CN106692127A - Application of luteolin in preparation of medicine for preventing and treating dengue virus infection - Google Patents

Application of luteolin in preparation of medicine for preventing and treating dengue virus infection Download PDF

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Publication number
CN106692127A
CN106692127A CN201611135620.1A CN201611135620A CN106692127A CN 106692127 A CN106692127 A CN 106692127A CN 201611135620 A CN201611135620 A CN 201611135620A CN 106692127 A CN106692127 A CN 106692127A
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medicine
cyanidenon
virus
dengue virus
dengue
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CN201611135620.1A
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CN106692127B (en
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李耿
彭敏桦
吴建国
萨博哈什·瓦苏德凡
渡边哲
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Dongguan Institute of Traditional Chinese Medicine Engineering Guangzhou Univers
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Dongguan Institute of Traditional Chinese Medicine Engineering Guangzhou Univers
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Priority to PCT/CN2017/078685 priority patent/WO2018107614A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an application of luteolin in preparation of a medicine for preventing and treating dengue virus infection. The medicine in the application consists of luteolin and medically acceptable adjuvant materials, wherein the mass percentage of the luteolin used in the medicine is 0.1-90%. The medicine provided by the invention has an effect of resisting dengue viruses, and can be used for preventing and treating dengue virus infection.

Description

Application of the cyanidenon in the medicine for preparing preventing and treating dengue virus infection
Technical field
Pharmaceutical products the present invention relates to contain organic effective component, and in particular to the medicine containing flavone compound.
Background technology
Dengue virus (dengue virus) belongs to flaviviridae, Flavivirus in classification.Including 4 different serotypes, I.e. I, II, III, IV type dengue virus.It is different according to disease severity, can clinically be divided into dengue fever (dengue fever), Dengue hemorrhagic fever (dengue hemorrhagic fever) and dengue shock syndrome (dengue shock syndrome). Dengue fever spread speed is fast, and the incidence of disease is high, and dengue hemorrhagic fever and the dengue shock syndrome state of an illness are violent, and case fatality rate is high.With complete Ball warp the Ji quickening of integrated degree and persistently warming for weather, add the quickening of mosquito matchmaker diffusion velocity, distribution and become wide, cause The disease worldwide spreads rapidly.Dengue fever has become international financial burden, every year about 500,000 dengue fever Patient with severe symptoms needs hospitalization, about 2.5% death rate.
Although global first dengue vaccine is granted in three countries, the effect of this vaccine is also not very especially desirable, its drop Low people suffer from dengue fever disease probability only reached 60% level, and the child of less than 9 years old is not in the scope of application. Therefore, preventing and treating dengue virus infection has turned into the medical field task of top priority with propagation.Because the mechanism of causing a disease of dengue virus is not explained It is bright, the vaccine and effective medicine for human body are there is no, find a kind of medicine of effective treatment dengue fever extremely urgent.
Cyanidenon, belongs to flavone compound, wooden yellow needles, 328-330 DEG C of fusing point.Water is slightly soluble in, has weak acid Property, dissolve in alkaline solution, stablize under normal condition.Density：1.654g/cm3, fusing point：330 DEG C, boiling point：616.1℃ At760mmHg, flash-point：239.5℃.Vapour pressure：9.03E-16mmHg at 25℃.
Shown in the chemical constitution of cyanidenon such as following formula (I).
Cyanidenon, leaf initial from Resedaceae Reseda herbaceous plant reseda (ResedaodorataL.), Isolate and gain the name in stem, branch, can be isolated from various crude drugs, vegetables fruit.Have now been found that and be primarily present in gold In the crude drug such as honeysuckle flower, chrysanthemum, schizonepeta, ajuga decumbens, arithoke, Perilla, Scutellaria, callicarpa nudiflora, and Brussels sprouts, In the vegetables fruit such as cabbage, cauliflower, beet, cabbage, carrot, celery, pimento, capsicum, peanut.With antitumor, anti- Inflammation, antiallergy, anti-fibrosis, antifertility and immunological regulation etc. are acted on.But, do not occur reseda also in current document report Report of the element with anti-dengue virus activity.
The content of the invention
The technical problem to be solved in the present invention is to provide the new application of cyanidenon, i.e., the new opplication in pharmacy.
The above-mentioned new opplication in pharmacy is, application of the cyanidenon in the medicine for preparing preventing and treating dengue virus infection.
In above-mentioned application, described dengue virus is dengue fever I, II, III or IV type virus.
In above-mentioned application, described cyanidenon can be using conventional method from extracted form natural plant, it is also possible to by closing Into or other method be obtained.
In above-mentioned application, described medicine is made up of cyanidenon and medically acceptable auxiliary material, wherein, cyanidenon Weight/mass percentage composition in medicine is 0.1%~90%.
In above-mentioned application, described medicine can be clinically acceptable injection, capsule or tablet.
Injection of the present invention, capsule and tablet have the effect of anti-dengue virus, can be used to prevent and treat dengue fever Infection.
Present invention cyanidenon anti-dengue virus are to determine cyanidenon to dengue fever using virus plaque titre method Ith, the inhibitory action of II, III, IV type virus, observation cyanidenon to the toxic action of Huh-7 cells and to dengue fever I, II, IIIth, the inhibitory action of IV type virus, utilizesDetection reagent measures the poisonous concentration of half of test medicine (CC50) be 45.89, be respectively 7.2 to the ceiling effect concentration (EC50) of the type dengue fever virus of half I, II, III, IV, 5.19, 5.40th, 8.38, its selection index SI is respectively 6.38,8.84,8.07,5.48, is efficient low toxicity.
Present invention cyanidenon anti-dengue virus additionally use AG129 mouse animal experiments and determine cyanidenon to stepping on The inhibitory action of hot II type virus is removed from office, observation cyanidenon is to the AG129 death prevention rates by the virus infection of the type of dengue fever II Effect, its Death prevention rate is 33.33%.
1. experiment material
1.1 cell lines
Human liver cancer cell (Huh-7), is purchased from American Type Culture collection warehousing (ATCC), T5 generations.By Duke-NUS Medical School freeze conservation.
Newborn hamster kidney cell (BHK-21), is purchased from American Type Culture collection warehousing (ATCC), T6 generations.By Duke-NUS Medical School freeze conservation.
1.2 experimental groups and its corresponding test medicine
Given the test agent：Take and be purchased from Baoji time bio tech ltd (Lot：0151024) cyanidenon, adds DMSO, it is the storing solution of 20mM that concentration is obtained.NITD008 as positive control, by Novartis of Singapore tropical disease research center (Novartis Institute for Tropical Disease, Singapore) is presented, and is made the deposit that concentration is 20mM Liquid.
1.3 Strain
DENV-1(EDEN-1,GenBank accession EU081230)
DENV-2(EDEN-2,GenBank accession EU081177)
DENV-3(EDEN-3,GenBank accession EU081190)
DENV-4(EDEN-4,GenBank accession GQ398256)
From Nanyang Technological University professor Luo great Hai present, DENV plants leads in the amplification of C6/36 cells, supernatant - 80 DEG C are stored in after crossing 0.45 μm of filtering with microporous membrane.Virus titer is by plaque assay in BHK-21 raji cell assay Rajis.
1.4 animals
Sv/129 mouse lack I and II types interferon receptors (AG129), are purchased from B＆K Universal (UK) company.It is all Singapore National guidelines (protocol 2012/SHS/713) are observed in zoopery, by Institutional Animal Care and Use Committee at Singapore Health Services are criticized It is accurate.All experiments are carried out in Duke-NUS BSL-2 grades of laboratory.
1.5 reagents and instrument newborn calf serum and DMEM culture mediums (Gibco companies)；DMSO (Sigma companies)；Pancreas Protease (DIFCO companies of the U.S.).Olympus PM-6 inverted microscopes (Japanese OLYMPUS companies).
2. method
The measure of 2.1 cyanidenons toxic concentration on Huh-7 cells
By the Huh-7 of growth digests counting with EDTA- pancreatin in flakes in cell bottle, with 2 × 104The inoculation of/100 μ l/ holes is thin Born of the same parents' (white flat bottom) in 96 orifice plates, 37 DEG C of 5%CO2Overnight incubation.By medicine cell growth nutrient solution (containing 10% serum) By 50,25,12.5,6.25,3.125,1,0.1,0.01 μM of dilutions of final concentration.Culture medium is sucked, drug solution 100 is added per hole μ l, if normal cell controls, 100 μ l cell growth nutrient solutions are added per hole.In 37 DEG C of 5%CO2Culture 48h.Will CellTiter-GloBuffer is added in CellTiter-Glo Substrate, forms the mixture of enzyme and substrate, i.e., CellTiter-Glo reagents.The CellTiter-Glo reagents of isometric (100 μ l) are added per hole, 10 points are incubated at room temperature Clock, reads Luminescence numerical value under ELIASA (Tecan Infinite 200PRO).
Cell survival rate=medicine group Luminescence/ normal group Luminescence × 100%
The measure of 2.2 antiviral effect in vitro
By the Huh-7 of growth digests counting with EDTA- pancreatin in flakes in cell bottle, with 1 × 105The inoculation of/500 μ l/ holes is thin Born of the same parents are in 24 orifice plates.37 DEG C of 5%CO2Overnight incubation.Medicine is pressed into final concentration with cell growth nutrient solution (containing 10% serum) 50,25,12.5,6.25,3.125,1,0.1,0.01 μM of dilutions.EDEN-1, EDEN-2, EDEN-3 and EDEN-4 virus liquid is not with Culture medium containing serum is diluted by infection multiplicity (multiplicity of infection) MOI=0.3.Culture medium is sucked, often Hole adds drug solution and each 100 μ l of virus liquid, in 37 DEG C of 5%CO2 cultures 1h.Virus-medicinal mixture is sucked, is added per hole Enter 400 μ l pastille culture mediums, in 37 DEG C of 5%CO2 cultures 48h.Supernatant is collected, 9000rpm is centrifuged 3 minutes to remove cell Fragment.Be stored in -80 DEG C it is standby.Virus titer is determined by plaque assays.
The measure of 2.3 virus titers
By the BHK-21 of growth digests counting with EDTA- pancreatin in flakes in cell bottle, with 2 × 105The inoculation of/500 μ l/ holes is thin Born of the same parents are in 24 orifice plates.37 DEG C of 5%CO2Overnight incubation.Virus Sample is diluted with the culture medium without serum, two dilutions are set Multiple, each extension rate sets two multiple holes, extension rate：10-2-10-7.Culture medium is sucked, 200 μ l virus liquids is added per hole, In 37 DEG C of 5%CO2 cultures 1h.Inoculum is removed, 0.8%CMC, 37 DEG C 5%COs of the 500 μ l containing 2% serum are added per hole2Culture 4-5 days (EDEN-2, EDEN-3, EDEN-4 are cultivated 5 days, and EDEN-1 is cultivated 4 days).Fixed with 3.7% paraformaldehyde, 1% crystallization Purple dyeing, counts plaque.The inverse of Pfu/ml=plaques number × 1000/200 × dilution gfactor.
The measure of 2.4 interior resisting virus effect
Take the mouse of 7-11 weeks, the 4G2 antibody of infection the previous day intraperitoneal injection 50 μ g.1 × 10 is injected intravenously respectively8pfu EDEN-1, EDEN-2, EDEN-3, EDEN-4 virus make infection, the subsequent 4 days cyanidenons to mouse stomach 100mg/kg, Four times per day, by 4/4/4/12h (9AM, 1PM, 5PM and 9PM) cycle administration.Mouse survival situation is observed the tenth day.Often Group sets 6 mouse.
3. result
3.1 drug toxicity results see the table below 1.
Evaluation of the cyanidenon of table 1 to Huh-7 cytotoxicities
Drawn using software GraphPad Prism5.0, as a result as shown in Figure 1.
The measurement result of 3.2 Antiviral Effects effect see the table below 2.
The measure of the virus titer of table 2
Drawn using software GraphPad Prism5.0, as a result as shown in Figure 2.
Dead protective effect of 3.3 cyanidenons to AG129 mouse is shown in Table 3- tables 6
Time-to-live of the cyanidenon of table 3 to EDEN-1 virus infection AG129 mouse
Time-to-live of the cyanidenon of table 4 to EDEN-2 virus infection AG129 mouse
Time-to-live of the cyanidenon of table 5 to EDEN-3 virus infection AG129 mouse
Time-to-live of the cyanidenon of table 6 to EDEN-4 virus infection AG129 mouse
Drawn using software GraphPad Prism5.0, as a result as shown in figures 3 to 6.
Brief description of the drawings
Fig. 1 is curve map of the cyanidenon to Huh-7 cytotoxic effects.
Fig. 2 is curve map of the cyanidenon to the inhibitory action of dengue virus.
Fig. 3 is survivorship curve figure of the cyanidenon to dengue virus 1 infecting mouse.
Fig. 4 is survivorship curve figure of the cyanidenon to dengue virus II infecting mouse.
Fig. 5 is survivorship curve figure of the cyanidenon to dengue virus 3 infecting mouse.
Fig. 6 is survivorship curve figure of the cyanidenon to dengue virus IV infecting mouse.
Specific embodiment
Example 1：(injection)
Take cyanidenon 1000mg, plus citric acid 1000mg, sodium citrate 500mg, sodium chloride 1800mg, plus 1000ml Water for injection, is stirred to dissolve, degerming filtration, embedding, through 100 DEG C of 15 minutes flowing steam sterilizations, is made every 2mg/2ml's Parenteral solution is used for injection.
Example 2：(capsule)
Take cyanidenon 4500mg and 200mg microcrystalline celluloses, 200mg sodium carboxymethyl starches, 100mg dodecyl sulphates The auxiliary materials such as sodium are sufficiently mixed, and dry granulation is carried out using roll-in method, then are mixed with appropriate magnesium stearate, are packed into the hollow glue of 3# Capsule, is made the capsule that specification is 100mg/ and supplies to orally use.
Example 3：(tablet)
Cyanidenon 5000mg is taken to be well mixed with 4000mg starch, 200mg cross-linked pvps, 300mg sodium carboxymethyl starches, With 75% ethanol solution of 5%PVP as adhesive, softwood processed is pelletized with 18 mesh sieves, 1h after 60 DEG C of dryings, after 20 mesh whole grains Appropriate talcum powder is added, is mixed, compressing tablet, be made the tablet that specification is 100mg/ pieces and supply to orally use.

Claims (3)

1. application of the cyanidenon in the medicine for preparing preventing and treating dengue virus infection.
2. application according to claim 1, it is characterised in that：Described medicine is by cyanidenon and medically acceptable Auxiliary material is constituted, and the weight/mass percentage composition that wherein cyanidenon is used in medicine is 0.1%~90%.
3. the application according to right 2, it is characterized in that, described medicine is injection, capsule or tablet.
CN201611135620.1A 2016-12-12 2016-12-12 Application of luteolin in preparation of medicine for preventing and treating dengue fever virus infection Active CN106692127B (en)

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PCT/CN2017/078685 WO2018107614A1 (en) 2016-12-12 2017-03-30 Use of luteolin in preparation of medicament for preventing and treating dengue virus infection

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1325393A (en) * 1998-10-30 2001-12-05 默克专利股份有限公司 Method for producing luteolin and luteolin derivatives
CN1947747A (en) * 2005-10-10 2007-04-18 黄振华 Traditional Chinese medicine composition contg. luteolin and capsule of sweeping forsythia and its prepn. method and use
CN103142581A (en) * 2013-03-18 2013-06-12 中国科学院新疆理化技术研究所 Application of natural compound luteolin in anti-hepatitis B virus

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY169312A (en) * 2013-01-17 2019-03-21 Herbitec M Sdn Bhd An antiviral pharmaceutical composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1325393A (en) * 1998-10-30 2001-12-05 默克专利股份有限公司 Method for producing luteolin and luteolin derivatives
CN1947747A (en) * 2005-10-10 2007-04-18 黄振华 Traditional Chinese medicine composition contg. luteolin and capsule of sweeping forsythia and its prepn. method and use
CN103142581A (en) * 2013-03-18 2013-06-12 中国科学院新疆理化技术研究所 Application of natural compound luteolin in anti-hepatitis B virus

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. HAKOBYAN ET AL: "Apigenin inhibits African swine fever virus infection in vitro", 《ARCH VIROL》 *
I. SA´NCHEZ ET AL: "Antiviral Effect of Flavonoids on the Dengue Virus", 《PHYTOTHERAPY RESEARCH》 *
KEIVAN ZANDI ET AL: "Antiviral activity of four types of bioflavonoid against dengue virus type-2", 《VIROLOGY JOURNAL》 *
KRISHNAN SARAVANA MURALI ET AL: "Anti-chikungunya activity of luteolin and apigenin rich fraction from Cynodon dactylon", 《ASIAN PACIFIC JOURNAL OF TROPICAL MEDICINE》 *
VIVEK DHAR DWIVEDI ET AL: "Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database", 《VIRUSDIS》 *

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