CN105769842A - Rheidin application and antiviral drugs - Google Patents

Rheidin application and antiviral drugs Download PDF

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Publication number
CN105769842A
CN105769842A CN201610353741.7A CN201610353741A CN105769842A CN 105769842 A CN105769842 A CN 105769842A CN 201610353741 A CN201610353741 A CN 201610353741A CN 105769842 A CN105769842 A CN 105769842A
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virus
reidin
infection
influenza
group
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萧伟
丁玥
曹泽彧
李娜
曹亮
丁岗
王振中
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Jiangsu Kanion Pharmaceutical Co Ltd
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Jiangsu Kanion Pharmaceutical Co Ltd
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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/708—Rheum (rhubarb)

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides application of rheidin in preparing drugs for treating viral diseases. It is proved through experiments that rheidin has the inhibiting effects on cell lesions induced by an influenza virus, a respiratory syncytial virus, a herpes virus and enterovirus EV71 type, and the survival rate of virus infected cells can be increased; meanwhile, virus replication can be inhibited in a body, the survival rate of virus infected animals is increased, the survival time of the virus infected animals is prolonged, symptoms of diseases caused by virus infection are relieved, and therefore the effects of treating influenza, viral pneumonia, upper respiratory tract infection, skin herpes simplex viruses and hand-foot-mouth diseases and an application value are achieved.

Description

The purposes of reidin and antiviral drugs
Technical field
The invention belongs to pharmaceutical technology field, particularly relate to purposes and the antiviral drugs of reidin.
Background technology
Radix Et Rhizoma Rhei is the dry root and rhizome of polygonum rheum palmatum RheumpalmatumL., Rheum tanguticum RheumtanguticumMaxim.ExBalf or Rheum officinale RheumofficinaleBaill., begin to be loaded in Shennong's Herbal, history tree all records, nature and flavor bitter cold, return spleen, stomach, large intestine, liver, pericardium channel, there is the multiple efficacies such as heat and toxic materials clearing away, clearing away heat-fire, removing toxic substances, hemostasis, activating blood and removing stasis.Radix Et Rhizoma Rhei has been carried out big quantity research by recent domestic, and its pharmacological action is constantly realized, and clinical application range progressively expands, in addition the people's continuous accreditation to Chinese medicine so that Radix Et Rhizoma Rhei Clinical practice amount strengthens year by year.Radix Et Rhizoma Rhei tool multiclass drug activity composition, wherein maximum with Anthraquinones, dianthrone class, class, tannin and polysaccharide researches, modern study find, its pharmacological action mainly have adjustment gastrointestinal function, antitumor, anti-inflammation, antiviral, arteriosclerosis, blood pressure lowering, rush down lower diuresis, hepatic cholagogic, scavenging free radicals, adjustment immunity etc. multiple effect.Radix Et Rhizoma Rhei has broad-spectrum disease resistance toxic action, and herpes simplex virus, cells of coxsackie B 3 virus, Avian pneumo-encephalitis virus, HIV (human immunodeficiency virus) (HIV), hepatitis B virus (HBV) etc. are all had certain inhibitory action, and cytotoxicity is relatively low.Therefore, Radix Et Rhizoma Rhei has vast potential for future development as antiviral drugs.
Influenza, is a kind of acute suction tract disease with hyperinfection that influenza virus causes, and is that human health is threatened one of maximum infectious disease, has the sickness rate feature such as extensively high, popular, still can not effectively control so far.Influenza virus can pass through air droplet transmission, propagates rapidly, once large-scale outbreak is difficult to control to.Influenza onset is hurried, complication rate is high, general malaise can be caused, feel cold including sneeze, cough, headache, heating, the symptom such as lassitude and weak, inappetence, pneumonia, congestive heart failure and other complication that its hazardness causes when being more embodied in serious, often jeopardizes the life of infant, old people and immunocompromised person.Influenza A H1N1 in 2009, in China, ground adds up report severe cases 4328 example, dead 326 examples；H7N9 avian influenza people's case of China's appearance in 2013 amounts to 130 examples, and wherein 35 people are dead, and this epidemic situation causes society once again to the extensive concern of influenza and the urgent needs to resisiting influenza virus medicament research and development.At present, the Western medicine treating influenza mainly has M2 inhibitors of ion channels (amantadine and rimantadine), NA inhibitor (Oseltamivir and zanamivir) and influenza vaccines.Influenza A virus is only had inhibitory action by amantadine and rimantadine, and there is untoward reaction.Oseltamivir uses as a line anti-influenza virus medicament, but is found that Oseltamivir persister occurs and propagates successively, and expensive.Zanamivir is mainly used in the early treatment of influenza, but is not suitable for child, and the patient having asthma or chronic obstructive pulmonary disease is likely to have the danger increasing bronchospasm.And the influenza virus sub-strain that oneself is only known by vaccine has preventive effect, invalid to being changed produced novel influenza by antigenic drift or antigenicity, influenza vaccines are developed and use relatively lags behind.Traditional Chinese Medicine Anti influenza virus has feature integrally-regulated, Mutiple Targets treatment, there is stronger antivirus action, its effect wide spectrum often, can not only virus replication, suppress inflammatory reaction and antipyretic, also there is immunoloregulation function simultaneously, fundamentally resist virus infraction, Chinese medicine compound multicomponent, multipath, Mutiple Targets feature can reach the effect of " whole synthesis adjustment ", the chemicals of more single resisiting influenza virus is with the obvious advantage.
Herpes simplex virus (HSV) belongs to Herpesvirus Alphaherpesvirinae, it it is a kind of tunicary wire double-stranded DNA virus, enter internal through respiratory tract, oral cavity, eye, genital mucosa and damaged skin, have that host's excursion is big, infection site extensive, the feature such as destructible infection cell and latent infection.HSV mainly includes HSV-1 and HSV-2 amphitypy, HSV-1 main infection mouth, eye, the skin of lip and mucosa and central nervous system, skin herpes simplex, herpes labialis, serious corneal infection (keratitis) and inflammation of the central nervous system (encephalitis) can be caused, if treat not in time may threat to life for the encephalitis that HSV-1 causes；HSV-2 is general relevant with external genitalia infection and infection of newborn, genital herpes can be caused, infection of pregnant women HSV easily miscarries or causes fetus congenital malformation and mental retardation, and neonate occurs that after being infected by HSV-2 by birth canal high heat, dyspnea and central nervous system pathological change are even dead.It is relevant with lip cancer and cervical cancer generation respectively that medical circle research in recent years shows that HSV-1 and HSV-2 is likely to, and HSV-2 external genitalia infects and become the sexually transmitted disease (STD) being only second to AIDS viral infection, therefore HSV causes again the attention that medical circle is new.The choice drug of present clinical anti-HSV is acycloguanosine, is described as the milestone in anti-HSV drug development history with its high-efficiency low-toxicity, but its antiviral spectrum is narrow, is easily generated drug resistance and expensive so that it is clinical practice is very limited.Additionally, when the Drug therapy HSV such as iodouracil desoxyriboside, vidarabine infects, drug resistance phenomenon often occurs, is all difficult to clean off virus lays dormant.Also have some chemical classes medicines, mostly apply less because having stronger cytotoxicity or untoward reaction.Owing to the gene of HSV is double-stranded DNA, easy and host DNA generation integration, or form latency, limit the effect of viral vaccine.In recent years, the research about Traditional Chinese Medicine Anti HSV effect gets more and more, and domestic and international researcher has screened from Chinese herbal medicine and searched out some Effective Antis HSV medicine, and some of which has been developed that and is applied to clinic.As Radix Et Rhizoma Rhei ethanol extraction subcutaneous injection is suitable with ACV positive controls effect, in each internal organs, virus titer declines rapidly, presents dose-dependence.Clinical practice single Radix Et Rhizoma Rhei has cured genital herpes case 35 example, and the healing for genital herpes illustrates a method more likely.Resources of Chinese medicinal herb is extensive, curative effect affirmative, and toxic and side effects is little, and its antivirus action is increasingly subject to pay attention to, and is develop one of new focus of herpes class medicine.
Hand-foot-mouth disease (HFMD) is that the common transmittable caused by multiple enterovirus is sick, propagates mainly through approach such as digestive tract, respiratory tract and close contacts, based on infant morbidity.Hand-foot-mouth disease is mainly infected by RNA viruses section enterovirus genus coxsackie virus A 16-type (CoxA16) and enterovirns type 71 (EV71) and causes, the most serious with 71 type viruses.HFMD main manifestations is heating companion's myoclonus, stomatocace herpes and limb end vesicle sample erythra, seriously can causing the multiple diseases relevant to nervous system such as encephalitis, brain stem encephalitis, poliomyelitis sample paralysis, acute flaccid paralysis, harm is serious.There is no the vaccine of specific treatment medicine and correspondence at present, so this disease receives the common concern of medical circle.When there is no specific drug, treatment based on antiviral, should adopt whole body therapeutic to combine with local treatment, Chinese medicine and Western medicine use in conjunction, the more preferably effect such as recovery from illness, Shorten the Treatment Process, reduction complication and case fatality rate can be obtained.Chinese medicine plays positive role by overall multi-direction synthetic response to treatment, has been increasingly subject to the concern of people.
Respiratory syncytial virus (RSV) belongs to Paramyxoviridae pneumonia and belongs to, it it is a kind of sub-thread minus-stranded rna virus having after birth, it is divided into A, two hypotypes of B, epidemiological study shows that A hypotype accounts for higher ratio in popular period, it is cause the most important cause of disease of infant lower respiratory infection, bronchitis can be caused, bronchiolitis, the diseases such as respiratory syncytial virus pneumonia, clinical manifestation is heating, cough and dyspnea, breathe heavily and suppress, caused pneumonia clinical manifestation is more critical, it it is one of the important risk factor that occurs of children with asthma simultaneously, the critical situations such as heart failure can be there is in some weak infant, even can be lethal.Finding again that rsv infection is old people and the important virus of immunosuppressant adult in recent years, at present, doctor trained in Western medicine there is no safely and effectively vaccine and medicine and controls.RSV virus was extremely easily sent out in the rainy season of the spring of Temperate Region in China, winter and torrid areas, and popular region is wide, and explosion time is long, and mainly by droplet transmission, nasal mucosa contacts with eye mucosa and causes infection.Main infection object is child and the infant of less than 5 years old, has more than the childhood infection RSV virus of less than 33,000,000 5 years old every year, and the infant immunization function of less than 6 months is still immature, is severe infections and dead high-incidence season.Antiviral chemotherapy rsv infection curative effect is not ideal enough, there is potential toxic and side effects；Hormone, bronchodilator curative effect are not affirmed；It is expensive that passive immunity medicine IVIG, RSV-IGIV and Palivizumah prevent and treat rsv infection, is difficult to well-established greatly；Gene therapy and vaccine prevention are still in conceptual phase.Children Treated with Chinese Traditional Drugs rsv infection is evident in efficacy, from entirety, treating both the principal and secondary aspects of a disease, and achieves good therapeutic effect by clinical verification, and untoward reaction is relatively fewer, cheap.Chinese medicine is all innovated to some extent in dosage form and route of administration etc., and for the feature of medication in children comparatively difficulty, the basis of scientific experiments carries out form improvement, route of administration also develops into oral liquid, intravenous injection, aerosol inhalation, the number of ways such as administration of applying ointment or plaster from traditional oral decoction, is expected to develop that more curative effect is prominent, the new product of Chinese medicine of safe ready, good mouthfeel, reliable in quality.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is in that to provide purposes and the antiviral drugs of a kind of reidin.
The invention provides the application in the medicine of preparation prevention and/or treatment viral disease of a kind of reidin.
Preferably, described virus is influenza virus, respiratory syncytial virus, herpesvirus, Coxsackie virus or enterovirus EV 71.
Preferably, the active dose of described reidin is 50～400mg/kg/d.
Preferably, described virus is influenza virus, Coxsackie virus or enterovirus EV 71；The active agent dose of described reidin is 50～200mg/kg/d.
Preferably, described virus is respiratory syncytial virus or herpesvirus；The active dose of described reidin is 100～400mg/kg/d.
Present invention also offers a kind of antiviral drugs, including reidin.
Preferably, pharmaceutically acceptable carrier is also included.
Preferably, described antiviral drugs is oral agents, inhalant or injection.
Present invention also offers the application in the medicine of preparation prevention and/or treatment skin herpes simplex or treatment hand-foot-mouth disease of a kind of reidin.
Present invention also offers the application in the medicine of preparation prevention and/or treatment viral pneumonia or treatment viral upper respiratory tract infection of a kind of reidin.
The invention provides the application in the medicine of preparation prevention and/or treatment viral disease of a kind of reidin.Be experimentally confirmed reidin infected by influenza, respiratory syncytial virus, herpesvirus, enterovirus EV 71 type induction cytopathy all have inhibitory action, the survival rate of virus infected cell can be improved；The duplication of virus can be suppressed in vivo on the one hand simultaneously, improve the survival rate of virus-infected animal, extend the life span of infection animal, alleviate the disease that viral infection causes, thus having effect and the using value for the treatment of influenza, viral pneumonia, upper respiratory tract infection, skin herpes simplex and hand-foot-mouth disease；On the other hand also can breed in vivo and spread and normal tissue causes damage by anti-virus in advance, thus playing the pathogenetic effect of prophylaxis of viral infections disease.
Experiments show that, reidin infected by influenza H1N1 in vitro, H3N2, respiratory syncytial virus RSV, herpesvirus HSV-1, HSV-2 EC50Respectively 121.89 μm of ol/L, 152.92 μm of ol/L, 108.22 μm of ol/L, 116.31 μm of ol/L, 150.27 μm of ol/L, SI respectively 6.59,5.24,7.42,6.90,5.34；Reidin is to enterovirus type CoxA16, EV71 virus, EC50Respectively 203.96 μm of ol/L, 219.73 μm of ol/L, SI respectively 3.94,3.65.
Detailed description of the invention
Below in conjunction with the embodiment of the present invention, the technical scheme in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art obtain under not making creative work premise, broadly fall into the scope of protection of the invention.
The invention provides the application in the medicine of preparation prevention and/or treatment viral disease of a kind of reidin.Wherein, described virus is preferably influenza virus, respiratory syncytial virus, herpesvirus, Coxsackie virus or enterovirus EV 71.Wherein, in some embodiments of the invention, described influenza virus is preferably H1N1 or H3N2；In some embodiments of the invention, described herpesvirus is preferably HSV-1 or HSV-2；In some embodiments of the invention, described Coxsackie virus is preferably CoxA1.
In the present invention, the active dose of described reidin is preferably 50～400mg/kg/d；When described virus is preferably influenza virus, Coxsackie virus or enterovirus EV 71, the active dose of described reidin is preferably 50～200mg/kg/d, more preferably 100～200mg/kg/d；When being preferably respiratory syncytial virus or herpesvirus when described virus, the active dose of described reidin is preferably 100～400mg/kg/d, more preferably 200～300mg/kg/d.
The invention provides the application in the medicine of preparation prevention and/or treatment viral disease of a kind of reidin.Be experimentally confirmed reidin infected by influenza, respiratory syncytial virus, herpesvirus, enterovirus EV 71 type induction cytopathy all have inhibitory action, the survival rate of virus infected cell can be improved；The duplication of virus can be suppressed in vivo simultaneously, improve the survival rate of virus-infected animal, extend the life span of infection animal, alleviate the disease that viral infection causes, thus having effect and the using value for the treatment of influenza, viral pneumonia, upper respiratory tract infection, skin herpes simplex and hand-foot-mouth disease.
Reidin is a kind of anthrone class monomeric compound of separation and Extraction from Radix Et Rhizoma Rhei, and the mechanism of its treatment viral disease is for suppressing virus replication.In some embodiments of the invention, described reidin also can alleviate the inflammatory reaction of host.
Present invention also offers a kind of antiviral drugs, including reidin, it is preferable that also include pharmaceutically acceptable adjuvant；Described antiviral drugs is preferably oral agents, inhalant or injection.
Reidin can use by monomer, also it can be mixed use with any excipient for preparing clinical medicament, prepare into the clinically-acceptable pharmaceutical dosage forms such as oral agents, external preparation, injection to use, it is preferred to tablet, capsule, injection, oral liquid or granule.
Present invention also offers the application in the medicine of preparation prevention and/or treatment hand-foot-mouth disease of a kind of reidin.
Present invention also offers the application in the medicine of preparation prevention and/or treatment skin herpes simplex of a kind of reidin.
Present invention also offers the application in the medicine of preparation prevention and/or treatment viral pneumonia of a kind of reidin.
Present invention also offers the application in the medicine of preparation prevention and/or treatment viral upper respiratory tract infection of a kind of reidin.
Present invention also offers the application in the medicine of preparation prevention and/or treatment influenza infection of a kind of reidin.
In order to further illustrate the present invention, it is described in detail below in conjunction with the embodiment purposes to a kind of reidin provided by the invention and antiviral drugs.
Reagent used in following example is commercially available.
Embodiment 1 reidin extracorporeal antivirus effect pharmacodynamic experiment
By Hep-2 cell (people's laryngeal carcinoma epithelial cell) by the DMEM culture medium containing 2% hyclone by 5 × 104Individual/ml concentration inoculates 96 well culture plates, every hole 100 μ l, puts 37 DEG C, 5%CO2In incubator, overnight incubation forms cell monolayer.After abandoning supernatant, being washed 1 time by cell with PBS, to wash away the hyclone of residual, be divided into normal group and experimental group, experimental group addition is diluted to 100TCID by the DMEM culture medium without hyclone50Each strain virus, every hole 100 μ l, 35 DEG C hatch 2h after, discard virus liquid.By the DMEM culture medium of 2% hyclone, reidin being configured to variable concentrations, be separately added into normal group with experimental group monolayer Hep-2 cell, if 3 multiple holes, Hep-2 cell is in 37 DEG C, 5%CO2In incubator cultivate 48h, every day observation of cell pathological changes phenomenon；After 48h, after abandoning supernatant, add 100 μ l10% formaldehyde fixing 1h, 0.1% (w/v) violet staining 15min, microplate reader 570nm and measure absorbance.Experiment repeats 3 times altogether.Calculate viral suppression, and calculate the reidin EC to virocyte50(medium effective concentration), SI (selection index), obtain result in Table 1 and table 2.
Table 1 reidin TC to Hep-2 cell0And TC50
Table 2 reidin In vitro antibacterial test
From table 1 and 2: reidin infected by influenza H1N1 in vitro, H3N2, respiratory syncytial virus RSV, herpesvirus HSV-1, HSV-2 institute cytopathogenic effect have obvious inhibiting effect, its EC50Respectively 121.89 μm of ol/L, 152.92 μm of ol/L, 108.22 μm of ol/L, 116.31 μm of ol/L, 150.27 μm of ol/L, SI respectively 6.59,5.24,7.42,6.90,5.34；Enterovirus type CoxA16, EV71 virus are had certain inhibitory action, EC by reidin50Respectively 203.96 μm of ol/L, 219.73 μm of ol/L, SI respectively 3.94,3.65, test result indicate that reidin is inhibited to above strain replication in vitro, improve the survival rate of virus infected cell, possess the Pharmacodynamics in vitro basis being applied to resisiting influenza virus, respiratory syncytial virus, herpesvirus, Coxsackie virus, enterovirns type 71 treatment of infection.
Experimental example 2: the protective effect that reidin infected by influenza H1N1 induced mice is dead
In reidin resisiting influenza virus body, drug effect formally tests the Balb/C mice adopting 18-20g, it is randomly divided into 6 groups, often group 10, male and female half and half, respectively Normal group, model group, reidin low dose group 50mg/kg/d, dosage group 100mg/kg/d, reidin high dose group 200mg/kg/d and positive drug ribavirin positive controls 100mg/kg/d in reidin.Adaptability proceeds by experiment after cultivating 3 days.Except Normal group, other respectively organizes mice ether light anesthesia, intranasal vaccination normal saline dilution be equivalent to 8LD50Influenza virus A/FM1/1/47 (H1N1) chick embryo allantoic liquid 50 μ l/ only, the normal saline of the capacity such as Normal group inoculation, each administration group first administration after viral infection 1h, the each dosage group of reidin and ribavirin group tail intravenously administrable, every day 1 time, 1 0.2ml, administration 5 days altogether, Continuous Observation 14 days (infecting this day calculating), the survival condition of record mice, obtain result in Table 3.
The existence protective effect of table 3 reidin influenza virus infected
Note: * P < 0.05, * * P < 0.01 compares with model group
As shown in Table 3: the Balb/c mice of influenza infection is within 14 days observation periods; the death toll of the high, medium and low dosage treated animal of reidin is all less than model group; Death prevention rate respectively 70%, 50%, 20%; wherein there were significant differences compared with model group (P < 0.05) for the high, medium and low dosage group of reidin; test result indicate that reidin can substantially reduce the mortality rate of mice after influenza infection, and present dose-dependant trend.
Experimental example 3: the reidin protective effect to mouse influenza virus pneumonia
Balb/c mouse modeling, packet, administration are with experimental example 2, and after mouse infection virus, water 8h is prohibited in fasting in the 6th day, record body weight, and excision eyeball blood-letting is lethal, alcohol disinfecting, the full lung of aseptic taking-up, cleans lung tissue 2 times with normal saline, blots with filter paper, records lung weight.Calculate Lung Exponent and lung index according to formula below, obtain result in Table 4.
The protective effect of table 4 reidin influenza virus infected viral pneumonia
Note: * * P < 0.01, * P < 0.05 compares with model group
As shown in Table 4: the Lung Exponent of the high, medium and low dosed administration group mice of reidin is compared with virus group, present dose-dependent downward trend, suppression ratio respectively 41.18%, 24.25%, 11.55%, wherein reidin amount administration group high, middle compares with infection group and viral infection group significant difference, test result indicate that reidin slow down the symptom that mouse lung infects, mouse influenza virus pneumonia is had obvious inhibitory action.
Experimental example 4: the reidin therapeutical effect to infecting respiratory syncytial virus mice
Balb/c mice, 60, male and female half and half, body weight 16～18g, often group 10, is randomly divided into 6 groups: normal group, model group, ribavirin granule group 200mg/kg/d and reidin low amounts group 100mg/kg/d, middle dosage group 200mg/kg/d, high dose group 400mg/kg/d.All the other equal etherizations of each treated animal except normal group, intranasal inoculation is equivalent to 8LD50Respiratory syncytial virus RSVLong strain 50 μ l/ only, the normal saline of the capacity such as normal group inoculation, 1h administration after infection, each dosage of reidin and ribavirin granule group all with gastric infusion, each 0.2ml, successive administration 5 days.Lung homogenate detection virus titer: add structural equation liquid by 10ml/g, grind lung tissue, 4 DEG C, the centrifugal 5min of 10000r/min, take supernatant-80 DEG C preservation, detect virus titer with RSV plaque assay.Bronchoalveolar lavage fluid cell counting: after rsv infection the 5th day, gives the de-neck of mice and puts to death, alveolar wass, and irrigating solution cell counting obtains result in Table 5.
Table 5 reidin therapeutical effect to infecting respiratory syncytial virus mice
Note: * * P < 0.01, * P < 0.05 compares with model group
As shown in Table 5, compared with model group, each dosage group of reidin can reduce the virus titer of respiratory syncytial virus infection mouse lung significantly, and has dose-dependence, illustrates that reidin can reduce in RSV body and replicates；Simultaneously, reidin high, medium and low dosage group can cause substantial amounts of pulmonary inflammatory cell infiltration (based on lymphocytic infiltration) after reducing rsv infection mice significantly, and there is dose-dependence, illustrate that reidin can alleviate the RSV airway inflammation caused.Test result indicate that reidin has the activity in vivo suppressing respiratory syncytial virus, point out it to can apply to the treatment of anti respiratory syncytial virus.
Experimental example 5: the therapeutical effect that guinea pig skin I type herpes virus hominis is infected by reidin
The white hair Cavia porcellus of Dunkin-Harthey, weighs 300～350g, male, and every day feeds 3 green vegetable and feedstuff.Experiment shares 12 Cavia porcelluss, and often group 3, is divided into 4 groups, is grouped respectively acyclovir group, the high, medium and low dosage group of reidin, and every according to circumstances selects 6 dermatotome modelings, administrations.After pentobarbital sodium anesthesia, guinea pig back is lost hair or feathers according to a conventional method, cleaning, sterilization, with marker pen, guinea pig back is sloughed fur part and be divided into 4 dermatotomes.Center intradermal injection 10 in each dermatotome6Pfu/0.1mlHSV-1HS-1 strain virus (Pfu refers to plaque forming unit).During anaesthetizing, animal feeding is at 30 DEG C of 2h.4 dermatotomes of acyclovir group are coated with acyclovir, and other 2 dermatotomes are coated with the PBS (solvent) of 1.0ml/LTween-80；The high, medium and low dosage group of reidin is often organized 4 dermatotomes and is coated with the reidin of various dose, and other 2 dermatotomes are coated with the PBS of 1.0ml/LTween-80.Adding 30 μ l acyclovirs, reidin high, medium and low dosage medicinal liquid, PBS on each self-corresponding dermatotome with micro sample adding appliance, smear infection site, till waiting pharmaceutical drying, every day smears medicine twice, is administered 5d.Day by day Cavia porcellus diseased region recovery from illness situation is observed.For the effect of pharmaceutical, by SAlenius and the BOberg score system established, as shown in table 6, after inoculating HSV-1HS-1 strain to Cavia porcellus, every day is pressed symptom score 1 time in the region of inoculation.Scoring when herpes occurs shows with Arabic numerals, when herpes starts dry doubling incrustation, score and use Roman number instead, all carry out with scoring equal double blinding, Arab all of in course of infection and Rome scoring number are added together and obtain scoring of accumulation, obtain result in Table 7.
The scoring system that table 6 Cavia porcellus HSV infects
The therapeutical effect that guinea pig skin I type herpes virus hominis is infected by table 7 reidin
Note: * * P < 0.01, * P < 0.05 compares with model group
Table 7 result shows, after guinea pig skin inoculation HSV-1HS-1 strain, compared with the dermatotome of the PBS (solvent) smearing 1.0ml/LTween-80, score and the recovery from illness natural law of smearing the HSV infection in the dermatotome of reidin all significantly reduce, presenting dose-dependant piping, and have significant difference, the HSV-1 of guinea pig skin is infected and has therapeutical effect by prompting reidin, infection symptoms can be slowed down, shorten cure time.
Experimental example 6: the therapeutical effect that enterovirus EV 71 is infected by reidin
3 age in days BALB/c neonatal rats are randomly divided into normal group, model group, ribavirin group 100mg/kg/d, reidin low dose group 50mg/kg/d by nest, middle dosage group 100mg/kg/d, high dose group 200mg/kg/d, often group 10, except Normal group, all the other respectively organize lumbar injection enterovirus EV 71 liquid (107TCID50) infect, only, each administration group is with intraperitoneal injection for 0.1mL/, each 0.2ml, continuous 5 days, after being used that after being administered every time or infecting that 75% ethanol sprays neonatal rat parcel bedding and padding, putting back in cage and jointly raise with dams, Normal group and virus control group give distilled water.After infection, every day observes the survival condition of neonatal rat, observes 14d altogether, and according to following scale, calculates the order of severity 0 point infected: be healthy；1 point: the back of a bow, perpendicular hair (observing after growing hair), become thin, activity minimizing etc.；2 points: hind leg diminished strength；3 points: unilateral hindlimb paralysis or paralysis；4 points: bilateral hindlimb paralysis or paralysis；5 points: dying or dead.Calculate each group of mortality rate and increase in life span and carry out statistical analysis with SPSS software, obtaining result in Table 8 and table 9.
Enterovirus EV 71 is infected the impact of BALB/c neonatal rat gradient of infection by table 8 reidin therapeutic administratp
Note: P compares with model group
Enterovirus EV 71 is infected the dead protective effect of Babl/c neonatal rat by table 9 reidin
Note: * * P < 0.01, * P < 0.05 compares with model group
As shown in Table 9, after each dosage group of reidin carries out therapeutic, it is possible to significantly slow enterovirus EV 71 and infect becoming thin of causing of neonatal rat, hind leg diminished strength, the symptoms such as unilateral hindlimb paralysis, its gradient of infection integration compares with model group and is respectively provided with significant difference；The Death prevention rate of the high, medium and low dosage of reidin respectively 77.78%, 44.44%, 33.33%; increase in life span respectively 79.45%, 50.32%, 30.11%; show that each dosage group gradient of infection of reidin all significantly reduces enterovirus EV 71 and infects neonatal rat mortality rate and gradient of infection; extend its life span; comparing with model group and have significant difference, enterovirus EV 71 is infected and has therapeutical effect by prompting reidin.

Claims (10)

1. a reidin prevents in preparation and/or treats the application in the medicine of viral disease.
2. application according to claim 1, it is characterised in that described virus is influenza virus, respiratory syncytial virus, herpesvirus, Coxsackie virus or enterovirus EV 71.
3. application according to claim 1, it is characterised in that the active dose of described reidin is 50～400mg/kg/d.
4. application according to claim 1, it is characterised in that described virus is influenza virus, Coxsackie virus or enterovirus EV 71；The active agent dose of described reidin is 50～200mg/kg/d.
5. application according to claim 1, it is characterised in that described virus is respiratory syncytial virus or herpesvirus；The active dose of described reidin is 100～400mg/kg/d.
6. an antiviral drugs, it is characterised in that include reidin.
7. antiviral drugs according to claim 6, it is characterised in that also include pharmaceutically acceptable carrier.
8. antiviral drugs according to claim 6, it is characterised in that described antiviral drugs is oral agents, inhalant or injection.
9. a reidin prevents and/or treats the application in the medicine of skin herpes simplex or treatment hand-foot-mouth disease in preparation.
10. a reidin prevents and/or treats the application in the medicine of viral pneumonia or treatment viral upper respiratory tract infection in preparation.
CN201610353741.7A 2016-05-25 2016-05-25 Rheidin application and antiviral drugs Pending CN105769842A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106344549A (en) * 2016-11-02 2017-01-25 江苏康缘药业股份有限公司 Application of rhein in preparation of drugs for preventing and/or treating hand-foot-and-mouth disease
CN113662931A (en) * 2021-09-14 2021-11-19 中国食品药品检定研究院 Application of dianthrone compound in preparation of anti-inflammatory and liver-protecting drugs

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CN1634425A (en) * 2004-11-23 2005-07-06 王玉生 Composition of bitter tea and rhubarb horsetails and preparation method thereof

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106344549A (en) * 2016-11-02 2017-01-25 江苏康缘药业股份有限公司 Application of rhein in preparation of drugs for preventing and/or treating hand-foot-and-mouth disease
CN113662931A (en) * 2021-09-14 2021-11-19 中国食品药品检定研究院 Application of dianthrone compound in preparation of anti-inflammatory and liver-protecting drugs
CN113662931B (en) * 2021-09-14 2023-03-14 中国食品药品检定研究院 Application of dianthrone compound in preparation of anti-inflammatory and liver-protecting drugs

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