CN109550041A - Application of the oritavancin phosphate in preparation prevention and treatment infectious bovine rhinotrachetis drug - Google Patents
Application of the oritavancin phosphate in preparation prevention and treatment infectious bovine rhinotrachetis drug Download PDFInfo
- Publication number
- CN109550041A CN109550041A CN201910030001.3A CN201910030001A CN109550041A CN 109550041 A CN109550041 A CN 109550041A CN 201910030001 A CN201910030001 A CN 201910030001A CN 109550041 A CN109550041 A CN 109550041A
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- oritavancin
- phosphate
- virus
- drug
- infectious bovine
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- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000010458 rotten stone Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a kind of application of oritavancin phosphate in the drug of preparation prevention and treatment infectious bovine rhinotrachetis, oritavancin phosphate is tested in vitro can inhibit and kill infectious bovine rhinotrachetis virus on MDBK cell model, the invasion and duplication of infectious bovine rhinotrachetis virus can be effectively inhibited, and cytotoxicity is small, it can be used as the drug of a new class of anti-infectious bovine rhinotrachetis virus, it lays a good foundation for the prevention and control and medicament research and development of infectious bovine rhinotrachetis disease, also it establishes experiment basis for the efficiently special anti-infectious bovine rhinotrachetis virus drug of exploitation and the new visual field is provided.
Description
Technical field
The present invention relates to field of medicaments, and in particular to oritavancin phosphate prevents and treats infectious bovine rhinotrachetis medicine in preparation
Application in object.
Background technique
Disclosing the information of the background technology part, it is only intended to increase understanding of the overall background of the invention, without certainty
It is considered as recognizing or implying in any form that information composition has become existing skill well known to persons skilled in the art
Art.
Infectious bovine rhinotrachetis (infectious bovine rhinotracheitis, IBR) is by ox infectiousness nose
One kind caused by bronchitis virus (Infectious bovine rhinotracheitis virus, IBRV) is acute, it is hot,
Contagious disease, characterized by high fever, expiratory dyspnea, stream nose juice, the upper respiratory tract and tracheae, mucous membrane inflammation etc..20th century 50
Early stage in age, the certain pastures in Colorado first appear the infectiousness cattle disease using rhinotracheitis as symptom, and nineteen fifty-five is first
The secondary clinical symptoms for reporting the disease.It is identified in import kind ox for the first time the 1970s and separates acquisition, Niu Chuan in China
Metachromia rhinotracheitis virus can lead to persistent infection, which is classified as B class disease by World Organization for Animal Health (OIE), and
Inward animal must examine one of disease in China.The effective vaccine of infectious bovine rhinotrachetis virus is inactivated vaccine and weak malicious epidemic disease at present
Seedling, but the problems such as there are immunosupress and latent infections.Individual can not be identified with natural infection individual after inactivated vaccine is immune
Diagnosis, therefore certain obstacle can be brought to infectious bovine rhinotrachetis is eradicated.There are virulence to return strong phenomenon for traditional Attenuate vaccine, deposits
In some potential safety problems.Most importantly infectious bovine rhinotrachetis virus is endogenous multiplication virus, and inactivated vaccine cannot be clear
Except intracorporal virus, can only prevent.Difficult point and immune limitation, research and development based on prevention and control can inhibit and kill ox infectiousness nose gas
The drug of the scorching virus of pipe becomes one of the hot spot of numerous researchers.
Oritavancin phosphate (Oritavancin Diphosphate), is glycopeptide antibiotics, has multiple action machine
System leads to cell death such as by combining the peptide for inhibiting Cell wall synthesis to destroy the integrality of bacterial cell membrane；Suitable for controlling
Treat acute bacterial skin and skin structure infection as caused by sensitive gram-positive bacteria.No. CAS is 192564-14-0, is changed
Scientific name is known as: (4 " R) -22-O- (3-Amino-2,3,6-trideoxy-3-C-methyl- α-L-arabino-
hexopyranosyl)-N3"-[(4′-chloro[l,1′-biphenyl]-4-yl)methyl]vancomycin
Diphosphate, empirical formula (Xi Er representation) C86H97Cl3N10O26·2H3PO4, molecular weight 1989.09.Ao Liwan
Shown in the phosphatic structure of star such as formula (I):
Summary of the invention
The present invention provides oritavancin phosphate compounds to inhibit and/or kill in infectious bovine rhinotrachetis virus
Application, oritavancin phosphate compounds can effectively inhibit the proliferation of infectious bovine rhinotrachetis virus, to cell
Toxicity is smaller, has exploitation at the prospect of anti-infectious bovine rhinotrachetis drug.Application of the present invention be it is first public, with Austria
Clinical application purposes known to sharp ten thousand star phosphate is different.
Oritavancin phosphate (Oritavancin Diphosphate) of the present invention is the diphosphonic acid of oritavancin
Salt, structure and information are as known from prior art.
The present invention establishes infectious bovine rhinotrachetis virus drug screening system on a cellular level.Ao Liwan has been determined
Half toxic concentration (CC of the star phosphate to MDBK cell (i.e. bovine kidney cells)50) it is greater than 100 μM, to infectious bovine rhinotrachetis
Medium effective concentration (the EC of virus50) it is 0.3944 μM, treatment of the oritavancin phosphate to infectious bovine rhinotrachetis virus
Index is greater than 253.55.
The present invention also provides the pathogenic mechanisms according to virus, and different time points administration experiment and first dosing is respectively adopted
Afterwards plus virus, dosing, 3 kinds of different role modes acting in advance of virus have carried out extracorporeal antivirus effect and inhibit examination first plus after virus
It tests.
Specifically, technical solution of the present invention is as shown:
In the first aspect of the present invention, the present invention provides oritavancin phosphate or include phosphatic group of oritavancin
Close the application of object or its preparation in preparation treatment infectious bovine rhinotrachetis drug.
In the second aspect of the present invention, the present invention provides oritavancin phosphate or include phosphatic group of oritavancin
Close the application of object or its preparation in the drug for preparing anti-infectious bovine rhinotrachetis virus.
In the third aspect of the present invention, the present invention provides oritavancin phosphate or include phosphatic group of oritavancin
It closes object or its preparation and inhibits and/or kill the application in the drug of infectious bovine rhinotrachetis virus in preparation.
In the fourth aspect of the present invention, the present invention provides oritavancin phosphate or include phosphatic group of oritavancin
Close the application of object or its preparation in the drug that preparation inhibits infectious bovine rhinotrachetis virus proliferation.
In the fifth aspect of the invention, the present invention provides oritavancin phosphate or include phosphatic group of oritavancin
Close the application of object or its preparation in the drug that preparation blocks infectious bovine rhinotrachetis virus duplication.
In the sixth aspect of the present invention, the present invention provides oritavancin phosphate or include phosphatic group of oritavancin
Close the application of object or its preparation in the drug that preparation inhibits infectious bovine rhinotrachetis virus proliferation.
Preparation of the present invention includes the phosphatic preparation of oritavancin or comprising the phosphatic composition of oritavancin
Preparation.
Of the present invention includes the phosphatic composition of oritavancin for using oritavancin phosphate as the group of active constituent
Close object, using oritavancin phosphate as the composition of main active or using oritavancin phosphate as sole active agent
Composition.
Above-mentioned application according to the present invention, oritavancin phosphate are effectively dense to the half of infectious bovine rhinotrachetis virus
Spend (EC50) it is 0.3944 μM；Oritavancin phosphate is greater than 253.55 to the therapeutic index of infectious bovine rhinotrachetis virus.
Embodiment according to the present invention, oritavancin phosphate is in drug concentration safe range, with the liter of concentration
Height, inhibits or killing effect is promoted therewith.Drug of the present invention refers to that drug is inhibiting or killing in concentration safe range
Go out infectious bovine rhinotrachetis virus cell when, the permissive cell of infectious bovine rhinotrachetis virus is not injured.
Oritavancin phosphate is low to the permissive cell toxicity of infectious bovine rhinotrachetis virus, for example, MDBK cell half
Number toxic concentration (CC50) be greater than 100 μM, be prepared as drug application in, not in contact with or not by ox infectiousness nose gas
The drug is used under the situation of pipe inflammation virus infection, and ox is infected after then contacting or being infected by infectious bovine rhinotrachetis virus
Property rhinotracheitis virus inhibiting effect be not obvious, effective inhibiting rate be lower than 20%.As shown in Fig. 3 of the present invention, formerly it is administered
It is several compared to other administration times in the case where postoperative infection infectious bovine rhinotrachetis virus virus (- the 2h in corresponding diagram 3)
Do not play inhibiting effect.Therefore, oritavancin phosphate is main to the antivirus action of infectious bovine rhinotrachetis virus
It is played after being infected after infectious bovine rhinotrachetis virus is adsorbed onto cell or by infectious bovine rhinotrachetis virus.
And multidigit point, too many levels is presented to the effect of infectious bovine rhinotrachetis virus in oritavancin phosphate,
It can be found that (such as embodiment 4 and 5) in vitro Drug research of the invention, the different dosing time include administration before virus infection,
After virus infection administration and while virus infection three kinds of administration times of administration and different role mode include after first dosing plus
Virus first adds dosing, drug and viral three kinds of modes of action of effect in advance after virus, is found by different time administration, removes sense
Catch an illness before poison administration without positive effect outside, oritavancin phosphate, which has infectious bovine rhinotrachetis virus, apparent to be inhibited to make
With；And by different role mode be administered discovery oritavancin phosphate directly contact with infectious bovine rhinotrachetis virus (or
Referred to as effect in advance) it can be achieved to the direct killing effect (EC of infectious bovine rhinotrachetis virus50=0.4091 μM, Fig. 4)；It will
Infectious bovine rhinotrachetis virus is added in the cell for having added good oritavancin phosphate (after acting in advance with cell),
Oritavancin phosphate, which does not embody infectious bovine rhinotrachetis virus, significantly blocks its suction-operated to cell；It will
Oritavancin phosphate is added in the cell for having added good venom (after acting in advance with cell), and oritavancin phosphate is to ox
Infectious bovine rhinotracheitis virus has duplication blocking effect (EC50=2.030 μM, Fig. 5).
According to the present invention, the representation of concept of " treatment " is any is suitable for treatment infectious bovine rhinotrachetis virus related disease
Measure, perhaps answering for this disease is treated or avoided to the disease for this performance or the symptom showed
Hair, for example, finish treatment time section after recurrence or the symptom for the disease broken out is treated.
Drug described in the above-mentioned application of the present invention indicates a kind of substance, contained by oritavancin phosphate ox is passed
Metachromia rhinotracheitis virus has apparent inhibition and/or killing effect, and mainly acts on infectious bovine rhinotrachetis virus
The direct duplication killed, can block or inhibit the virus to the virus may be implemented, especially in multiple stages of life cycle
Have the effect of especially excellent to the direct inhibition of the virus or killing.
In addition, the invention also discloses apply the group of oritavancin phosphate and other at least one active pharmaceutical ingredients
When conjunction, this effect can be enhanced.As the substituted or supplemented of other medicines active constituent, oritavancin phosphate can also be with
Other non-drug active ingredient combinations use.
In a specific embodiment of the invention, a kind of pharmaceutical composition of anti-infectious bovine rhinotrachetis, the medicine are provided
Compositions are by oritavancin phosphate and at least one other active pharmaceutical ingredient and/or at least one other non-drug activity
Ingredient is constituted.
In still another embodiment of the invention, oritavancin phosphate ratio can such as be taken not less than medium effective concentration
Drug concentration EC50=0.3944 μM；Certainly, inhibit and/or kill or assist when oritavancin phosphate has with other
The drug or activity with the same application mentioned in the content of present invention such as inhibition and/or killing infectious bovine rhinotrachetis virus
Ingredient combination is in use, its drug concentration can theoretically be lower than above-mentioned effective concentration, but also be not excluded for special exception.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition.Form of administration can be Austria
The sharp common dosage form of ten thousand star phosphate or other feasible dosage forms, such as those skilled in the art can be in routines
Selection is suitable for the phosphatic dosage form of oritavancin in dosage form, by the way that the carrier compatible with oritavancin phosphate, figuration is added
Agent, adhesive, solvent etc. are realized.The regular dosage form such as liquid dosage form, solid dosage forms, external preparation, spray at this
Agent etc., such as following dosage forms: true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed dosage form, tablet, capsule, drop
Ball, aerosol, pill, pulvis, solution, suspension, emulsion, granule, suppository, freeze drying powder injection, inclusion compound, landfill agent,
Patch, liniment etc..
Common carrier can also be contained in pharmaceutical composition or pharmaceutical preparation of the invention, pharmaceutical acceptable carrier described here is first
It is phosphatic that oritavancin should be first suitable for, those skilled in the art can select in following common carrier: ion
Exchanger, aluminium oxide, aluminum stearate, lecithin, haemocyanin such as human albumin, buffer substance such as phosphate, glycerol, sorb
Ester, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, phosphorus
Sour disodium hydrogen, potassium hydrogen phosphate, sodium chloride, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material,
Polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, wool grease etc..Content of the carrier in pharmaceutical composition can be with
It is 1wt%-98wt%, generally about accounts for 80wt%.For convenience, local anesthetic, preservative, buffer etc. can be direct
It is dissolved in carrier.
Oral tablet and capsule can contain excipient such as adhesive, but it should be suitable for oritavancin phosphoric acid first
Salt, such as syrup, Arabic gum, sorbierite, tragacanth or polyvinylpyrrolidone, filler, as lactose, sucrose, corn form sediment
Powder, calcium phosphate, sorbierite, amion acetic acid, lubricant, such as magnesium stearate, talcum, polyethylene glycol, tripoli, disintegrating agent, such as Ma Ling
Sweet potato starch or acceptable dibutyl phthalate, such as laurel sodium alkoxide sulfate.Tablet can be coated with method well known in pharmaceutics.
Suspension, solution, emulsion, syrup can be made with the phosphatic solvent of oritavancin is suitable in oral solution,
Dry product can be made, with preceding supplement suitable solvent or known in the art be suitable for the phosphatic medium of oritavancin.This liquid
Preparation may include conventional additive, but these additives equally should be that be suitable for oritavancin phosphatic first, such as
Suspending agent: sorbierite, methyl cellulose, dextrose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate are solidifying
Glue, hydrogenation edible oil and fat；Emulsifier: such as lecithin, sorbitan mono-oleate, gum arabic；Or nonaqueous carrier (may
Include edible oil): such as apricot kernel oil, grease such as glycerol, ethylene glycol or ethyl alcohol；Preservative, such as methyl p-hydroxybenzoate or third
Ester, sorbic acid.As needed that flavoring agent or colorant can be added.
Detailed description of the invention
Hereinafter, carrying out the embodiment that the present invention will be described in detail in conjunction with attached drawing, in which:
Fig. 1 is shown as in embodiment 2 oritavancin phosphate to the half cytotoxic concentration (CC of MDBK cell50)；
Fig. 2 is shown as in embodiment 3 oritavancin phosphate to the medium effective concentration of infectious bovine rhinotrachetis virus
(EC50)；
Fig. 3 is shown as oritavancin phosphate different time points in embodiment 4 and (40 μM) is administered to ox infectious rhinotracheitis
The effect picture of scorching HIV suppression；
Fig. 4 is shown as oritavancin phosphate in embodiment 5 and imitates to infectious bovine rhinotrachetis virus direct killing effect
Fruit figure；
Fig. 5 is shown as oritavancin phosphate in embodiment 5 and replicates function and effect figure to infectious bovine rhinotrachetis virus.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.The materials, reagents and the like used in the following examples, unless otherwise specified,
It obtains from commercial channels.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art
Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Below
Drug described in embodiment indicates oritavancin phosphate unless otherwise specified.Preferable implementation method described in the text and material
Material is for illustrative purposes only.
Embodiment 1Infectious bovine rhinotrachetis virus TCID50Measurement
With every hole 1 × 10 after MDBK cell (Cow Research Center, Shandong Academy of Agricultural Sciences's preservation) is digested5A/mL's
Cell density is inoculated into 96 porocyte culture plates, is put into 37 DEG C, 5%CO2Cell incubator in be trained cell monolayer after,
Hole inner cell growth-promoting media is discarded, even by infectious bovine rhinotrachetis virus (Cow Research Center, Shandong Academy of Agricultural Sciences's preservation)
(dilution is respectively 10 to continuous 10 times of diluted viral dilutions-1~10-10) it is inoculated in 96 orifice plates for covering with cell monolayer, every hole
100 μ L, are put into 37 DEG C, 5%CO2Incubator in continue to cultivate, and day by day observe cell CPE (cytopathic effect) feelings
Condition, and record cytopathy hole count in detail.Normal cell controls group and blank control group are set simultaneously, every group sets 8 repetitions,
Result is determined when not continuing to occur cytopathy.Cytopathy variable orifice be more than cell the corresponding cell hole of lesion occurs,
And virus TCID is calculated by Karber method50。
The TCID of table 1, infectious bovine rhinotrachetis virus-F950
Note: TCID50, Tissue culture infective dose, tissue culture infective dose, also known as 50%
Tissue cytopathogenic dose；Half cytopathy or death (cytopathic can be caused in cultivation plate hole or test tube by referring to
Effect, CPE) needed for virus quantity.
As a result: under the microscope morphological observation reveals that the viral dilution of various concentration causes cell when 48h
The refractivity of lesion, cell changes, and single layer structure is destroyed, and circle contracting necrosis occurs in cell, is gradually in seine shape and is formed
Vacuole, some cell crackings fall off the shape that fragmentates, and the cytopathy in each hole does not continue to after 5 days, counts the CPE of various concentration
Hole count, and the CPE ratio of various concentration is calculated, and the TCID of infectious bovine rhinotrachetis virus is calculated by Karber method50Value:
LgTCID50=L-D (S-0.5)
(L: the logarithm of highest dilution；D: the difference between dilution logarithm；S positive hole ratio summation)
LgTCID50=L-D (S-0.5)=- 1-1 × (5.5-0.5)=- 6
TCID50=10-6/0.1mL
It will the viral dilution 106Being inoculated with 100 μ L can make 50% cell that lesion occur.
Embodiment 2Toxicity test of the oritavancin phosphate to MDBK cell:
MDBK cell is the permissive cell of infectious bovine rhinotrachetis virus.Therefore, oritavancin phosphate is detected first
To the cytotoxicity of MDBK cell, steps are as follows for specific experiment:
(1) 100 μ L cells (the 5000/hole MDBK) is inoculated in 96 orifice plates.
(2) after cultivating about 12h, next step dosing analysis is carried out.Culture medium is discarded, every hole adds 100 μ L dense containing different pharmaceutical
It spends and (with 50 μM for initial concentration, is successively diluted by twice of gradient and obtain 25 μM, 12.5 μM, 6.25 μM, 3.125 μM equal 9 dense
Degree) 2%FBS DMEM, each concentration do 3 it is parallel.While control wells: add 2%FBS DMEM of the 100 μ L containing 0.9%DMSO
Culture medium.Zeroing hole: cell is not spread.
(3) at 37 DEG C, 5%CO2Under the conditions of cultivate 48h after, discard the culture medium in hole.It is washed twice with 100 μ L PBS,
Exclude the influence that drug reacts MTT.+ 10 μ L MTT of 100 μ L DMEM culture medium is added again in every hole.
(4) 37 DEG C, 5%CO2Under the conditions of continue after cultivating 4h, 100 μ L Formazan lysates are added in every hole.37 DEG C,
5%CO2Continue to be incubated for, until Formazan purple crystal is completely dissolved.
(5) light absorption value is measured in 570nm.The A570nm of the cell of 0.9%DMSO processing is set as 100% cell controls.
(6) data are analyzed, calculate the phosphatic half cytotoxic concentration of oritavancin using GraphPad Prism 5
(CC50) value.Its result is as shown in Figure 1.
As a result: there is dose-dependence and then shows cell that is, with the increase of drug concentration in oritavancin phosphate
Lesion is more obvious.Through statistical analysis, determine that oritavancin phosphate median toxic concentration is greater than 100 μM.
Embodiment 3Inhibition test of the oritavancin phosphate to infectious bovine rhinotrachetis virus:
(1) 1 × 10 is inoculated in each hole of 96 orifice plates4A MDBK cell, 37 DEG C, 5%CO2It is incubated overnight in incubator；
(2) culture medium is discarded, 100 μ L, 100 TCID is added in every hole50Infectious bovine rhinotrachetis virus viral dilution
(viral dilution is added after being covered with 2%FBS DMEM cell, according to 50 μM of initial concentrations, double strength gradient dilution dosing,
5%CO2It is cultivated in incubator；
(3) it after 48h, is operated by CCK-8 kit specification, with the OD value at microplate reader measurement 450nm.
(4) analysis data, viral suppression (%)=(drug-treated group D450nm value-virus control group D450nm value)/
(normal cell controls group D450nm value-virus control group D450nm value) × 100%, must be changed with GraphPad Prism5 software
Close the medium effective concentration (EC of object50) value.Its result is as shown in Figure 3.Then formula TI=CC is pressed50/EC50, calculate and control accordingly
Treat index TI value.
As a result: cell viability being detected by CCK-8 kit, drug can be calculated to infectious bovine rhinotrachetis virus
Effective inhibiting rate.From the results, it was seen that oritavancin phosphate, within the scope of safe concentration, effective inhibiting rate is with medicine
The increase of object concentration and increase, in a certain amount imitate relationship.By analyzing software, to the half of infectious bovine rhinotrachetis virus
Effective concentration (EC50) it is 0.3944 μM.Oritavancin phosphate is greater than the therapeutic index of infectious bovine rhinotrachetis virus
253.55。
Embodiment 4The Primary Study of oritavancin phosphate influence mechanism
It is that postoperative infection viral (before 0h), first virus infection is first administered by different administration times, that is, at the time of corresponding to
(after 0h), virus and drug are administered afterwards, three time points of cell (0h) are added simultaneously, untested compound is added to and is vaccinated with
In the MDBK cell of infectious bovine rhinotrachetis virus, and then tentatively judge the phosphatic effect stage of oritavancin.It is specific real
Test that steps are as follows:
(1) 1 × 10 is inoculated in each hole of 96 orifice plates4A MDBK cell, 37 DEG C, 5%CO2It is cultivated in incubator.
(2) according to the pharmacodynamic evaluation of related drugs measured as a result, determine test needed for drug concentration, and with tieing up
Culture medium is held drug dilution to required concentration.
(3) after cell pellet overnight culture, the cell conditioned medium of three multiple holes of secondary series in 96 orifice plates is siphoned away, phosphate buffer is used
Cleaning cell 2 times.Then the drug to be measured of 50 μ L is added, is denoted as -2h.
(4) after 2h, the cell conditioned medium in other holes is all siphoned away, the infectious bovine rhinotrachetis virus diluted is diluted
Liquid is added in every hole of 2-11 column, and every hole injection volume is 50 μ L.It is corresponding that 50 μ L are added in three multiple holes of the 3rd column simultaneously
Determinand is denoted as 0h this moment.
(5) corresponding untested compound is added in three multiple holes of next column at regular intervals later, label is good corresponding
Time.Using the MDBK cell of the 11st column as virus control group.
(6) after cultivating 48h, the measurement of OD value is carried out.Analyze data, it was therefore concluded that, result when administration concentration is 40 μM is such as
Shown in Fig. 3.
As a result: analysis of experimental results is administered from different time points it is found that oritavancin phosphate is in viruses adsorption and virus
Apparent antivirus action is all played after infection, shows the effect of multidigit point, too many levels.
Embodiment 5The influence replicated to infectious bovine rhinotrachetis virus is added in oritavancin phosphate different time
We have carried out further study on mechanism to oritavancin phosphate.It is respectively adopted after first dosing plus sick
Poison first adds dosing, drug and the viral 3 kinds of different role modes acted in advance after virus to carry out extracorporeal antivirus effect inhibition examination
It tests.
(1) direct killing effect of the drug to virus
By 100 TCID of equivalent50The drug dilution liquid of virus liquid and various concentration is (with 50 μM for initial concentration, by twice
Gradient, which successively dilutes, obtains 25 μM, 12.5 μM, 6.25 μM, 3.125 μM of equal 9 concentration) it is uniformly mixed and is placed in 37 DEG C, 5%CO2Training
It supports after acting on 4h in advance in case, addition grows up in 96 porocyte culture plates of single layer, each 100 hole μ L/ of medical fluid gradient, incubator
Middle effect 2h, discards supernatant liquid, and cell maintenance medium is added to continue to cultivate.It is right that normal cell controls group, virus is arranged in this test simultaneously
According to group and blank control group, each concentration sets 3 repetitions, and 48h carries out cell viability detection, with 5 software of GraphPad Prism
Obtain the EC of compound50。
As a result: under the administration mode that oritavancin phosphate acts in advance with infectious bovine rhinotrachetis virus, each concentration
Test dosing group cytopathy it is slight compared with virus control group, the pathological phenomenons such as being rounded, fall off of cell, vacuolation are subtracted
Gently, by analyzing software, oritavancin phosphate is as shown in Figure 4 to the function and effect of infectious bovine rhinotrachetis virus.From Fig. 4
In as can be seen that under this action type, oritavancin phosphate shows certain suppression to infectious bovine rhinotrachetis virus
Production is used, and drug, within the scope of safe concentration, effective inhibiting rate increases with the increase of drug concentration, in certain
Dose-effect relationship.Show oritavancin phosphate to infectious bovine rhinotrachetis virus have the function of it is certain directly inactivate, Fig. 4
Oritavancin phosphate is to ox infectiousness nose gas when showing -4 hours (i.e. first effect 4h is added in cell for drug and virus)
The EC of the scorching virus of pipe50Value is 0.4091 μM.
(2) blocking effect that drug adsorbs infectious bovine rhinotrachetis virus
By the cell density in every hole by the cell inoculation digested into orifice plate, discarded supernatant after growing up to cell monolayer
Liquid, by each 100 hole μ L/ of medical fluid gradient of the drug dilution liquid of various concentration, addition grows up in 96 porocyte culture plates of single layer,
After acting on 4h in advance in incubator, liquid is discarded supernatant, is washed twice with PBS, 100 TCID of equivalent are added50Virus liquid is placed in 37
DEG C, 5%CO2It is cultivated in incubator.Normal cell controls group, virus control group and blank control group is arranged simultaneously in this test, often
A concentration sets 3 repetitions, and cell viability detection is carried out after 48h, and calculates the antiviral of various concentration drug under the mode of action
It is efficient.
As a result: CPE is observed the results show that drug pre-processing group is compared with virus control group, and the degree of cytopathy is equal
Do not change significantly.Cell viability testing result shows, effective inhibition of such drug to infectious bovine rhinotrachetis virus
Rate is 20% hereinafter, showing that oritavancin phosphate cannot prevent suction-operated of the infectious bovine rhinotrachetis virus to cell.
(3) blocking effect that drug replicates infectious bovine rhinotrachetis virus
By the cell density in every hole by the cell inoculation digested into orifice plate, discarded supernatant after growing up to cell monolayer
Liquid, by 100 TCID of equivalent50Virus liquid addition grows up in 96 porocyte culture plates of single layer, is placed in 37 DEG C, 5%CO2Culture
After acting on 2h in advance in case, liquid is then discarded supernatant, PBS washes cell 2 times, the drug dilution liquid of various concentration is then added,
Normal cell controls group, virus control group and blank control group is arranged simultaneously in each 100 hole μ L/ of medical fluid gradient, this test, each
Concentration sets 3 repetitions, is placed in 37 DEG C, 5%CO2It is cultivated in incubator, cell viability detection is carried out after 48h, analyzed data, obtain
Conclusion.
As a result: under this kind of administration mode, the test dosing group cytopathy of each concentration is slight compared with virus control group, cell
Be rounded, fall off, the pathological phenomenons such as vacuolation are mitigated, by analyzing software, oritavancin phosphate is to ox infectiousness nose gas
The function and effect of the scorching virus of pipe are as shown in Figure 5.From figure 5 it can be seen that oritavancin phosphate is to ox under this action type
Infectious bovine rhinotracheitis virus shows certain inhibiting effect, and drug is within the scope of safe concentration, effective inhibiting rate
Increase with the increase of drug concentration, imitates relationship in a certain amount, show oritavancin phosphate to ox infectious rhinotracheitis
Scorching virus has the function of directly inactivating centainly, when Fig. 5 shows 2 hours (i.e. adding drug after virus infection cell 2h)
EC of the oritavancin phosphate to infectious bovine rhinotrachetis virus50Value is 2.030 μM.
Application Example of the present invention with bovine kidney cells (MDBK) be carrier, on cytopathicity model, after first dosing
Add that virus, 3 kinds of different role modes of dosing, virus effect dosing object again in advance have carried out extracorporeal antivirus effect suppression first plus after virus
System research.It was found that the phosphatic novel antiviral effect of oritavancin, there is certain inhibition to infectious bovine rhinotrachetis virus
Effect, and direct killing effect and duplication blocking effect to virus.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, although referring to aforementioned reality
Applying example, invention is explained in detail, for those skilled in the art, still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features.It is all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (9)
1. oritavancin phosphate is treated and ox infectiousness comprising the phosphatic composition of oritavancin or its preparation in preparation
Application in the drug of the relevant disease of rhinotracheitis virus.
2. application according to claim 1, which is characterized in that the disease relevant to infectious bovine rhinotrachetis virus
For infectious bovine rhinotrachetis.
3. oritavancin phosphate is preparing anti-ox infectiousness nose gas comprising the phosphatic composition of oritavancin or its preparation
Application in the drug of the scorching virus of pipe.
4. oritavancin phosphate inhibits and/or kills ox in preparation comprising the phosphatic composition of oritavancin or its preparation
Application in the drug of infectious bovine rhinotracheitis virus.
5. oritavancin phosphate inhibits ox infectiousness nose in preparation comprising the phosphatic composition of oritavancin or its preparation
Application in the drug of bronchitis virus proliferation.
6. oritavancin phosphate blocks ox infectiousness nose in preparation comprising the phosphatic composition of oritavancin or its preparation
Application in the drug of bronchitis virus duplication.
7. oritavancin phosphate inhibits ox infectiousness nose in preparation comprising the phosphatic composition of oritavancin or its preparation
Application in the drug of bronchitis virus proliferation.
8. application according to any one of claim 1 to 6, which is characterized in that the preparation includes oritavancin phosphoric acid
The preparation of salt or preparation comprising the phosphatic composition of oritavancin.
9. application according to any one of claim 1 to 7, which is characterized in that described phosphatic comprising oritavancin
Composition is using oritavancin phosphate as the composition of active constituent, using oritavancin phosphate as the group of main active
Close object or using oritavancin phosphate as the composition of sole active agent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405504A (en) * | 2013-09-02 | 2013-11-27 | 天津生机集团股份有限公司 | Traditional Chinese medicine granules for treating respiratory bovine infectious rhinotracheitis and preparation method thereof |
| CN105596627A (en) * | 2014-11-25 | 2016-05-25 | 周晓丽 | Traditional Chinese medicine for preventing infectious bovine rhinotracheitis |
| CN106177156A (en) * | 2016-08-25 | 2016-12-07 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of Chinese medicine composition preventing and treating infectious bovine rhinotrachetis and application thereof |
| CN107793472A (en) * | 2016-09-07 | 2018-03-13 | 浙江海正药业股份有限公司 | Crystal formation of oritavancin diphosphate and its production and use |
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Patent Citations (4)
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|---|---|---|---|---|
| CN103405504A (en) * | 2013-09-02 | 2013-11-27 | 天津生机集团股份有限公司 | Traditional Chinese medicine granules for treating respiratory bovine infectious rhinotracheitis and preparation method thereof |
| CN105596627A (en) * | 2014-11-25 | 2016-05-25 | 周晓丽 | Traditional Chinese medicine for preventing infectious bovine rhinotracheitis |
| CN106177156A (en) * | 2016-08-25 | 2016-12-07 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of Chinese medicine composition preventing and treating infectious bovine rhinotrachetis and application thereof |
| CN107793472A (en) * | 2016-09-07 | 2018-03-13 | 浙江海正药业股份有限公司 | Crystal formation of oritavancin diphosphate and its production and use |
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