CN101829077B - Application of dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases - Google Patents
Application of dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases Download PDFInfo
- Publication number
- CN101829077B CN101829077B CN201010182593XA CN201010182593A CN101829077B CN 101829077 B CN101829077 B CN 101829077B CN 201010182593X A CN201010182593X A CN 201010182593XA CN 201010182593 A CN201010182593 A CN 201010182593A CN 101829077 B CN101829077 B CN 101829077B
- Authority
- CN
- China
- Prior art keywords
- cooh
- formula
- chohch
- mycoplasma
- choh
- 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.)
- Expired - Fee Related
Links
- 0 CC1(*)C(C=CC(*C(*)(*)*C(*)(*C(C=Cc2c(*)c(*)c(*)c(I)c2*)=O)I)=O)=C([*+])C(*)=C(*)C1* Chemical compound CC1(*)C(C=CC(*C(*)(*)*C(*)(*C(C=Cc2c(*)c(*)c(*)c(I)c2*)=O)I)=O)=C([*+])C(*)=C(*)C1* 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to application of a dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases.
Description
Technical field
The present invention relates to medical technical field, be specifically related to dicaffeoylguinic acid ramification is used for treating the mycoplasma infection diseases medicine in preparation purposes.
Technical background
Mycoplasma is a kind of another kind of small pathogen that is different from antibacterial and fungus; The pathogenic mycoplasma relevant with human urogenital infections has Ureaplasma urealyticum (UU), mycoplasma hominis (MH) and genital tract mycoplasma (MG), relevant disease such as mycoplasm urethritis, cervicitis, vaginitis, pelvic inflammatory disease, adnexitis, prostatitis etc.The treatment common drug has antibiotic such as doxycycline, minocycline, azithromycin, clarithromycin, ofloxacin.There is more problem at present in antibiotic therapy, and the one, Tetracyclines is big with big lopps esters antibiotic gastrointestinal reaction, and liver function is had side effects, and compliance is poor.The 2nd, because antibiotic abuse and use lack of standardization cause the Resistant strain of mycoplasma increasing, the drug resistance cycle constantly shortens, life and health that serious harm is human.Therefore, it is high to seek sensitivity, and side effect is little, is difficult for producing chemical sproof novel anti-mycoplasma drug, for improving curative effect, alleviates the patient suffering, and protection body microecological balance has extremely important meaning.
Chinese medicine is motherland's medical treasure-house; Many Chinese medicine preparation and antibiotic medicine are relatively; Clinical efficacy is good; Toxic and side effects is little, and under face of mankind mycoplasma drug resistance and the ever-increasing severe situation of antibiotic untoward reaction, searching and discovery anti-mycoplasma drug have important scientific meaning from the infection Chinese medicine with clinical basis and unique theoretical system.
Dicaffeoyl quinic acid extensively exists in Compositae, pulse family, Umbelliferae, Caprifoliaceae and convolvulaceous plant; Common has 1,5-two-O-caffeoyl guinic acid, 3,5-two-O-caffeoyl guinic acid, 4; 5-two-O-caffeoyl guinic acid and 3,4-two-O-caffeoyl guinic acid etc.The inventor finds that unexpectedly dicaffeoylguinic acid ramification has significant inhibitory effect to mycoplasma in herbal medicine efficacy material base research process.The present invention is based on above-mentioned discovery is accomplished.
Dicaffeoylguinic acid ramification and the analog that first purpose of the present invention relates to formula 1 (if having enantiomer, comprise two enantiomer) is used for treating the purposes of mycoplasma infection diseases medicine in preparation,
Formula 1
Wherein
Q
1Be a valence link, or CH
2, CHOH, CH
2CH
2, CH
2CHOH, CHOHCH
2, CHCOOH, CH
2CH
2CHOH, CHOHCH
2CH
2, CH
2CHOHCH
2, CH
2CHOHCHOH or CHOHCHOHCH
2
Q
2And Q
3Can be respectively H or lump together expression CH
2CH
2, CH
2CHOH, CHOHCH
2, CH
2CH
2CHOH, CHOHCH
2CH
2, CH
2CHOHCH
2, CH
2CHOHCHOH, CHOHCHOHCH
2, CH
2COH (COOH) CH
2, CH
2CH
2COH (COOH) CH
2, CH
2COH (COOH) CH
2CH
2, CHOHCH
2COH (COOH) CH
2Or CH
2COH (COOH) CH
2CHOH, thus circulus formed,
X
1Be O, NH, CH
2Or CHCOOH;
X
2Be O, NH, CH
2Or CHCOOH;
Y
1, Y
2, Y
3And Y
4Respectively be a valence link, O or NH;
Work as Y
1, Y
2, Y
3And Y
4When respectively being a valence link, R
1, R
2, R
3, R
4Be H, CH
2COOH, CH
2CH
2COOH or CH
2CH
2CH
2COOH;
Work as Y
1, Y
2, Y
3And Y
4When respectively being O or NH, R
1, R
2, R
3, R
4Be H, CH
3, CH
3CO, CH
3CH
2CO or CH
3CH
2CH
2CO;
Y
5, Y
6, Y
7, Y
8, Y
9, Y
10Be H, Cl, Br or I;
Z
1And Z
2Be H, COOH, COOM, wherein M representes C1-6 alkyl, benzyl, alkali metal or alkaline-earth metal.
A purpose more of the present invention relates to the pharmaceutical composition that contains formula 1 chemical compound, and this pharmaceutical composition has significant inhibitory effect to mycoplasma.According to the present invention, this pharmaceutical composition can be added with various pharmaceutical excipients, additive and carrier.
According to the present invention, formula 1 chemical compound of the present invention or the pharmaceutical composition that contains formula 1 chemical compound can be used for treating mycoplasma infection, the genital diseases and the urinary tract disease that cause like mycoplasma infection.Wherein genital diseases is meant cervicitis, vaginitis, pelvic inflammatory disease and the adnexitis that Ureaplasma urealyticum, mycoplasma hominis, genital tract mycoplasma or mixed infection cause.The urinary tract disease that mycoplasma causes is meant that Ureaplasma urealyticum, mycoplasma hominis, genital tract mycoplasma or mixed infection cause urethritis, prostatitis.
According to the present invention; Pharmaceutical composition of the present invention can become pharmaceutical composition with pharmaceutically acceptable vehicle group; Process various preparations, comprising: the preparation of intestinal such as capsule, tablet, granule, drop pill, oral liquid, suppository, effervescent tablet, gel or parenterai administration.
According to the present invention, formula 1 chemical compound of the present invention is mainly from various plants such as Compositae, Caprifoliaceaes, like Ainsliasa fragrans Champ Ainsliaea fragrans, Flos Lonicerae Lonicera japonica, Flos Inulae Inula japonica etc.Or through complete synthesis or semisynthesis preparation.
According to the present invention, the preferred anti-mycoplasma chemical compound of the present invention is a dicaffeoyl quinic acid.
According to the present invention, the most preferred anti-mycoplasma chemical compound of the present invention is 3,5-two-O-caffeoyl guinic acid, 4,5-two-O-caffeoyl guinic acid, 3,4-two-O-caffeoyl guinic acid.
According to the present invention; Dicaffeoyl quinic acid can prepare through following extraction, disjunctive path from above-mentioned plant: get plant (Ainsliasa fragrans Champ, Flos Lonicerae etc.), add 70% alcohol reflux, reclaim under reduced pressure is to there not being the alcohol flavor; Concentrated solution adopts ethyl acetate extraction, continues through column chromatography (silica gel, C
18) separate, obtain monomeric compound.Or get concentrated solution and be splined on macroporous adsorptive resins, the alcohol-water gradient elution is collected 60% ethanol elution, and reclaim under reduced pressure obtains the dicaffeoyl quinic acid effective part extract to doing.
According to the present invention, dicaffeoyl quinic acid can be through 3, and the quinic acid of protected coffee acyl chlorides of 4-dihydroxy and the protection of being selected property of hydroxyl is through the esterification preparation.
To be used for further setting forth the present invention through anti-mycoplasma in the external and body of dicaffeoyl quinic acid below.
Test the anti-mycoplasma external activity research of one or two coffee acyl quinic acids
1 material
1.1 testing drug: 3,5-two-O-caffeoyl guinic acid (1), 4,5-two-O-caffeoyl guinic acid (2) 3,4-two-O-caffeoyl guinic acids (3), the molecular formula of chemical compound 1～3 is: C
25H
24O
12, purity＞95%, above chemical compound are Natural Medicine Chemistry teaching and research room of China Medicine University and provide; Positive drug: azithromycin (Bio Basic Inc, Lot:GS1219B508C), ciprofloxacin (Bio Basic Inc, Lot:0916S06).
1.2 mycoplasma strain: (UU T1) is provided by HSPH of Southeast China University EL the Ureaplasma urealyticum type strain; (MH ATCC25114) purchases in American National strain preservation center the mycoplasma hominis type strain; Ureaplasma urealyticum (UU) clinical strain (12 strain) and mycoplasma hominis (UH) clinical strain (12 strain) are to separate in the large hospital gynecological outpatient service urogenital infections patient BIAO and BEN in the Southeast China University and obtain.
1.3 culture medium: purchase in Nanjing biological product company limited at dawn, the import packing.
2 experimental techniques adopt the fluid medium dilution method.
With UU or UH culture medium doubling dilution medicine to be checked and control drug, each hole amount of liquid medicine is 180 μ l on 96 hole polyethylene boards.Every hole inoculum density is about 10
4The UU of CCU or UH type strain or clinical separation strain culture 20 μ l seal.Set up the positive and negative contrast simultaneously.The rearmounted 36.5 ℃ of incubators of inoculation are hatched observed result behind 24～48hr.According to culture medium change color judged result: culture medium becomes redness by yellow and shows that the mycoplasma growth is arranged.Observe the UU growth change in the 24h, the change color identical with control wells occur like the dosing hole, the corresponding concentration that expression institute adds medicine is to UU unrestraint effect, and the drug level that change color is grown for effective inhibition UU does not still appear in 24h; Observe the MH growth change in 24～48h, the change color identical with control wells occur like the dosing hole, the corresponding concentration that expression institute adds medicine is to MH unrestraint effect, and the drug level that change color is grown for effective inhibition MH does not still appear in 48h.The dosing group is the drug level (MIC) that smallest effective suppresses the mycoplasma growth with the Cmin that change color do not occur.Experiment adopts UU type strain, UU clinical strain, MH type strain and MH clinical strain to do reference.
3 results
Experimental result shows, 3, and 5-two-O-caffeoyl guinic acid (1), 4,5-two-O-caffeoyl guinic acid (2), and 3,4-two-O-caffeoyl guinic acid (3) is to the MIC of UU
50Difference 0.625,0.625, and 1.25mg/ml, the positive drug azithromycin is to the MIC of UU
50Value is 1.25mg/ml.The MIC of 1～3 couple of UH of chemical compound
50Value is respectively 1.25,1.25, and 0.625mg/ml, and the positive drug azithromycin is to the MIC of UU
50Value is 1.25mg/ml.Be subjected to the external anti-UU and the MH effect measurement result of reagent thing to see Table 1.
The external inhibition to UU and UH of table 1 dicaffeoylguinic acid ramification is active
External anti-mycoplasma medicine efficacy screening shows that 1～3 pair of Ureaplasma urealyticum of dicaffeoylguinic acid ramification (UU) and mycoplasma hominis (UH) all have good inhibitory effect.Above chemical compound derives from Chinese medicine, differs greatly with big lopps esters, Tetracyclines, the quinolone antibiotic class chemical constitution of clinical application, is applicable to that the genitourinary tract that treatment drug resistance mycoplasma causes catches.
Test the anti-mycoplasma activity in vivo research of two or two coffee acyl quinic acids
1. laboratory animal and material
60 of female BALB/C mices in 8～10 weeks, are purchased in Institute of Zoology, Academia Sinica; (UU T1) is provided by HSPH of Southeast China University EL the Ureaplasma urealyticum type strain.The UU fluid medium is available from Nanjing biological product at dawn company limited.Azithromycin, 0.25g/ sheet, Yangtze River, Jiangsu pharmaceutical Co. Ltd.Estradiol benzoate injection, 1mg/ml, Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd..3,5-two-O-caffeoyl guinic acid, purity＞95%, Natural Medicine Chemistry teaching and research room of China Medicine University provides.
2. method
2.1UU cultivation and CCU thereof (Colour changing unit, change color unit measures) press document (Robertson JA, nineteen eighty-two) method.
2.2 bacterium liquid preparation with UU bacterial strain continuous passage 3 times, get the 3rd generation exponential phase bacterium liquid (10
6CCU/ml), be diluted to 2.0 * 10 with culture medium
5CCU/ml is as work bacterium liquid.
2.3 the preparation of mice ureaplasma urealyticum infection animal model
BALB/C mice, 6～8 weeks, subcutaneous injection estradiol benzoate 0.125mg, concentration 1mg/ml, continuous 4 weeks, 1 time weekly; The 2nd week of medication, vagina inoculation UU bacterial strain 50 μ l, concentration 2.0 * 10
5CCU/ml.After inoculating for 1 week, get vaginal secretions, UU cultivates, and the result shows that 48 culture medium become pink, shows modeling success rate 80%; Negative culture results person continues inoculating strain, and amount is the same, and 1 week back UU cultivates, and all culture medium all become pink, show the modeling success.Modeling result: 49 of the 3rd all positive numbers, positive rate 80%; The 4th week: 60 of positive numbers, positive rate 100%.
2.4 pharmaceutical intervention and collection of specimens
With modeling success mice be divided into model group at random, tried drug group, positive azithromycin group; Model group gives normal saline, is tried drug group gastric infusion 3,5-two-O-caffeoyl guinic acid (100mg/kg); Positive group gastric infusion azithromycin group (100mg/kg); The administration volume is 0.4ml, every day 1 time, intervenes for 2 weeks continuously.Get vaginal secretions, UU cultivates.
3 results
3,5-two-O-caffeoyl guinic acid is tried drug group 18 examples and is turned out cloudy, and 2 examples are positive, negative conversion rate 90%; Azithromycin group 12 examples are turned out cloudy, and 7 examples are positive, and 1 example is dead, negative conversion rate 60%, mortality rate 5%; Model group 2 examples are negative, and 16 examples are positive, and 3 examples are dead, negative conversion rate 10%, mortality rate 15%.3,5-two-O-caffeoyl guinic acid, azithromycin group and model group compare, P＜0.01, and there were significant differences.3,5-two-O-caffeoyl guinic acid and azithromycin group compare, and there is statistical significance P＜0.05.The drug effect result shows in the body, and dicaffeoyl quinic acid has therapeutical effect preferably to the mycoplasma reproductive tract infection.
Three, acute toxicity test
The acute toxicity test in mice result shows, oral administration 3, the LD of 5-two-O-caffeoyl guinic acid
50Value＞3g/kg.
Claims (4)
1. the dicaffeoylguinic acid ramification of following formula is used for treating the genital diseases that mycoplasma infection causes and the purposes of urinary tract disease medicine in preparation,
Formula 1
Wherein
Q
1Be a valence link, or CH
2, CHOH, CH
2CH
2, CH
2CHOH, CHOHCH
2, CHCOOH, CH
2CH
2CHOH, CHOHCH
2CH
2, CH
2CHOHCH
2, CH
2CHOHCHOH or CHOHCHOHCH
2
Q
2And Q
3Can be respectively H or lump together expression CH
2CH
2, CH
2CHOH, CHOHCH
2, CH
2CH
2CHOH, CHOHCH
2CH
2, CH
2CHOHCH
2, CH
2CHOHCHOH, CHOHCHOHCH
2, CH
2COH (COOH) CH
2, CH
2CH
2COH (COOH) CH
2, CH
2COH (COOH) CH
2CH
2, CHOHCH
2COH (COOH) CH
2Or CH
2COH (COOH) CH
2CHOH, thus circulus formed,
X
1Be O, NH, CH
2Or CHCOOH;
X
2Be O, NH, CH
2Or CHCOOH;
Y
1, Y
2, Y
3And Y
4Respectively be a valence link, O or NH;
Work as Y
1, Y
2, Y
3And Y
4When respectively being a valence link, R
1, R
2, R
3, R
4Be H, CH
2COOH, CH
2CH
2COOH or CH
2CH
2CH
2COOH;
Work as Y
1, Y
2, Y
3And Y
4When respectively being O or NH, R
1, R
2, R
3, R
4Be H, CH
3, CH
3CO, CH
3CH
2CO or CH
3CH
2CH
2CO;
Y
5, Y
6, Y
7, Y
8, Y
9, Y
10Be H, Cl, Br or I;
Z
1And Z
2Be H, COOH, COOM, wherein M representes C1-6 alkyl, benzyl, alkali metal or alkaline-earth metal.
2. the purposes of claim 1 when there are two enantiomer in formula 1, comprises two enantiomer.
3. according to the purposes of claim 1, wherein dicaffeoylguinic acid ramification is:
3,5-two-O-caffeoyl guinic acid, suc as formula 2,
Formula 2;
3,4-two-O-caffeoyl guinic acid, suc as formula 3,
Formula 3;
3,4-two-O-caffeoyl guinic acid, suc as formula 4,
Formula 4;
And their acetyl derivatives and corresponding salt thereof.
4. according to the purposes of claim 1, reproductive tract that wherein said mycoplasma causes and urinary tract disease are cervicitis, vaginitis, pelvic inflammatory disease, adnexitis, urethritis or the prostatitis that mycoplasma infection causes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010182593XA CN101829077B (en) | 2010-05-26 | 2010-05-26 | Application of dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010182593XA CN101829077B (en) | 2010-05-26 | 2010-05-26 | Application of dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101829077A CN101829077A (en) | 2010-09-15 |
| CN101829077B true CN101829077B (en) | 2012-01-18 |
Family
ID=42713398
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010182593XA Expired - Fee Related CN101829077B (en) | 2010-05-26 | 2010-05-26 | Application of dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101829077B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434896A (en) * | 2013-09-12 | 2015-03-25 | 中国药科大学 | Application of dicaffeoylquinic acid derivative for preparing chemokine receptor 2b antagonist |
| CN112891334B (en) * | 2021-01-19 | 2022-05-03 | 浙江大学 | Application of caffeic acid derivatives in preparation of medicine for treating gonorrhea |
| CN115417830B (en) * | 2022-08-09 | 2024-10-15 | 温州医科大学 | Ethane-1, 2-bis (3-aryl acrylate) compound and application thereof in preparation of medicines |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1175411A (en) * | 1996-08-29 | 1998-03-11 | 中国人民解放军军事医学科学院放射医学研究所 | Use of dicafeoyl quininic acid in treatment of hepatitis B and diseases associated with retrovirus and cafeoyl quininic acid derivs. |
| CN1449751A (en) * | 2003-05-07 | 2003-10-22 | 中国人民解放军军事医学科学院放射医学研究所 | Use of dicaffeoylquinic acid derivative and analogs in treating disease related to coronavirus infection |
| CN101040851A (en) * | 2006-03-20 | 2007-09-26 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The use of dicaffeoylguinic acid ramification and the analog in the treatment of diabetes and the corresponding disease |
-
2010
- 2010-05-26 CN CN201010182593XA patent/CN101829077B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1175411A (en) * | 1996-08-29 | 1998-03-11 | 中国人民解放军军事医学科学院放射医学研究所 | Use of dicafeoyl quininic acid in treatment of hepatitis B and diseases associated with retrovirus and cafeoyl quininic acid derivs. |
| CN1449751A (en) * | 2003-05-07 | 2003-10-22 | 中国人民解放军军事医学科学院放射医学研究所 | Use of dicaffeoylquinic acid derivative and analogs in treating disease related to coronavirus infection |
| CN101040851A (en) * | 2006-03-20 | 2007-09-26 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The use of dicaffeoylguinic acid ramification and the analog in the treatment of diabetes and the corresponding disease |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101829077A (en) | 2010-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103665080B (en) | Triterpenoid compounds and application thereof in diabetes treatment drugs | |
| CN102961469B (en) | Traditional Chinese medicine dispersible tablet for treating upper respiratory infection, and preparation method and quality detection method thereof | |
| CN103193772A (en) | Preparation method and application of substituted aryl propionic berberine ion-pair compound | |
| CN111166734A (en) | Use of naphthoquinones to treat pneumonia caused by pathogenic organisms | |
| CN1730015A (en) | Honey suckle extract and its preparing process and application | |
| US20140031434A1 (en) | Use of Patchouli Alcohol in Preparation of Drug Against Helicobacter Pylori | |
| CN101700290B (en) | Pharmaceutical composition for preventing and treating warm-heat diseases of livestock and poultry and preparation method thereof | |
| CN101829077B (en) | Application of dicaffeoyl-quinic acid derivative in preparing drugs for treating mycoplasma infection diseases | |
| CN103157095A (en) | Kidney bean phytolectin applications in preparation of human drugs and drug composition thereof | |
| CN102716223A (en) | Chinese medicinal composition for treating upper respiratory tract infection and preparation method thereof | |
| CN103130865A (en) | Sophocarpidine, oxymatrine glycyrrhetinic acid double salt, and preparation method and use thereof | |
| CN103251844B (en) | For the tablet of cleaning throat and moistening larynx | |
| CN1903254B (en) | Compound medicine for treating wind-heat type cold and preparing method thereof | |
| CA3167551A1 (en) | Use of pharmaceutical composition in preparing antibacterial drug | |
| CN102030809B (en) | Theasapogenol derivative with antibacterial effect as well as preparation method and application thereof | |
| CN105168375B (en) | Application of the thinfruit hypecoum herb extract in preparation antibacterials | |
| CN101411752A (en) | Granular formulation for treating children's pneumonia | |
| CN101313928A (en) | Southernwood oil and medicine uses of its preparations | |
| CN103191264A (en) | Traditional Chinese veterinary medicine oral solution for preventing and treating colibacillosis of poultry | |
| CN103251845B (en) | For the compositions of cleaning throat and moistening larynx | |
| CN101313914A (en) | Uses and preparations of common camptotheca fruit glycosides of common camptotheca fruit extract | |
| WO2007059649A1 (en) | Chinese pharmaceutical compositions for treating upper respiratory tract infection and processes for preparation thereof | |
| CN1943665A (en) | A Chinese traditional medicinal composition and its preparation method | |
| CN102078529B (en) | Chinese medicinal preparation for treating common cold in children | |
| CN100469378C (en) | Pharmaceutical composition for treating pharyngitis |
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 | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120118 Termination date: 20140526 |