CN102068452B - Antiviral medicinal composition - Google Patents
Antiviral medicinal composition Download PDFInfo
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Abstract
The invention relates to a synergic antiviral medicinal composition, which contain baicalein and ribavirin in a weight ratio ranging from 20:1 to 1:10. The medicinal composition has the advantages of low medicament tolerance, fewer side effect and adverse effects, and the like. In addition, the medicinal composition has the function of inhibiting the duplication of viruses, and has outstanding advantages and a bright development prospect in preventing and treating influenza viruses.
Description
Technical field
The present invention relates to the pharmaceutical composition of synergistic corrosion virus.Specifically, this pharmaceutical composition contains baicalin and ribavirin.
Background technology
Influenza virus (Influenza virus) is called for short influenza virus, is grippal pathogen, belongs to orthomyxoviridae family (Orthomyxoviridae), is single minus-stranded rna virus.Virus is spherical in shape or thread, and peplos is arranged.The spherical viruses particle diameter is 80～200nm, and is thread different in size, can reach several microns.The structure of influenza virus is divided into 3 parts from the inside to the outside successively: core, stromatin and peplos.
Different with the antigenicity of stromatin (M) according to nucleoprotein (N), influenza virus is divided into first (A), second (B), third (C) type.Influenza A virus is divided into some hypotypes again according to HA is different with the NA antigenicity, and wherein HA antigen has 16 hypotypes (H1～H16), NA antigen have 9 hypotypes, and (N1～N9), the strain hypotype is by following order expression: type/separation place/numbering/separation time.
Influenza A virus can be propagated in populations such as people, fowl, pig, horse; Influenza B virus only has among the mankind and infects; Influenza virus C is propagated in people, pig.Look back the popular history of influenza, causing pandemic mainly is influenza A virus, and B-mode also once had a localized epidemics, and influenza virus C is seldom popular.1957～1961 years more with influenza due to the H2N2 subtype influenza virus, and 1968～nineteen fifty-seven is main epidemic strain with the H3N2 hypotype, and 1977～nineteen eighty-three, then H1N1 hypotype and H3N2 hypotype all had popular.The bird flu of wreaking havoc recently mainly is the H5N1 type, and it is the H1N1 type that Mexican influenza is played in the source.
The maximum characteristics of influenza virus are antigenic variabilities, and this variability can cause the variation of transmissibility.Wherein first type antigenic variability is the strongest, and little variation often takes place, and is called " antigenic drift ".When big variation or hypotype transformation take place influenza virus, be called " antigen transfer ".Approximately whenever will take place once to make a variation, approximately whenever big variation will take place simultaneously, and this variation tend to bring the world of an influenza to be very popular at a distance from the HA and the NA of 30～40 years influenza A viruss at a distance from the HA of 10 years influenza A viruss.
At present, the Tamiflu of official listing is divided into two types substantially: the amantadine of finding with middle 1960s (amantadine) is the ion channel blocking agent of representative; With oseltamivir phosphate capsule (oseltamivir) is the NA inhibitor of representative.In addition, be target spot with the different links of influenza virus reproduction process, also have some medicines to be in laboratory research or clinical experimental stage.
Respiratory syncytial virus (Respiratory syncytial virus; RSV) being the main pathogens that causes infant, child, old people and the serious lower respiratory infection of immunodeficiency crowd in the world, also is the dangerous factor of bringing out infantile asthma simultaneously, can cause lower respiratory illnesses such as interstitial pneumonia and bronchiolitis; Disease progression is fast; Breathe heavily and suppress seriously, be prone to merge heart failure, respiratory failure, even serious consequence such as death takes place.The pneumonia clinical manifestation that RSV caused is heavy, and case fatality rate is high.However, up to the present still there is not safe and effective vaccine approval listing.
RSV is a kind of tunicary sub-thread minus-stranded rna virus, belongs to Paramyxoviridae, and pneumonitis virus belongs to.The RSV genome has 15222 nucleotide, and 10 the proteic genes of difference of mainly encoding wherein have three transmembrane proteins (G, F and SH), two stromatins (M and M2), three nucleocapsid proteins (N, P and L) and two non-structural proteins (NS1 and NS2).Transmembrane glycoprotein G and F are 2 main protection antigen of RSV.According to the difference of G Argine Monohydrochloride sequence, can RSV be divided into A and two hypotypes of B.
At present, still lacking the specific treatment to respiratory syncytial virus pneumonia, mainly is to suit the medicine to the illness and Supporting Therapy.Main medicine is ribavirin (virazole), is the medicine that the unique approval of U.S. FDA is used to treat the respiratory syncytial virus high-risk patient.But comprehensive therapeutic effect is dissatisfied, and side effect is more, largely limit its clinical practice.
Adenovirus (Adenovirus) is from the tonsil tissue of excision, to separate a kind of DNA viruses that obtains, and mainly breeding in nuclear often causes that people's upper respiratory tract and eye epithelial cell infect.Adenovirus is a kind of common opportunistic pathogen, and long-term existence is in the crowd, and the probability of the patient infection adenovirus of immunologic hypofunction is bigger.In the intensive crowd that lives, cause the outbreak of epidemic of febris acuta property respiratory tract disease easily.
According to the difference of host range, adenovirus is divided into mastadenovirus (Mastadenovirus) and birds Adenovirus (Aviadenovirus).Adenovirus hominis (Human adenoviruses; HAdV) belong to Adenoviridae (Adenoviridae); According to the difference of immunology, biology, biochemical characteristic, can it be divided into 7 subspecies of A～G, have 52 serotypes; And different serotype has different organ affinitys, and causes corresponding clinical manifestation.Do not have formal medicine to be used for the treatment of anti-adenovirus infection at present, have only several kinds of antiviral drugs such as ganciclovir, vidarabine, virazole etc. are used for the research of some cases and colony.
Baicalin, 5,6,7-3-hydroxyl-flavone, molecular formula is C
15H
10O
5, molecular weight is 270.24.Baicalin has multiple functions such as antiviral, antibiotic, antiinflammatory, antitumor, antiallergic, antioxidation, anticoagulation, blood pressure lowering and immunomodulating.The experimental results shows, baicalin is inhibited to HIV (HIV), Human Cytomegloviru (HCMV), respiratory syncytial virus (RSV), adenovirus (Adv3, Adv7), herpesvirus (HSV21, HSV22), Coxsackie virus B multiple viruses such as (Cox B3, Cox B4, Cox B5).Its antiviral pharmacology effect and Study on Mechanism are shown, baicalin mainly through stop virus penetrate cell, suppress viral organism synthetic, suppress virus and discharge or strengthen multiple modes such as host anti-virus ability and suppress virus replication.
The activity of the anti-immunodeficiency virus of baicalin is existing report in 1989.Thereby the external HIV-1 of the inhibition reverse transcriptase of baicalin suppresses HIV-1 in cell culture, and lures the cell generation apoptosis of infected by HIV into.Quiet can make AIDS patient P 24 antigens descend, and the T4 lymphocyte rises.Zhao Jing research confirms that 6 hydroxyls of baicalin are essential for suppressing the active institute of hiv reverse transcriptase.The IC of baicalin HIV-RT
50Be 10.26 μ g/ml, baicalin suppresses the IC of HIV-RT
50Be 65.88 μ g/ml, baicalin suppresses the HIV-RT activity and cytotoxicity all is better than baicalin, but two kinds of compounds for treating indexes are close.
The main of the anti-Human Cytomegloviru (HCMV) of baicalin possibly be the infection of blocking HCMV in early days.Evers DL etc. discovers that baicalin is effective blocker (IC of HCMV
50=0.4～1.2mg/ml), it can significantly reduce the early stage protein level with late period of HCMV, and can suppress synthesizing of viral DNA.Baicalin can not be blocked duplicating of HCMV in the preparatory cultivation of viral concentrate; This phenomenon prompting; The antivirus action of baicalin is not direct inactivated virus particle, but on function, blocks the activity of epidermal growth factor recipient tyrosine kinase, and the nuclear transposition of HCMV.
Baicalin and ribavirin use the Pharmacological action study report of antagonism virus a lot of separately, and do not have antiviral pharmacological action to be shown in report by the compound preparation that these two kinds of medicines are formed, and comprise the effect of resisiting influenza virus.
Summary of the invention
The present invention is directed to deficiency; A kind of antiviral medicinal composition is proposed; Can effectively prevent and treat the respiratory tract infectious disease that causes by influenza virus, respiratory syncytial virus or adenovirus etc.; The flu that causes like viral pneumonia, bronchitis etc., and directly or indirectly add acceptable accessories through conventional processing and promptly can be made into various dosage forms.
In order to realize the foregoing invention purpose, the present invention provides following technical scheme: a kind of antiviral medicinal composition is 20 in weight ratio: 1-1 usually: select in 10 the scope, be preferably 10: 1-1: 5, more preferably 8: 1-2: 1.Take by weighing mentioned component in proportion, mixing gets final product.Also can be through conventional operational means; In pharmaceutical composition, directly or indirectly add acceptable accessories and promptly can be made into various dosage forms, as: capsule, granule, pill, powder, tablet, oral liquid, syrup, oral cavity disintegration tablet, gargarism, granula subtilis, powder or injection.
Baicalin
Labiate Radix Scutellariae (Seutellaria baiealensis Geogri) is the Chinese medicine of China; Cold in nature, bitter in the mouth; Have clearing away heat-fire, detoxifcation, hemostasis, effect such as antiabortive, be usually used in treating diseases such as upper respiratory infection, urinary system infection, bacillary dysentery, hepatitis, hypertension clinically.The active ingredient of Radix Scutellariae is a flavone compound, mainly contains baicalin (Baicalein), baicalin (Baicalin), also has wogonin (Wogonin), wogonoside (Wogonoside) and neobaicalein (Neobaicalein) etc. in addition.
Baicalin, 5,6,7-3-hydroxyl-flavone, molecular formula is C
15H
10O
5, molecular weight is 270.24.Have multiple functions such as antiviral, antibiotic, antiinflammatory, antitumor, antiallergic, antioxidation, anticoagulation, blood pressure lowering and immunomodulating.
(1) antiviral: The experimental results shows that baicalin is inhibited to multiple viruses such as HIV, human cytomegalic inclusion disease virus, respiratory syncytial virus, adenovirus, herpesvirus, Coxsackie virus Bs.Baicalin mainly through stop virus penetrate cell, suppress viral organism synthetic, suppress virus and discharge or strengthen multiple modes such as host anti-virus ability and suppress virus replication.
(2) antibiotic: baicalin is inhibited to Fusarium oxysporum and Candida albicans, and MIC (MIC) is respectively 0.112mg/ml and 0.264mg/ml.Baicalin has stronger inhibitory action to yeast, under the same terms, to tinea pedis and thread Fungi Imperfecti unrestraint effect; To certain specific flora of generation bromhidrosis and beriberi, as: set micrococcus luteus, epidermis glucose coccus, people's glucose coccus and Corynebacterium xerosis have inhibitory action, and its fungistatic effect is relevant with 7 hydroxyl.
(3) antiinflammatory: baicalin is realized anti-inflammatory response through suppressing effects such as histamine release, anti-arachidonic acid metabolic, inhibition vascular permeability.Baicalin all has inhibitory action to epoxidase and lipoxygenase in the rat platelet arachidonic acid metabolic; This has just suppressed the biosynthesis of inflammatory mediators such as PGE2 and leukotriene B4/C4, reduces arachidonic release through suppressing the activated protein kinase of mitogen-cytosolic phospholipase A2 passage (MAPK-cPLA2).
(4) antitumor: baicalin can be induced the apoptosis of multiple cancerous cell and tumor cell, and its mechanism of action is: 1. act on apoptosis relevant gene and albumen.2. BAI blocks cell proliferation and cell death inducing through the mitochondrion approach: baicalin suppresses the S phase of HepG2 cell growth cycle, makes the increase of the reduction of mitochondrion transmembrane potential and cell membrane integrity destruction and DNA fragment.3. baicalin reduces the activation of IL-6 and XIAP gene expression and Caspase-9, Caspase-3 through suppressing the phosphorylation of I κ B-α, and the myeloma cell is brought into play antiproliferative effect, particularly jejune MPC-1-myeloma cell is had inhibitory action.4. suppress its anticancer, anti-tumor activity of 12-LOX performance through specificity: a large amount of platelet type 12-LOX are at many tumor tissues; As: reach all overexpressions in the multiple JEG-3 in breast carcinoma, colon cancer, renal cell carcinoma and the carcinoma of prostate, regulate the growth and the survival of many cancerous cell.5. through suppressing cyclooxygenase-2 anticancer propagation.
(5) remove free radical and antioxidation: baicalin can be removed free radical, the fibroblast damage that prevention such as oxygen-derived free radicals such as hydroperoxidation enzyme, superoxide anion cause.Can suppress the inductive rat liver microsomal lipid peroxidation thing of ascorbic acid enzyme through forming iron chelate.10 μ mol/l baicalins can effectively suppress Fe
2+The inductive rat brain cortex mitochondrial lipid peroxidation of-Vit C, NAPH or NADPH makes cell avoid H
2O
2Inductive damage.
(6) anticoagulation: baicalin can suppress collagen-induced platelet aggregation effect; The Fibrinogen of thrombin induction is converted into fibrin; Platelet aggregation to arachidonic acid-induction also has inhibitory action; And prevent disseminated inravascular coagulation (DIC) and rat platelet and fibrinogenic minimizing by endotaxin induction, and the generation of ability Trombin inhibiting and the inductive PAI-1 of thrombin receptor tonin, its mechanism possibly be to have reduced Ca
2+Rising.
(7) other: baicalin also has function of gallbladder promoting, diuresis, blood fat reducing, treatment acute pancreatitis, suppress the 3T3-L1 mice before adipose cell break up to adipose cell, and suppress effect such as fatty acid synthetase.
Ribavirin
Ribavirin (ribavirin), chemical name are 1-β-D-ribofuranosyl-1H-1,2, and 4-triazole-3-carboxylic acid amides, another name virazole, ribavirin, Xin Bolin granule, RTC, Virazole, RBV are guanosine inosine analog.Molecular formula is C
8H
12N
4O
5, relative molecular weight is 244.21, fusing point is 174～176 ℃, is white crystalline powder, and odorless, tasteless, (greater than 10g/100mL, 19 ℃) soluble in water is slightly soluble in ethanol, is insoluble to ether or chloroform.
Indication: antiviral agents.Be used for viral pneumonia and bronchitis that respiratory syncytial virus causes.
Description of drawings
Fig. 1 baicalin and ribavirin infect the influence of the cell survival rate of mdck cell to influenza A virus A/FM/1/47 (H1N1)
The specific embodiment
For verifying reliability of the present invention, three antivirus tests have been carried out.
Embodiment 1: baicalin and ribavirin are to the influence of the dead protective rate of influenza A virus A/FM/1/47 (H1N1) infecting mouse (♀)
The ICR female mice of 17～19g is adopted in experiment; Be divided into 7 groups at random; Be made as normal control group, virus control group, ribavirin group 50mg/kg/d and baicalin group 400mg/kg/d, dose groups 250mg/kg/d (baicalin/ribavirin=4: 1 in sample low dose group 150mg/kg/d (baicalin/ribavirin=2: 1, weight ratio), the sample; Weight ratio), sample high dose group 450mg/kg/d (baicalin/ribavirin=8: 1, weight ratio).Adaptability was cultivated after 2 days, began experiment.Except that the normal control group, other is respectively organized mice and slightly anaesthetizes with ether, and intranasal vaccination is equivalent to 8LD
50The chick embryo allantoic liquid that contains influenza virus 50 μ l/ only, each administration group is 24h gastric infusion first before viral infection, infect and infected the 1h gastric infusion same day, later every day 1 time, 1 0.2ml, administration is 5 days altogether.Virus control group and normal control group give 0.2ml sodium carboxymethyl cellulose (0.5%CMC-Na) with method.After the mouse infection virus, 14d observes survival condition continuously, record death toll, death time, calculates dead protective rate and mean survival time.
Experimental result (table 1) shows that ribavirin 50mg/kg/d reaches 50% to the dead protective rate of mice; Baicalin 400mg/kg/d reaches 20% to the dead protective rate of mice; Compare with the virus control group, give the baicalin and the ribavirin of different proportionings, can effectively reduce the influenza infection mortality of mice, improve the dead protective rate (P＜0.001) of mice, prolong the time-to-live.In the different proportionings of baicalin and ribavirin, wherein the action effect of sample high dose group 450mg/kg/d is preferable, and dead protective rate reaches 100%, is superior to baicalin group and the ribavirin group used separately.In the different proportionings of baicalin and ribavirin, each proportioning group all has the certain protection effect to the body weight of mice, and the mice weight loss reduces.
Table 1 baicalin and ribavirin are to the influence of the dead protective rate of influenza A virus A/FM/1/47 (H1N1) infecting mouse (♀)
Annotate: compare *, P＜0.05, * *, P＜0.01, * * *, P＜0.001 with the virus control group.
Embodiment 2: baicalin and ribavirin are to the influence of influenza A virus A/FM/1/47 (H1N1) infecting mouse (♀) pneumonia protection
A the same test of experimental animal and normal control group, virus control group and sample sets.Each administration group is 24h gastric infusion first before viral infection, and infect and infected the 1h gastric infusion same day, later every day 1 time, 1 0.2ml, administration is 5 days altogether.Virus control group and normal control group give 0.2ml sodium carboxymethyl cellulose (0.5%CMC-Na) with method.After the mouse infection virus, water 8h is prohibited in fasting in the 5th day, and mice is weighed, and extracts the eyeball blood-letting and causes death, and takes out full lung, and clean filter paper wiped clean is weighed.Calculate lung index and lung index suppression ratio, press standards of grading shown in the table 2 the Mus lung is marked.
Table 2 pulmonary lesion integration standard
Result of the test (table 3) shows that the baicalin and the ribavirin that give different proportionings all can to a certain degree suppress the lung index, and the pathological changes situation alleviates to some extent, and the lung scoring reduces.Compare with ribavirin single dose administration group, the baicalin and the ribavirin that give different proportionings obviously improve lung index suppression ratio, and wherein sample high dose group 450mg/kg/d reaches 53.52%.Normal control group lung tissue all is normal morphology.No exudate in the bronchial lumen, mucosal epithelium does not have degeneration necrosis and comes off, and tube wall and surrounding tissue thereof do not have cell infiltration; Alveolar septum does not thicken, no cell infiltration, no exudate in the alveolar space.And virus control group lung tissue all be in to severe bronchitis and interstitial pneumonia.Show as bronchial epithelial cell degeneration, necrosis, intracavity is seen a spot of non-viable non-apoptotic cell and exudate.Pathological changes bronchial wall and lung tissue structure is still clear on every side has lymphocyte, neutrophil cell to soak into.Alveolar wall generally thickens, vasodilation in it, and the above-mentioned cell infiltration that more or less is arranged.Along with dosage increases, the pathological changes situation alleviates to some extent, shows as the lung scoring and reduces, and each administration group has the effect of pulmonary infection disease due to the antiviral.Wherein sample high dose group 450mg/kg/d form and normal control winding are near, and different proportioning group forms are better than independent medication group.
Table 3 baicalin and ribavirin are to the influence of influenza A virus A/FM/1/47 (H1N1) infecting mouse (♀) pneumonia protection
Annotate: compare *, P＜0.05, * *, P＜0.01, * * *, P＜0.001 with the virus control group.
Embodiment 3: according to the cytotoxicity experiment result, normal control group, virus control group, ribavirin group 25,12.5,6.25 μ g/ml and baicalin group 0.25,0.125 μ g/ml and each drug combination group are established in experiment.Mdck cell is by 5 * 10
4/ ml concentration is inoculated 96 well culture plates, and every hole 100 μ l put 37 ℃ of 5%CO
2After cultivating 24h formation cell monolayer in the incubator, culture fluid is discarded.Add 100TCID
50Influenza virus A/FM1/1/47 (H1N1) infection cell is hatched 1h for 37 ℃, treat virus absorption after, remove virus removal liquid, in cell, add each administration group of 100 μ l cell maintenance mediums dilution, 3 multiple holes of each concentration inoculation.Cell was cultivated 2～3 days in 37 ℃ of 5% CO2 gas incubator, observed CPE day by day, abandon supernatant after, add 100 μ l10% formaldehyde fixed, 0.1% (w/v) violet staining 15min, 570nm measures absorbance.Through MacSynergy II software, obtain the situation of drug interaction.
Result of the test shows; The external all certain table of degree of drug combination group reveals good CPE and suppresses (table 4); Cell to being infected provides protection, collaborative/the antagonism capacity is 225.46, it is active to demonstrate stronger synergistic corrosion virus; Wherein ribavirin 25 μ g/ml and baicalin 0.25 μ g/ml drug combination group action effect are preferable, and synergism is (accompanying drawing 1) the most by force.
Table 4 baicalin and ribavirin infect the cell survival rate influence (OD of mdck cell to influenza A virus A/FM/1/47 (H1N1)
570)
Claims (3)
1. the pharmaceutical composition of a synergistic corrosion virus, its active component is 8 by weight ratio: 1-2: 1 baicalin and ribavirin are formed.
2. the application of the pharmaceutical composition of claim 1 in preparation treatment influenza virus infectious disease medicine.
3. the application of claim 2, wherein influenza virus infectious disease is viral pneumonia or bronchitis.
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| CN113244212B (en) * | 2020-02-10 | 2023-05-05 | 中国医学科学院药物研究所 | Application of baicalein in preparing medicament for preventing and/or treating novel coronavirus infection diseases |
| CN111467466A (en) * | 2020-05-13 | 2020-07-31 | 广州白云山光华制药股份有限公司 | New application of radix bupleuri granule in preventing and treating syncytial virus and adenovirus |
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| CN101879218A (en) * | 2009-05-05 | 2010-11-10 | 天津市天合力药物研发有限公司 | Compound shuanghuanglian oral solution used for treating cold of dog and preparation method thereof |
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| CN1606979A (en) * | 2003-10-16 | 2005-04-20 | 车庆明 | Effect of scutellarein as antifebrile, analgesic, antiphlogistic, antibiotic and antiviral agent |
| CN101879218A (en) * | 2009-05-05 | 2010-11-10 | 天津市天合力药物研发有限公司 | Compound shuanghuanglian oral solution used for treating cold of dog and preparation method thereof |
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