CN103893171A - Application of benzydamine hydrochloride in preparing medicament for preventing or treating influenza virus infections - Google Patents
Application of benzydamine hydrochloride in preparing medicament for preventing or treating influenza virus infections Download PDFInfo
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Abstract
The invention relates to the technical field of medicines and in particular discloses an application of benzydamine hydrochloride in preparing a medicament for preventing or treating influenza virus infections. Firstly, the toxicity of benzydamine hydrochloride for an MDCK cell is detected, and a result shows that the maximum nontoxicity concentration of benzydamine hydrochloride is 50.0 mu M; secondly, the antiviral activity of benzydamine hydrochloride is measured in the safe and nontoxic concentration range, and a result shows that the small molecule compound has remarkable antiviral activity and the antiviral effect has a dose-dependent effect; finally, the antiviral activity of benzydamine hydrochloride for different types and subtypes of influenza viruses is detected, and a result shows that benzydamine hydrochloride can inhibit replication of all detected influenza virus strains in a dose-dependent manner and the anti-influenza virus activity of benzydamine hydrochloride has broad spectrum. Therefore, the invention discloses benzydamine hydrochloride as a novel broad-spectrum anti-influenza virus medicament for the first time. Benzydamine hydrochloride can be used for preparing the medicament for preventing or treating influenza virus infections.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the application of a kind of benzydamine hydrochloride in preparation treatment or flu-prevention virus infective medicament.
Background technology
Influenza virus belongs to orthomyxoviridae family (Orthomyxoviridae), Influenza Virus.According to virion nucleoprotein (NP) and the antigenic characteristic of stromatin (M) and the difference of genetic characteristics, influenza virus is divided into A, B, C tri-types, also claims first, second, the third three types.The full genome of A type influenza virus is made up of 8 sub-thread strand RNAs that differ in size, and names respectively with sections 1 to sections 8.The about 13.6kb of viral genome total length, encode 10 kinds of structural protein (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-F2 and NS2/NEP) and non-structural protein (NS1).According to the difference of virion surface glycoprotein hemagglutinin (HA) and neuraminidase (NA), A type influenza virus can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotype.Human influenza virus is mainly H1, H2 and H3 hypotype.Mostly be H5, H7 and H9 hypotype and endanger at present serious high pathogenic avian influenza, wherein the highest with the fatality rate of H5N1 hypotype.Type B influenza virus often causes influenza localized epidemics, does not cause worldwide influenza great outburst, only in people and sea dog, finds.C type influenza virus exists mainly with the form that is dispersed in, and mainly attacks infant, does not generally cause influenza pandemic, can infect the mankind and pig.
The whole biocycle of influenza virus need to complete in Cytoplasm and nucleus.Infect initial be the furcella HA identification on virion surface and in conjunction with host cell surface containing sialic receptor.The connecting key of sialic acid and time terminal galactose, has determined viral host specificity, and this connecting key is α (2-3) in birds, is α (2-6) in the mankind.After virus absorption onto cell, cell is taken in virus by the receptor-mediated pinocytosis of clathrin.In cell, clathrin molecular dissociation, virus merges and forms phagosome with endosome, makes virion pH value around drop to 5.0 left and right.Under this pH condition, the conformation of viral HA albumen changes, and the fusogenic peptide that is positioned at light chain (HA2) N end is exposed, thereby causes that virus envelope and cell membrane merge.Low pH environment also causes a large amount of H
+enter virion inside via M2 ion channel, cause dissociating of M1 albumen and vRNPs.Both common results cause the vRNPs of virion to be discharged into the endochylema of infected cell.VRNPs forwards to subsequently and in nucleus, carries out genomicly copying and transcribing, and while copying, virus is first take self RNA as template synthesize complementary rna (cRNA), then take cRNA as template resynthesis vRNA.Transcribe the mRNA of generation by transferring to endochylema in core, translate viral structural protein and non-structural protein.Part synthetic proteins is assembled into vRNP as NP need to transfer in core again with newly-generated vRNA, vRNP starts to be assembled into new virion with remaining virus protein after going out core, newly-generated progeny virus is by the glycoprotein of neuraminidase (NA) hydrolysis cell surface, discharge N-acetyl-neuraminate, impel virion to discharge from the site of sprouting.The final step of virus maturation is that HA is cracked into HA1 and HA2 polypeptide under the effect of host protein enzyme, and such virion just has infectivity, thereby starts copying of new round virus.
Influenza virus has been caused in the world and has been very popular for five times since 20 beginnings of the century were found, about 10 years, can produce an outbreak of epidemic, has caused in the world huge loss.Influenza pandemic can cause 250,000～500,000 examples dead every year, 3,000,000～5,000,000 severe disease examples, and it is infected that the whole world approximately has 5～15% people.Vaccination and use antiviral drugs are the important means of reply flu outbreak, but because influenza antigen variation ability is strong, substantially can not large-scale production vaccine before being very popular.At present, there are two classes through the anti-influenza virus medicament of food and drug administration (FDA) approval official listing: (1) M2 ion channel blocking agent take amantadine and rimantadine as representative.This type of medicine only has preventive and therapeutic action to influenza A virus, and research shows that this type of medicine has the toxic and side effects such as neurotoxicity, and due to the ubiquity of persister, so CDC advises that this type of medicine is not used further to flu-prevention viral infection.(2) neuraminidase inhibitor, the representative of this type of medicine is oseltamivir and Zha La meter Wei.This type of medicine is all effective to all known human influenza viruses and high pathogenic avian influenza virus.But really constantly there is report about oseltamivir persister in recent years.Therefore, research development of new anti-influenza virus medicament are significant.
Benzydamine hydrochloride (Benzydamine Hydrochloride), another name benzydamine or benzydamine hydrocloride, chemistry 1-benzyl-3-[3-(dimethylamino) propoxyl group by name]-1H-indazole hydrochlorate.This product is non-specific anti-inflammation drugs, has antiinflammatory, antipyretic, analgesic activity.Effective to the pain causing because of inflammation.This product still has papaverine sample spasmolysis.Be usually used in various inflammation and arthritis, tracheitis, pharyngitis etc. due to operation and wound.Can share better efficacy with antibiotics or sulfonamides.
At present, do not see the report that causes disease about benzydamine hydrochloride at resisiting influenza virus and treatment influenza infection.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, the application of a kind of micromolecular compound benzydamine hydrochloride in preparation treatment or flu-prevention virus infective medicament is provided, thereby provides one micromolecular compound safely and effectively for the treatment of influenza clinically.Benzydamine hydrochloride can effectively suppress copying of influenza virus within the scope of avirulence, can further be developed as the medicine for the treatment of or flu-prevention virus infection, is with a wide range of applications.
In order to prove the feasibility of benzydamine hydrochloride in preparation treatment or flu-prevention virus (A type or B-mode) infection medicine, the present invention has taked following experiment to verify:
The toxicity test of benzydamine hydrochloride to mdck cell: Madin-Darby canine kidney(cell line) (MDCK) is by 8 × 10
3individual cells/well is inoculated in 96 porocyte culture plates, after cell attachment, process with the benzydamine hydrochloride of 0.8 μ M, 1.6 μ M, 3.125 μ M, 6.25 μ M, 12.5 μ M, 25.0 μ M, 50.0 μ M and 100.0 μ M respectively, every group is repeated two holes, is placed in 37 ℃, 5%CO
2in incubator, cultivate after 48 hours, Alamarblue detects the survival rate of cell.Result shows, the CC of benzydamine hydrochloride to MDCK
50(median lethal concentration) is 84.5 μ M.
The evaluation of benzydamine hydrochloride anti-influenza virus activity: by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 ℃, 5%CO
2in cell culture incubator, cultivate.After 18-24h, use 100TCID
50virus liquid (A/PuertoRico/8/34(H1N1)) infection cell, add variable concentrations gradient medicine simultaneously.Cell is got each experimental port supernatant cultivate 48h in 37 ℃ of cell culture incubators after and is carried out the detection of neuraminic acid enzymatic activity.Result shows that benzydamine hydrochloride can rely on copying of ground inhibition influenza virus, its IC by dosage
50be 6.2 μ M.
The broad spectrum activity analysis of benzydamine hydrochloride resisiting influenza virus effect: by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 ℃, 5%CO
2in cell culture incubator, cultivate 18-24h after cell grows up to monolayer, use 100TCID
50virus liquid (being respectively A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8), B/human/Huber/1/2007) infection cell adds each Concentraton gradient medicine simultaneously.Cell is got each experimental port supernatant cultivate 48h in 37 ℃ of cell culture incubators after and is carried out the detection of neuraminic acid enzymatic activity.Result shows that benzydamine hydrochloride can obviously suppress copying of subtypes of influenza A virus H6N6 strain, subtypes of influenza A virus H7N8 strain and Influenza B virus, and all has dose-dependent effect.
The present invention compared with prior art, has the following advantages and effect:
1. benzydamine hydrochloride is micromolecular compound, its CC
50(median lethal concentration) is 84.5 μ M.Benzydamine hydrochloride can copy by dose-dependent inhibition influenza virus, its IC
50(half-inhibition concentration) is 6.2 μ M.Selection index (SI) is about 13.6.And benzydamine hydrochloride had the application of many decades clinically, safety is good.This explanation benzydamine hydrochloride is anti-influenza virus medicament safely and effectively.
Benzydamine hydrochloride can dose-dependent inhibition subtypes of influenza A virus H6N6 strain, the copying of subtypes of influenza A virus H7N8 strain and Influenza B virus, there is the very antiviral activity of wide spectrum.
3. utilize modern common drug preparation means, can make using benzydamine hydrochloride as active component any pharmaceutically acceptable dosage forms such as tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, nanometer formulation or injection.
Accompanying drawing explanation
Fig. 1 is that a kind of benzydamine hydrochloride cytotoxicity detects schematic diagram.
Fig. 2 is that a kind of benzydamine hydrochloride is processed neuraminic acid enzymatic activity schematic diagram in influenza infection cell culture fluid supernatant.
Fig. 3 is that a kind of benzydamine hydrochloride anti-influenza virus activity broad spectrum activity detects schematic diagram, wherein:
Fig. 3 A is subtypes of influenza A virus H6N6 strain (A/Duck/Hubei/5/2010 (H6N6));
Fig. 3 B is subtypes of influenza A virus H7N8 strain (A/Duck/Hubei/216/1983 (H7N8));
Fig. 3 C is Influenza B virus (B/human/Huber/1/2007).
The specific embodiment
In order to set forth better content of the present invention, below applicant in connection with specific embodiment, content of the present invention is described in further detail, but the scope of request of the present invention protection is not limited to following examples.
At present, anti-influenza virus medicament in-vitro screening model is divided into the cell free system screening model of cell culture model and viral enzyme.Enzyme reaction screening model has high-throughout feature, but the compound of screening still needs to carry out more cytology, histology and toxicity in vivo, effect experiment etc. to determine its effect.Cell culture model is the most frequently used screening model, its advantage is: can provide the identical cell of a large amount of hereditary characters to be object of study, and easy to operate, can eliminate the impact of other extraneous factor, and valid density and therapeutic index that can detection of drugs, for more how later stage mechanism research provide basis.The present invention adopts mdck cell to cultivate screening method and detects the impact that benzydamine hydrochloride infected by influenza infects, the detection of the neuraminidase expression based on to representing influenza virus levels of replication in supernatant, the anti-influenza virus activity of quantitative analysis benzydamine hydrochloride.
Embodiment 1: the evaluation of benzydamine hydrochloride anti-influenza virus activity
1. experiment material
1.1 cells, virus and medicine
Mdck cell is purchased from US mode DSMZ (ATCC); Strain: A/PuertoRico/8/34(H1N1); Medicine: benzydamine hydrochloride (CAS:132-69-4) is purchased from Sigma company.
1.2 experimental apparatus
Multiple labeling microwell plate reads instrument (Perkin Elmer).
2. experimental technique and result
2.1 cell culture: 37 ℃, 5%CO
2in humidification incubator, cultivate.The DMEM culture medium of the penicillin that use contains 10%FBS, 100U/mL and streptomycin.After cell to 90% degree of converging, go down to posterity, the ratio that goes down to posterity 1/3 – 1/4.
2.2 Virus culture: get 9～11 age in days SPF Embryo Gallus domesticus, use Egg checker inspection before virus inoculation, and at the position mark away from embryo, inoculate 2 by 0.2ml/ piece after sterilizing and punching
4the virus liquid of hemagglutinative titer, with nial polish sealing, puts 37 ℃ of calorstats and hatches after 48h(inoculation 24h dead Embryo Gallus domesticus to be generally misoperation lethal, abandons it).Take out Embryo Gallus domesticus and put 4 ℃ of cold embryo 12h.75% alcohol disinfecting chick embryo air sac, sterile working cuts off air chamber shell, and capillary pipette is drawn chick embryo allantoic liquid and amniotic fluid, and 3000rpm4 ℃ of centrifugal 30min detects hemagglutinative titer, and 200 μ l/ pipe subpackage juxtaposition-70 are ℃ frozen for subsequent use.
The cytotoxicity of 2.3 benzydamine hydrochlorides detects: mdck cell is by 8 × 10
3(volume 100 μ l) are inoculated in 96 porocyte culture plates cells/well, for subsequent use after cell attachment; With cell maintenance medium (DMEM+2% serum) by medicine according to 0.8 μ M, 1.6 μ M, 3.125 μ M, 6.25 μ M, 12.5 μ M, 25.0 μ M, 50.0 μ M and 100.0 μ M totally 8 gradient concentrations preparation, each gradient concentration is established 2 multiple holes.After cultivating 48h, discard culture supernatant, the new DMEM culture medium that adds 100 μ l to contain 10%Alamarblue reagent in every hole, put in cell culture incubator and continue to cultivate 1h, after 1h, read instrument with microwell plate and measure respectively fluorescence intensity and light absorption value, calculate cell survival rate.
Result shows that (Fig. 1) benzydamine hydrochloride does not have cytotoxicity completely to mdck cell within the scope of 50.0 μ M, illustrates that benzydamine hydrochloride has the safer scope of application, and the dosage of benzydamine hydrochloride is 0.0～50.0 μ M according to cell experiment consumption.
The antiviral activity evaluation of 2.4 benzydamine hydrochloride infected by influenza strain A/PuertoRico/8/34 (H1N1)
2.4.1. experimental principle: MUNANA(4-methylumbelliferyl-α-N-acetyl-neuraminate) be the specific substrate of influenza neuraminidase, the catalysate producing under neuraminidase effect is under 355nm excitation light irradiation, can produce 460nm fluorescence, the power of fluorescence intensity has represented the number of viral neuraminidase expression, has reflected the virus quantity in cultured cell supernatant.
2.4.2. mdck cell is pressed to 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, in 37 ℃ of cell culture incubators, cultivates after 14～18h, for subsequent use after cell grows up to monolayer.Culture medium in orifice plate is discarded, and PBS cleans after twice, adds 100TCID
50(l) (100 μ l) cultivate 100 μ virus liquid in 37 ℃ of cell culture incubators with variable concentrations medicine.Medicine is take 50.0 μ M as initial concentration, 6 gradients of continuous 2 times of gradient dilutions, and every gradient arranges two multiple holes.After cultivation 48h, get each experimental port supernatant and carry out the detection of neuraminic acid enzymatic activity.Experiment arranges blank group, positive controls (ribavirin), negative control group (after viral infection without drug treating) and Experimental agents group.
2.4.3. in black 96 hole micro plates, add 40 μ l buffer (32.5mmol/L MES, pH6.5,4mmol/LCaCl
2) preparation substrate 20umol/L MUNANA, add again each experimental port culture supernatant 20 μ l, 37 ℃ of lucifuges are hatched 60min, add reaction terminating liquid (0.014 μ M NaOH, 83% ethanol) 100 μ l/ holes, micropore reads to measure on plate instrument fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
2.4.4. calculate the suppression ratio that each detection hole Chinese medicine infected by influenza copies.
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: along with the increase of benzydamine hydrochloride drug level, the suppression ratio that medicine infected by influenza copies raises gradually, and the dosage presenting clearly relies on effect.It can suppress 50% virus replication in 6.2 μ M concentration, and selection index is 13.6, in the time of 50.0 μ M concentration, reaches and approaches 100% suppression ratio.(seeing Fig. 2).
Embodiment 2: the evaluation of benzydamine hydrochloride resisiting influenza virus effect broad spectrum activity
On the basis of embodiment 1, the present embodiment has further detected the antiviral activity of benzydamine hydrochloride to subtypes of influenza A virus H6N6 strain, subtypes of influenza A virus H7N8 strain and Influenza B virus.
1. experiment is used Strain to comprise: A/Duck/Hubei/5/2010 (H6N6),
A/Duck/Hubei/216/1983(H7N8)、B/human/Huber/1/2007
2. mdck cell is pressed to 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, in 37 ℃ of cell culture incubators, cultivates after 14～18h, for subsequent use after cell grows up to monolayer.Culture medium in orifice plate is discarded, and PBS cleans after twice, adds 100TCID
50(l) (100 μ l) cultivate 100 μ virus liquid in 37 ℃ of cell culture incubators with variable concentrations medicine.Medicine is take 50.0 μ M as initial concentration, 6 gradients of continuous 2 times of gradient dilutions, and every gradient arranges two multiple holes.After cultivation 48h, get each experimental port supernatant and carry out the detection of neuraminic acid enzymatic activity.
3. in black 96 hole micro plates, add 40 μ l buffer (32.5mmol/L MES, pH6.5,4mmol/LCaCl
2) preparation substrate 20umol/L MUNANA, add again each experimental port culture supernatant 20 μ l, 37 ℃ of lucifuges are hatched 60min, add reaction terminating liquid (0.014 μ M NaOH, 83% ethanol) 100 μ l/ holes, on multi-tester, measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
4. calculate the suppressed rate of neuraminidase in each detection hole.
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: benzydamine hydrochloride has obviously suppressed copying of various influenza virus strains within the scope of drug level, and is all dose-dependence (seeing Fig. 3).Its half-inhibition concentration (IC to influenza A virus H6N6, influenza A virus H7N8 and Influenza B virus
50) being respectively 27.9 μ M, 8.2 μ M and 10.3 μ M, corresponding selection index is respectively 3.0,10.3 and 8.2.Show that benzydamine hydrochloride is a kind of anti-influenza virus medicament of wide spectrum.
Claims (7)
1. the application of benzydamine hydrochloride in preparation treatment or flu-prevention virus infective medicament.
2. application as claimed in claim 1, is characterized in that: described influenza virus is influenza A virus or Influenza B virus.
3. application as claimed in claim 1, is characterized in that: described medicine is using benzydamine hydrochloride or its various salt forms as active constituents of medicine.
4. application as claimed in claim 1, is characterized in that: described medicine is oral administered dosage form, injecting medicine-feeding form, mucosa delivery dosage form or percutaneous dosing dosage form.
5. application as claimed in claim 1, is characterized in that: described medicine is any pharmaceutically acceptable dosage form.
6. application as claimed in claim 5, is characterized in that: described medicine is tablet, capsule, granule, oral liquid or injection.
7. application as claimed in claim 5, is characterized in that: described medicine is slow releasing preparation, controlled release preparation or nanometer formulation.
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Cited By (3)
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| CN107873024A (en) * | 2015-02-09 | 2018-04-03 | 塞尔利克斯生物私人有限公司 | For treating the composition and method of catarrh |
| WO2023046680A1 (en) | 2021-09-21 | 2023-03-30 | Krka, D.D., Novo Mesto | Combination of cetylpyridinium and benzydamine with virucidal effect on sars-cov-2 |
| CN116536255A (en) * | 2023-07-05 | 2023-08-04 | 夏同生物科技(苏州)有限公司 | Culture medium and method for efficiently inducing muscle stem cells |
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| RU2749968C2 (en) * | 2019-10-11 | 2021-06-21 | Псарева Нелли Александровна | Method for viral infection control |
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