CN103110652B - Application of chebulagic acid in preparation of medicament for treating diseases resulted from human enterovirus type 71 infection - Google Patents
Application of chebulagic acid in preparation of medicament for treating diseases resulted from human enterovirus type 71 infection Download PDFInfo
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- CN103110652B CN103110652B CN201310055549.6A CN201310055549A CN103110652B CN 103110652 B CN103110652 B CN 103110652B CN 201310055549 A CN201310055549 A CN 201310055549A CN 103110652 B CN103110652 B CN 103110652B
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Abstract
The invention discloses an application of chebulagic acid in the preparation of a medicament for treating diseases resulted from a human enterovirus type 71 infection. Preferably, the diseases resulted from the human enterovirus type 71 infection comprise foot and mouth disease, herpangina, viral meningitis, viral encephalitis, flaccid paralysis, pulmonary edema or viral myocarditis. In-vivo and in-vitro experiments show that chebulagic acid can inhibit replication and lesions of the human enterovirus type 71 in cells, has a good therapeutic effect for the diseases resulted from the human enterovirus type 71 infection, and has a clinical application prospect.
Description
Technical field
The present invention relates to field of medicaments, particularly Chebulagic acid infects the application in diseases induced medicine at preparation treatment human enterovirus 71.
Background technology
Chebulagic acid (Chebulagic acid), is mainly present in the fruit of Combretum Racemosum plant Fructus Chebulae, belongs to hydrolyzable tannin in structure, and molecular formula is C
41h
30o
27, its structural formula is suc as formula shown in I:
Formula I
Chebulagic acid has multiple biological activity, comprises antiinflammatory, antioxidation, antibacterial and antitumor etc.In addition, Chebulagic acid also suppresses copying of a small amount of virus, such as herpes simplex virus (HSV), viruses of human hepatitis C (HCV) and human immunodeficiency virus (HIV).
Human enterovirus 71 is the member of Picornaviridae enterovirus genus, belong to human intestine's virus A, be called for short EV71, often cause the diseases such as hand-foot-mouth disease, herpangina, viral meningitis, viral encephalitis, slowness paralysis, pulmonary edema, viral myocarditis, be referred to as enterovirns type 71 and infect.The multiple infant of being born in below 6 years old of this class disease, the minority state of an illness is comparatively serious, even can cause death.This disease all can occur throughout the year, is common in 4-9 month.
EV71 viral infection infant, mainly with heating onset, is generally 38 ℃ of left and right, heating simultaneously, in oral cavity, brothers, buttocks occur erythra, or occur ulcer in oral cavity, enanthema.Part patient has cough to wait the performance of flu sample in early days.Can there is severe complication in minority infant.This class patient continues high heat mostly, PD is rapid, how after morbidity, in 3-5 days, occurring central nervous system, respiratory system, blood circulation severe complication, and can cause death, the cause of death is mainly cerebral edema, cerebral hernia, central breathing, circulatory failure.EV71 virus is repeatedly outburst worldwide, via gastrointestinal tract or respiratory infectious, according to the data of Ministry of Public Health, from 2008 in October, 2012, interior ground hand foot and mouth disease incidence rate was always high, suffered from patient and surpassed 5,000,000 people, death toll surpasses 2000, and epidemic situation is still severe.
At present, for EV71, infect and still there is no generally acknowledged specific medicament or vaccine.
Summary of the invention
The technical problem to be solved in the present invention is for providing the application of Chebulagic acid in the medicine of the disease of preparation treatment human enterovirus 71 infection initiation.
As preferably, described Chebulagic acid is Chebulagic acid monomer and/or chebule hydrochlorate.
Human enterovirus 71 is called for short EV71, for the member of Picornaviridae enterovirus genus, spherical in shape, and icosahedron is three-dimensional symmetrical, without peplos and synapse, and diameter 24-30 nanometer, nucleic acid is sub-thread positive chain RNA.Polypeptide VP1, VP2, VP3, the VP4 of EV71 type viral gene group coding form protomer, and the latter is assembled into the subunit with pentamer spline structure again, and 60 subunits interconnect by domain separately, finally form viral shell.Tri-polypeptide of VP1, VP2 and VP3 are exposed to the surface of virus coat, and VP4 is embedded in the inner side of virus coat, are closely connected with virus core.EV71 virus can be via gastrointestinal tract or respiratory tract infection.
Described human enterovirus 71 infects the disease causing and refers to that enterovirns type 71 infection causes infectious disease, comprises the various diseases such as hand-foot-mouth disease, herpangina, viral meningitis, viral encephalitis, slowness paralysis, pulmonary edema and viral myocarditis.
The present invention utilizes the EV71 that laboratory is set up to infect people's rhabdomyoma cell model and mouse model, Chebulagic acid is suppressed to human enterovirus 71 to copy and treats human enterovirus 71 and infect diseases induced effect and be studied, result shows: EV71 viral infection is after 72 hours, without a large amount of pathological changes of medication therapy groups visible cell, and have no obvious pathological changes through the cell of 25 μ g/ml Chebulagic acid treatments, the Chebulagic acid concentration of effectively protecting 50% people's rhabdomyoma cell to avoid EV71 infection is 12.5 μ g/ml, and when drug level is more than or equal to 25 μ g/ml, can suppress people's rhabdomyoma cytopathy that virus causes completely.
EV71 infecting mouse scale-model investigation result shows: the Chebulagic acid that gives 1mg/kg body weight dosage every day, continue medication 5 days, the symptom of infecting mouse weakens, the mortality rate of mice is down to 60%, and model group mouse death rate is 100%, illustrate that Chebulagic acid, to infecting and have therapeutical effect due to EV71, has potential applicability in clinical practice.
Accompanying drawing explanation
Fig. 1 behaves, and rhabdomyoma cell infection EV71 virus gave Chebulagic acid after 2 hours or isopyknic normal saline is processed, and processed the cell AO/EB coloration result of latter 0 hour, 48 hours, 72 hours;
Fig. 2 is the survival rate curve of various dose Chebulagic acid treatment EV71 infecting mouse;
Fig. 3 is that Chebulagic acid is respectively organized the impact of virus load on EV71 virus infected mice.
The specific embodiment
The invention discloses a kind of Chebulagic acid and infect the application in diseases induced medicine at preparation treatment human enterovirus 71, those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Application of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
In order to make those skilled in the art understand better technical scheme of the present invention, below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1 Chebulagic acid suppresses EV71 virus copying in cell
At EV71, infect in people's rhabdomyoma cell model, will newly cultivate people's rhabdomyoma cell and be seeded in 96 orifice plates, every porocyte quantity is 2 * 10
4individual.In 37 ℃ of incubators, cultivate after 24 hours, start virus inoculation.
The EV71 that uses be CONTINENTAL AREA OF CHINA epidemic isolates, strain name FY0805, separated from Fuyang, it number is HQ882182 that gene order is stored in NCBI.The dosage of virus inoculation cell is 100TCID
50, volume is 98 microlitres, continues to cultivate in 37 ℃ of incubators.
Chebulagic acid physiological saline solution, and in as a child administration of virus infected cell 2, injection volume is 2 microlitres, the cell of administration does not give 2 microlitre normal saline.Observe 72 hours inner cell pathological changes, the half effective inhibition concentration that calculates medicine is 12.5 μ g/ml.
People's rhabdomyoma cell infection EV71 virus is after 2 hours, giving final concentration is the Chebulagic acid treatment of 25 μ g/ml, respectively within after administration 0 hour, 48 hours, 72 hours, carrying out AO/EB dyeing, using isopyknic physiologic saline for substitute Chebulagic acid as negative control, the pathological changes situation of observing Chebulagic acid treatment group cell and normal saline group cell, its result is as shown in Figure 1; Fig. 1 result shows: a large amount of pathological changes of normal saline group cell visible cell, the cell for the treatment of through 25 μ g/ml Chebulagic acids has no obvious cytopathy, illustrates: Chebulagic acid can suppress EV71 virus copying in cell.
The therapeutical effect of embodiment 2 Chebulagic acids to EV71 virus infected mice
The object of this experiment is checking Chebulagic acid therapeutic effect to EV71 viral infection in Mice Body, and model used is the model of CONTINENTAL AREA OF CHINA EV71 virus strain infection 10 age in days ICR mices.Strain is the adapted strain of clinical separation strain FY0805 in Mice Body, and strain is called MP10, and the storage of gene order in NCBI number is HQ712020.With 1 * 10
7tCID
50the MP10 virus of dosage after lumbar injection infects 10 age in days ICR mices, can cause mice to show in 4 days after acroparalysis and the symptom that loses weight, and all dead in infecting in latter 10 days.
Apply above-mentioned model, the therapeutic effect of Chebulagic acid is carried out to interior evaluating.Using mice is SPF level ICR mice, 10 ages in days, male and female half and half.First, lumbar injection MP10 virus is carried out viral infection to mice, infect pneumoretroperitoneum injection in 2 hours and give Chebulagic acid or normal saline, Chebulagic acid physiological saline solution, its dosage is respectively 0.2 mg/kg of body weight/day, 1 mg/kg of body weight/day, 5 mgs/kg of body weight/day, and every group of mice quantity is 30; Every day is administration at twice, and 12 hours, interval continues medication 5 days.From viral infection, continue to observe 14 days, record body weight, symptom and the survival rate of mice, evaluate the therapeutic effect of Chebulagic acid to EV71 viral infection.
As shown in Figure 2, Fig. 2 result shows result: give the Chebulagic acid of 1 mg/kg of body weight dosage every day, continue medication 5 days, the symptom of infecting mouse weakens, and the mortality rate of mice is down to 60%, and model group mouse death rate is 100%; Illustrate that Chebulagic acid has good therapeutic effect for EV71 infecting mouse.
Embodiment 3 Chebulagic acids are for the impact of virus load in EV71 virus infected mice tissue
Described virus load, refers to the viral load in Unit Weight tissue, for reflecting the virus replication situation of tissue.
The object of this experiment is to detect Chebulagic acid for the impact of virus load in EV71 virus infected mice different tissues, with the inhibitory action of verifying that Chebulagic acid copies in vivo for EV71 virus.
EV71 virus infected mice model described in Application Example 2, measures the virus load in Chebulagic acid treatment EV71 virus infected mice different tissues.Using mice is SPF level ICR mice, 10 ages in days, male and female half and half.Through lumbar injection MP10 virus, mice is infected, infect 2 and as a child through lumbar injection, gave Chebulagic acid or normal saline, Chebulagic acid physiological saline solution, its dosage is 1 mg/kg of body weight/day.Administration every day 2 times, 12 hours, interval, continues medication 5 days.After viral infection the 6th day, the de-neck of mice is put to death, get respectively blood, cerebral tissue and muscular tissue, with qRT-PCR method, carry out the detection of virus load, its testing result as shown in Figure 3, the viral copy number of Log(that Fig. 3 vertical coordinate is every milligram of tissue).
Fig. 3 result shows: the Chebulagic acid that gives 1 mg/kg of body weight dosage every day, continue medication 5 days, compare with giving normal saline group, the virus load in each group of administration group mice obviously reduces, and illustrates: Chebulagic acid can obviously suppress virus copying in vivo.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (1)
1. the application in the medicine of the disease that Chebulagic acid causes in the infection of preparation treatment human enterovirus 71; Described Chebulagic acid is Chebulagic acid monomer and/or chebule hydrochlorate;
It is hand-foot-mouth disease that described human enterovirus 71 infects the disease causing.
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Non-Patent Citations (4)
| Title |
|---|
| 《EV71 型重症手足口病的临床观察与护理》;仓艳红;《河北医药》;20120930;第34卷(第18期);2869-70页 * |
| 仓艳红.《EV71 型重症手足口病的临床观察与护理》.《河北医药》.2012,第34卷(第18期),2869-70页. |
| 沙磊等.《RP - HPLC法测定余甘子中诃黎勒酸、没食子酸、粘酸-2-o没食子酸酯的含量》.《药物分析杂志》.2011,第31卷(第2期),293-95页. |
| 沙磊等.《RP- HPLC法测定余甘子中诃黎勒酸、没食子酸、粘酸-2-o没食子酸酯的含量》.《药物分析杂志》.2011,第31卷(第2期),293-95页. * |
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