CN103893171B - The application of benzydamine hydrochloride in preparation treatment or flu-prevention virus infective medicament - Google Patents
The application of benzydamine hydrochloride in preparation treatment or flu-prevention virus infective medicament Download PDFInfo
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Abstract
The present invention relates to medical technical field, specifically disclose the application of a kind of benzydamine hydrochloride in preparation prevention or treatment influenza infection medicine. First the present invention has detected the toxicity of benzydamine hydrochloride to mdck cell, and result shows that the maximal non-toxic concentration of benzydamine hydrochloride is 50.0 μ M; Secondly, measured the antiviral activity of benzydamine hydrochloride in the concentration range of totally nontoxic, result shows that this micromolecular compound has significant antiviral activity, and antivirus action is dose-dependent effect; Finally, detect the antiviral activity of the influenza virus of benzydamine hydrochloride to different shaped and hypotype, result shows that benzydamine hydrochloride can rely on copying of all detected strains of influenza viruses of ground inhibition by dosage, shows that the anti-influenza virus activity of benzydamine hydrochloride has broad spectrum activity. Therefore, it is a kind of New-type wide-spectrum anti-influenza virus medicament that the present invention has disclosed benzydamine hydrochloride first, can be for the preparation of the medicine of prevention or treatment influenza infection.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of benzydamine hydrochloride at preparation treatment or flu-preventionApplication in virus infective medicament.
Background technology
Influenza virus belongs to orthomyxoviridae family (Orthomyxoviridae), Influenza Virus. According to virionThe antigenic characteristic of nucleoprotein (NP) and stromatin (M) and the difference of genetic characteristics, influenza virus be divided into A,B, C tri-types, also claim first, second, the third three types. The full genome of A type influenza virus is by 8 lists that differ in sizeThigh strand RNA composition, names with sections 1 to sections 8 respectively. The about 13.6kb of viral genome total length, compiles10 kinds of structural proteins of code (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-F2 and NS2/NEP)And non-structural protein (NS1). According to virion surface glycoprotein hemagglutinin (HA) and neuraminidase (NA)Difference, A type influenza virus can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotype. PeopleInfluenza virus is mainly H1, H2 and H3 hypotype. And endanger at present serious highly pathogenic bird flu mostly be H5,H7 and H9 hypotype are wherein the highest with H5N1 hypotype fatal rate. Type B influenza virus often causes influenza local flowOK, do not cause worldwide influenza great outburst, only in people and sea dog, find. C type influenza virus is mainly with being dispersed in shapeFormula exists, and mainly attacks infant, does not generally cause influenza pandemic, can infect the mankind and pig.
The whole life cycle of influenza virus need to complete in cytoplasm and nucleus. The initial of infection is virusThe furcella HA of particle surface identifies and contains sialic acceptor in conjunction with host cell surface. Sialic acid and time endThe connecting key of galactolipin, has determined viral host specificity, and this connecting key is α (2-3) in bird,In the mankind, be α (2-6). After virus absorption onto cell, cell is taken the photograph by the receptor-mediated pinocytosis of clathrinEnter virus. In cell, clathrin molecular dissociation, virus merges and forms phagosome with endosome, makes to fall illVirion pH value around drops to 5.0 left and right. Under this pH condition, the conformation of viral HA albumen occursChange, the fusogenic peptide that is positioned at light chain (HA2) N end is exposed, thereby cause 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 M1 albumen withVRNPs dissociates. 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 with self RNAFor template synthesize complementary rna (cRNA), then taking cRNA as template synthetic vRNA again. Transcribe generationMRNA, by transferring to endochylema in core, translates viral structural proteins and non-structural protein. The synthetic egg of a partWhite as NP need to transfer in core again and newly-generated vRNA is assembled into vRNP, and vRNP goes out after core and itRemaining virus protein starts to be assembled into new virion, and newly-generated progeny virus passes through neuraminidase(NA) glycoprotein of hydrolysis cell surface, discharges N-acetyl-neuraminate, impels virion from the position of sproutingPoint discharges. The final step of virus maturation be HA under the effect of host protein enzyme, be cracked into HA1 andHA2 polypeptide, 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 yearsCan produce an outbreak of epidemic, cause in the world huge loss. Influenza pandemic can cause every year250000～500,000 examples are dead, 3,000,000～5,000,000 grave illness examples, and it is infected that the whole world approximately has 5～15% people.Vaccine inoculation and use antiviral drugs are the important means of reply flu outbreak, but because influenza virus is anti-Former variation ability is strong, substantially can not large-scale production vaccine before being very popular. At present, through U.S. food andThe anti-influenza virus medicament of FAD (FDA) approval official listing has two classes: (1) is with amantadine and goldThe M2 ion channel blocking agent that just ethamine is representative. This type of medicine only has prevention and treatment to do to influenza A virusWith, 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 virus infections. (2) neuraminidase inhibitor,The representative of this type of medicine is oseltamivir and Zha La meter Wei. This type of medicine causes all known human influenza viruses and heightCharacteristic of disease avian influenza virus is all effective. 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 (BenzydamineHydrochloride), another name benzydamine or benzydamine hydrocloride, chemistry is by name1-benzyl-3-[3-(dimethylamino) propoxyl group]-1H-indazole hydrochloride. This product is non-specific anti-inflammation drugs, hasAnti-inflammatory, 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 with antibiotic or sulphurAmine share better efficacy.
At present, do not see about benzydamine hydrochloride and cause disease at resisiting influenza virus and treatment influenza infectionReport.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, a kind of micromolecular compound hydrochloric acid is providedThe application of benzydamine in preparation treatment or flu-prevention virus infective medicament, thus be the treatment of influenza clinicallyOne micromolecular compound is safely and effectively provided. Benzydamine hydrochloride can effectively suppress in non-toxic scopeCopying of influenza virus, can further be developed as treatment or the medicine of flu-prevention virus infection, has wideGeneral application prospect.
In order to prove that benzydamine hydrochloride is in preparation treatment or flu-prevention virus (A type or the B-mode) infection medicineFeasibility, the present invention has taked following experiment to verify:
The toxicity test of benzydamine hydrochloride to mdck cell: MDCK (MDCK) is by 8 × 103Individual cell/Hole is inoculated in 96 porocyte culture plates, after cell attachment, use respectively 0.8 μ M, 1.6 μ M, 3.125 μ M,The benzydamine hydrochloride of 6.25 μ M, 12.5 μ M, 25.0 μ M, 50.0 μ M and 100.0 μ M is processed, every groupRepeat two holes, be placed in 37 DEG C, 5%CO2In incubator, cultivate after 48 hours, Alamarblue detects cellSurvival rate. Result shows, the LD of benzydamine hydrochloride to MDCK50(LC50) is 84.5 μ M.
The evaluation of benzydamine hydrochloride anti-influenza virus activity: by mdck cell according to 1.5 × 104Cells/well inoculationIn 96 Tissue Culture Plates, 37 DEG C, 5%CO2In cell culture incubator, cultivate. After 18-24h, use 100TCID50Virus 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 DEG C 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 dosage50Be 6.2 μ M.
The broad spectrum activity analysis of benzydamine hydrochloride resisiting influenza virus effect: by mdck cell according to 1.5 × 104Cell/ hole is inoculated in 96 Tissue Culture Plates, 37 DEG C, 5%CO2In cell culture incubator, cultivate 18-24h and treat that cell is longBecome after individual layer, use 100TCID50Virus liquid (be respectively A/Duck/Hubei/5/2010 (H6N6),A/Duck/Hubei/216/1983 (H7N8), B/human/Huber/1/2007) infection cell, add each simultaneouslyConcentration gradient medicine. Cell is got each experimental port supernatant cultivate 48h in 37 DEG C of cell culture incubators after and is carried out nervePropylhomoserin enzymatic activity detects. Result show benzydamine hydrochloride can obviously suppress subtypes of influenza A virus H6N6 strain,Copying of subtypes of influenza A virus H7N8 strain and influenza B virus, and all there is dose-dependent effect.
The present invention compared with prior art, has the following advantages and effect:
1. benzydamine hydrochloride is micromolecular compound, its LD50(LC50) is 84.5 μ M. Hydrochloric acidBenzydamine can copy by dose-dependent inhibition influenza virus, its IC50(half-inhibition concentration) is 6.2 μ M.Selection index (SI) is about 13.6. And benzydamine hydrochloride has had the application of many decades, safety clinicallyProperty 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, Flu-A diseaseCopying of poison hypotype H7N8 strain and influenza B virus, has the very antiviral activity of wide spectrum.
3. utilize modern common drug preparation means, can make using benzydamine hydrochloride as active component tablet, glueAny pharmacy such as capsule, granule, oral liquid, sustained release preparation, controlled release preparation, nanometer formulation or injectionUpper acceptable formulation.
Brief description of the drawings
Fig. 1 is that a kind of benzydamine hydrochloride cytotoxicity detects schematic diagram.
Fig. 2 is that in a kind of benzydamine hydrochloride processing influenza infection cell culture fluid supernatant, neuraminidase is livedProperty schematic diagram.
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).
Detailed description of the invention
In order to set forth better content of the present invention, below applicant in connection with specific embodiment to content of the present inventionBe 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 acellular system of cell culture model and viral enzymeSystem screening model. Enzyme reaction screening model has high-throughout feature, but the compound of screening still needs to carry out moreCytology, histology and toxicity in vivo, effect experiment etc. to determine its effect. Cell culture model is the most normalWith screening model, its advantage is: it is research object that the cell that a large amount of inhereditary features are identical can be provided, operationConvenient, can eliminate the impact of other extraneous factor, and valid density and therapeutic index that can detection of drugs, forIt is more basic that later stage mechanism research provides. The present invention adopts mdck cell to cultivate screening method and detects benzydamine hydrochlorideThe impact that infected by influenza infects, the neuraminic acid expression of enzymes based on to representing influenza virus levels of replication in supernatantThe detection of level, 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 laboratory apparatus
Multiple labeling microwell plate reads instrument (PerkinElmer).
2. experimental technique and result
2.1 cells are cultivated: 37 DEG C, and 5%CO2In humidification incubator, cultivate. Use contains 10%FBS, 100U/mLPenicillin and the DMEM culture medium of streptomysin. 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 chicken embryos, use Egg checker inspection before virus inoculation, and farFrom embryo's position mark, after sterilizing and punching, inoculate 2 by 0.2ml/ piece4The virus liquid of hemagglutinative titer, with referring toNail polish sealing, put 37 DEG C of insulating boxs hatch 48h (after inoculation 24h, to be generally misoperation lethal for dead chicken embryo,Abandon it). Take out chicken embryo and put 4 DEG C of cold embryo 12h. 75% alcohol disinfecting chick embryo air sac, sterile working cuts off outside air chamberShell, capillary syring is drawn chick embryo allantoic liquid and amniotic fluid, and 3000rpm4 DEG C of centrifugal 30min detects hemagglutinative titer,200 μ l/ pipe packing juxtaposition-70 are DEG C frozen for subsequent use.
The cytotoxicity of 2.3 benzydamine hydrochlorides detects: mdck cell is by 8 × 103(volume 100 μ l) for cells/wellBe inoculated in 96 porocyte culture plates, 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 and100.0 μ M are totally 8 gradient concentration preparations, and each gradient concentration is established 2 multiple holes. After cultivating 48h, discard cultivationSupernatant, the new DMEM culture medium that adds 100 μ l to contain 10%Alamarblue reagent in every hole, puts thinIn born of the same parents' incubator, continue to cultivate 1h, after 1h, read instrument with microwell plate and measure respectively fluorescence intensity and light absorption value, meterCalculate cell survival rate.
Result shows that (Fig. 1) benzydamine hydrochloride does not have cell completely to mdck cell within the scope of 50.0 μ MToxicity, illustrates that benzydamine hydrochloride has the safer scope of application, and the dosage of benzydamine hydrochloride is according to carefullyBorn of the same parents' experimental measuring is 0.0～50.0 μ M.
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) isThe specific substrate of influenza neuraminidase, the catalysate producing under neuraminidase effect exists355nm exciting light can produce 460nm fluorescence under irradiating, and the power of fluorescence intensity has represented viral nerveThe number of propylhomoserin expression of enzymes amount, has reflected the virus quantity in cultured cell supernatant.
2.4.2. mdck cell is pressed to 1.5 × 104Cells/well is inoculated in 96 porocyte culture plates, 37 DEG C of cellsIn incubator, cultivate after 14～18h, for subsequent use after cell grows up to individual layer. Culture medium in orifice plate is discarded to PBSClean after twice, add 100TCID50(l) (100 μ are l) in 37 DEG C with variable concentrations medicine for 100 μ for virus liquidIn cell culture incubator, cultivate. Medicine is taking 50.0 μ M as initial concentration, 6 gradients of continuous 2 times of gradient dilutions,Every gradient arranges two multiple holes. After cultivation 48h, get each experimental port supernatant and carry out the detection of neuraminic acid enzymatic activity. RealTest and blank group, positive controls (Ribavirin), negative control group are set (after virus infections without medicineProcess) and Experimental agents group.
2.4.3. in black 96 hole micro plates, add 40 μ l buffer solution (32.5mmol/LMES, pH6.5,4mmol/LCaCl2) the substrate 20umol/LMUNANA of preparation, then add each experimental port culture supernatant 20 μ l, keep away for 37 DEG CLight is hatched 60min, adds reaction terminating liquid (0.014 μ MNaOH, 83% ethanol) 100 μ l/ holes, and micropore is readOn plate instrument, measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
2.4.4. calculate the inhibiting rate that each detection hole Chinese traditional medicine infected by influenza copies.
Inhibiting rate (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: along with the increase of benzydamine hydrochloride drug concentration, and the inhibiting rate that medicine infected by influenza copiesRaise gradually, the dosage presenting clearly relies on effect. It can suppress 50% virus in 6.2 μ M concentrationCopy, selection index is 13.6, in the time of 50.0 μ M concentration, reaches and approaches 100% inhibiting rate. (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 benzydamine hydrochloride to influenza A virus AsiaThe antiviral activity of type 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 × 104Cells/well is inoculated in 96 porocyte culture plates, 37 DEG C of cell trainingsSupport in case and cultivate after 14～18h, for subsequent use after cell grows up to individual layer. Culture medium in orifice plate is discarded, and PBS is clearWash after twice, add 100TCID50(l) (100 μ are l) thin in 37 DEG C with variable concentrations medicine for 100 μ for virus liquidIn born of the same parents' incubator, cultivate. Medicine is taking 50.0 μ M as initial concentration, and 6 gradients of continuous 2 times of gradient dilutions are everyGradient 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 solution (32.5mmol/LMES, pH6.5,4mmol/LCaCl2) the substrate 20umol/LMUNANA of preparation, then add each experimental port culture supernatant 20 μ l, keep away for 37 DEG CLight is hatched 60min, adds reaction terminating liquid (0.014 μ MNaOH, 83% ethanol) 100 μ l/ holes, multi-functionalOn detector, measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
4. calculate the suppressed rate of neuraminidase in each detection hole.
Inhibiting rate (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: benzydamine hydrochloride has obviously suppressed answering of various influenza virus strains within the scope of drug concentrationSystem, and be all dose-dependence (seeing Fig. 3). It is to influenza A virus H6N6, influenza A virusHalf-inhibition concentration (the IC of H7N8 and influenza B virus50) be 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 that a kind of anti-current of wide spectrum is susceptibleCytotoxic drug.
Claims (6)
1. benzydamine hydrochloride application in preparation treatment or flu-prevention virus infective medicament as antiviral activity composition.
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 oral administered dosage form, injecting medicine-feeding form, mucosa delivery formulation or percutaneous dosing formulation.
4. application as claimed in claim 1, is characterized in that: described medicine is any pharmaceutically acceptable formulation.
5. application as claimed in claim 4, is characterized in that: described medicine is tablet, capsule, granule, oral liquid or parenteral solution.
6. application as claimed in claim 4, is characterized in that: described medicine is sustained release preparation, controlled release preparation or nanometer formulation.
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| 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 |
| CN116536255B (en) * | 2023-07-05 | 2023-09-12 | 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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