CN103585155A - Use of Trigolutesins A in drugs for treating hemorrhagic fever with renal syndrome - Google Patents
Use of Trigolutesins A in drugs for treating hemorrhagic fever with renal syndrome Download PDFInfo
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- CN103585155A CN103585155A CN201310635065.9A CN201310635065A CN103585155A CN 103585155 A CN103585155 A CN 103585155A CN 201310635065 A CN201310635065 A CN 201310635065A CN 103585155 A CN103585155 A CN 103585155A
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- Prior art keywords
- trigolutesins
- hemorrhagic fever
- renal syndrome
- virus
- drugs
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- 229930194390 trigolutesin Natural products 0.000 title claims abstract description 29
- 208000032982 Hemorrhagic Fever with Renal Syndrome Diseases 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 229940079593 drug Drugs 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- 241000700605 Viruses Species 0.000 abstract description 22
- 238000002360 preparation method Methods 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 230000002147 killing effect Effects 0.000 abstract description 4
- 230000007541 cellular toxicity Effects 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000010166 immunofluorescence Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- TYGUTURXHKSOBP-UHFFFAOYSA-N 10-bromo-5,12-dihydroindolo[2,3-g]carbazole-2,3-diol Chemical compound C1=C(Br)C=C2NC3=C(C4=C(C=C(C(=C4)O)O)N4)C4=CC=C3C2=C1 TYGUTURXHKSOBP-UHFFFAOYSA-N 0.000 description 2
- 206010061192 Haemorrhagic fever Diseases 0.000 description 2
- 241000870682 Trigonostemon Species 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930187845 trigonostemon Natural products 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 241001290352 Caulerpa racemosa Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 241000150562 Hantaan orthohantavirus Species 0.000 description 1
- 208000021727 Hantavirus hemorrhagic fever with renal syndrome Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010030302 Oliguria Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000002364 anti-haemorrhagic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000009351 contact transmission Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel use of Trigolutesins A in preparation of drugs for treating hemorrhagic fever with renal syndrome. In-vivo and in-vitro inhibition experiments prove that Trigolutesins A has low cell toxicity and has effects of directly killing viruses of hemorrhagic fever with renal syndrome and obviously inhibiting multiplication of the viruses. Therefore, Trigolutesins A is an effective and safe drug for treating hemorrhagic fever with renal syndrome.
Description
Technical field
The present invention relates to the new purposes of compound Trigolutesins A, relate in particular to the application of Trigolutesins A in preparation treatment hemorrhagic fever with renal syndrome medicine.
Background technology
Hemorrhagic fever with renal syndrome is to cause by haemorrhagic fever with renal syndrome virus (or claiming Hantaan virus) disease of natural focus that the muroid of take is the main source of infection; Can pass through respiratory tract, digestive tract, contact transmission, mother-to-baby transmission and arthropod-borne; Take the acute viral infectious disease that heating, bleeding tendency and kidney damage be main clinical characteristics, typical hemorrhagic fever generally has heating, hypotension, oliguria, polyuria and recovers five phase processes, as it is very high to deal with case fatality rate improperly; The propagation of HFRS virus is each continent all over the world almost.Existing semicentennial when popular in China, the eighties is since mid-term, and China's primary disease year morbidity number exceedes 100,000, has become except viral hepatitis a kind of viral disease that harm is maximum.
The compound Trigolutesins A the present invention relates to is one and within 2013, delivers (Shan-Shan Ma, et al., Two New Types of Bisindole Alkaloid from Trigonostemon lutescens.Organic Letters, 2013, 15(7): noval chemical compound 1492 – 1495.), this compound has brand-new framework types, current purposes is found its energy anti-acetylcholinesterase (Shan-Shan Ma, et al., Two New Types of Bisindole Alkaloid from Trigonostemon lutescens.Organic Letters, 2013, 15(7): 1492 – 1495.), the purposes of the Trigolutesins A the present invention relates in preparation treatment hemorrhagic fever with renal syndrome medicine belongs to open first.
Summary of the invention
The object of the invention is to, according to not finding in existing Trigolutesins A research that it has the present situation of the report for the treatment of hemorrhagic fever with renal syndrome activity, provides the application of Trigolutesins A in preparation treatment hemorrhagic fever with renal syndrome medicine.
Described compound Trigolutesins A structure is as shown in formula I:
Formula I
The purposes of the Trigolutesins A the present invention relates in preparation treatment hemorrhagic fever with renal syndrome medicine belongs to open first, because framework types belongs to brand-new framework types, and it is active strong for treatment hemorrhagic fever with renal syndrome, possess outstanding substantive distinguishing features, be used for the treatment of hemorrhagic fever with renal syndrome simultaneously and obviously there is significant progress.
The specific embodiment
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to any restriction of specific embodiment, but be limited by claim.
The preparation method of compound Trigolutesins A involved in the present invention is referring to document (Ding-Quan Liu, et al., Trigolutesins A and B, two novel bisindole alkaloids from the green alga Caulerpa racemosa.Fitoterapia, 91 (2013): 15 – 20.), prepare according to the method described above compound Trigolutesins A.
Embodiment 1: the preparation of compound Trigolutesins A tablet involved in the present invention:
Get 5 and digest compound Trigolutesins A and add 195 grams, dextrin, mix, conventional tabletting is made 1000.
Embodiment 2: the preparation of compound Trigolutesins A capsule involved in the present invention:
Get 5 and digest compound Trigolutesins A and add 195 grams of starch, mix, encapsulatedly make 1000.
Below by pharmacodynamic experiment, further illustrate its pharmaceutically active.
The experimentation of the anti-hemorrhagic fever with renal syndrome virus of experimental example 1:Trigolutesins A
(1) to hemorrhagic fever with renal syndrome virus body outer suppressioning experiment
1 material
(1) Strain: international standard hemorrhagic fever with renal syndrome virus 76-118 Zhu，You China Preventive Medicial Science Institute institute is preserved.Every milliliter of virus (100TCID50/ml) containing 100 virus infection titers for experiment.
(2) cell: the E6 clone system that African green monkey kidney Vero goes down to posterity, 139～141 generations.Wherein containing 3% calf serum maintenance medium.
(3) medicine: Trigolutesins A, each dilution factor is all prepared by maintenance medium.In experimentation, set up blank.
2 methods
(1) toxic action of medicine to Vero E6 cell.By the Vero E6 cell that grows up to monolayer respectively with Trigolutesins A 0.05,0.1,0.5,1.0,2.0,3.0,5.0,7.5, the drug level of 10.0ug/ml processes and cultivates after 2 weeks, observation of cell form.
(2) medicine is invaded the blocking effect of cell to hemorrhagic fever with renal syndrome virus.With 0.2,0.5,1.0,2.0,3.0, the drug level pretreatment cell of 5.0ug/ml is after 12 hours, then attacks with hemorrhagic fever with renal syndrome virus, cultivate after 2 weeks and check by immunofluorescence.
(3) the direct killing action to hemorrhagic fever with renal syndrome virus.With 0.5,1.0,2.0,3.0,5.0, the drug level of 7.5ug/ml and the viral mixed in equal amounts of 100TCID50/0.1ml, after effect different time, then by its infection cell, by immunofluorescence, check.
(4) inhibited proliferation to hemorrhagic fever with renal syndrome virus.After virus infected cell 24 hours, with different drug level, add cell culture medium, cultivate after 2 weeks and check by immunofluorescence.
3 observation index
With immuno-fluorescence assay intracellular virus antigen, if infection cell has no the fluorescence positive, represent that virus has been killed or has suppressed, calculate antiviral index simultaneously.
4 results
(1) the drug level group of 10.0ug/ml is cultivated cell granulations after 5 days and is increased, and refractivity is poor, and cellular morphology obviously changes, part cell detachment, and all the other each concentration have no the toxic action of medicine to Vero E6 cell.
(2) all there is specificity fluorescent at the pretreated experimental group cell of different time and the cellular control unit that medication is not processed in each concentration, and virus infection titer is 105/0.1ml, antiviral index 1.Show that Trigolutesins A can not invade cell by blocking virus.
(3) the Trigolutesins A of 3.0ug/ml drug level has direct kill activity to virus, above each group of this concentration, its infection titer and matched group are than all there were significant differences (P<0.05), and drug level increases, and antivirus action strengthens (in Table 1).
(4) the Trigolutesins A of 0.5ug/ml drug level has inhibitory action to virus multiplication, above each group of this concentration, its infection titer and matched group are than all there were significant differences (P<0.05), and drug level increases, and antivirus action strengthens (in Table 2).
The direct killing action (X ± s) of table 1Trigolutesins A to hemorrhagic fever with renal syndrome virus
With matched group comparison,
*p<0.05.
The inhibitory action (X ± s) of table 2Trigolutesins A to hemorrhagic fever with renal syndrome virus propagation
With matched group comparison,
*p<0.05.
Sum up: Trigolutesins A is low to the toxic action of cell; Hemorrhagic fever with renal syndrome virus is had to direct killing action; The propagation of hemorrhagic fever with renal syndrome virus is had to obvious inhibitory action, and drug level increases, and antiviral efficacy increases.
Claims (1)
- The application of 1.Trigolutesins A in treatment hemorrhagic fever with renal syndrome medicine, described compound Trigolutesins A structure is as shown in formula I:Formula I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310635065.9A CN103585155B (en) | 2013-12-02 | 2013-12-02 | Use of Trigolutesins A in drugs for treating hemorrhagic fever with renal syndrome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310635065.9A CN103585155B (en) | 2013-12-02 | 2013-12-02 | Use of Trigolutesins A in drugs for treating hemorrhagic fever with renal syndrome |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103585155A true CN103585155A (en) | 2014-02-19 |
| CN103585155B CN103585155B (en) | 2015-05-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310635065.9A Expired - Fee Related CN103585155B (en) | 2013-12-02 | 2013-12-02 | Use of Trigolutesins A in drugs for treating hemorrhagic fever with renal syndrome |
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| Country | Link |
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| CN (1) | CN103585155B (en) |
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2013
- 2013-12-02 CN CN201310635065.9A patent/CN103585155B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| SHAN-SHAN MA ET AL.: "Two New Types of Bisindole Alkaloid from Trigonostemon lutescens", 《ORGANIC LETTERS》 * |
| 岑长春 等: "三宝木属植物化学成分和药理活性研究进展", 《海南师范大学学报(自然科学版)》 * |
| 王婷婷，徐国兴: "华蟾素的药理作用研究及临床应用进展", 《国际眼科杂志》 * |
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| Publication number | Publication date |
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| CN103585155B (en) | 2015-05-27 |
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Inventor after: Zhao Guijuan Inventor after: Li Maoxun Inventor after: Wan Zheng Inventor after: Li Qiang Inventor before: Li Qiang |
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Free format text: CORRECT: INVENTOR; FROM: LI QIANG TO: ZHAO GUIJUAN LI MAOXUN WAN ZHENG LI QIANG |
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Effective date of registration: 20171010 Address after: 226500 Jiangsu city of Nantong province Rugao City, Dong Chen Zhen Hong Bridge neighborhood 4 groups Patentee after: Rugao Chengdong hospital Address before: 266000 Shandong province Qingdao City Red Road No. 31 North Building 201 Patentee before: Li Qiang |
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Effective date of registration: 20191213 Address after: 063000 No.75, caoxiqin East Road, Fengrun District, Tangshan City, Hebei Province Patentee after: Hebei Sanshi Pharmaceutical Co.,Ltd. Address before: 226500 Jiangsu city of Nantong province Rugao City, Dong Chen Zhen Hong Bridge neighborhood 4 groups Patentee before: Rugao Chengdong hospital |
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Effective date of registration: 20211101 Address after: 063000 No. 75, Cao Xueqin East Road, Fengrun District, Tangshan City, Hebei Province (304, Sanshi pharmaceutical experimental building) Patentee after: Tangshan Liubai Pharmaceutical Technology Co.,Ltd. Address before: No.75, East CaoXueqin Road, Fengrun District, Tangshan City, Hebei Province 063000 Patentee before: Hebei Sanshi Pharmaceutical Co.,Ltd. |
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Granted publication date: 20150527 Termination date: 20211202 |