | |
CN113142233B (en) | Compatibility research of matrine and Lecanicillium wilsonii and insecticide combined with matrine and Lecanicillium wilsonii | |
CN101816646A (en) | Application of theaflavin as synergist of antifungal medicine | |
CN101816666A (en) | Use of forsythiaside as synergist of antifungal agents | |
Devi et al. | Favorable outcome of amphotericin B treatment of zygomycotic necrotizing fascitis caused by Apophysomyces elegans | |
CN1246005C (en) | Chinese medicine composition for deep fungus infection | |
CN115919883B (en) | Composition with function of resisting resistance of malassezia globosa and preparation method thereof | |
CN111888356B (en) | Application of isoquinoline alkaloid in preparation of drug-resistant hemolytic staphylococcus drug |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100519 Termination date: 20150606 |
|
EXPY | Termination of patent right or utility model |