CN109646440B

CN109646440B - Application of Cabotegravir in preparation of anti-bovine infectious rhinotracheitis medicine

Info

Publication number: CN109646440B
Application number: CN201910027743.0A
Authority: CN
Inventors: 楚会萌; 程凯慧; 杨宏军; 解晓莉; 张亮; 于志君; 任亚初
Original assignee: Poultry Research Institute Shandong Academy of Agricultural Sciences; Dairy Cattle Research Center Shandong Academy of Agricultural Science
Current assignee: Poultry Research Institute Shandong Academy of Agricultural Sciences; Dairy Cattle Research Center Shandong Academy of Agricultural Science
Priority date: 2019-01-11
Filing date: 2019-01-11
Publication date: 2021-04-20
Anticipated expiration: 2039-01-11
Also published as: CN109646440A

Abstract

The invention provides application of Cabotegravir in preparation of a medicament for resisting infectious bovine rhinotracheitis. The invention discovers for the first time that the compound Cabotegravir can effectively inhibit the proliferation of infectious bovine rhinotracheitis virus, has low toxicity to cells, and experiments prove that the Cabotegravir has half toxicity concentration (CC) to MDBK cells₅₀) Greater than 100. mu.M, and a concentration (EC) that is half as effective against infectious bovine rhinotracheitis virus₅₀) 1.419. mu.M; the therapeutic index of Cabotegravir to the infectious bovine rhinotracheitis virus is more than 70.47, which shows that the Cabotegravir has the prospect of being developed into an anti-infectious bovine rhinotracheitis drug, opens up new drug application for Cabotegravir, lays an experimental foundation for developing high-efficiency and specific anti-IBRV drugs and provides a new visual field.

Description

Application of Cabotegravir in preparation of anti-bovine infectious rhinotracheitis medicine

Technical Field

The invention belongs to the technical field of medicine, and particularly relates to application of Cabotegravir in preparation of a medicine for resisting infectious bovine rhinotracheitis.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Infectious Bovine Rhinotracheitis (IBR), also known as necrotic rhinitis and red nose disease, is an acute, febrile, and contact Infectious disease caused by Infectious Bovine Rhinotracheitis Virus (IBRV), and is characterized by high fever, dyspnea, rhinorrhea, inflammation of the upper respiratory tract, trachea, mucous membrane, and the like. Infectious bovine disease with rhinotracheitis as a symptom was first developed in some pastures in colorado in the united states in the early 50 s of the 20 th century, and clinical symptoms of the disease were first reported in 1955. The IBRV can cause persistent infection, and is classified as a B-type disease by the world animal health Organization (OIE) and is also one of the essential diseases of the entry animals in China.

The existing IBRV effective vaccines are inactivated vaccines and attenuated vaccines, but have the problems of immunosuppression, latent infection and the like. After the inactivated vaccine is immunized, the individual cannot be distinguished and diagnosed from a naturally infected individual, so that certain obstacles are brought to the eradication of IBR. The traditional attenuated vaccine has the phenomenon of virulence reversion and certain potential safety hazard. Most importantly, IBRV is intracellular proliferative virus, and the inactivated vaccine cannot eliminate the virus in the body and only can prevent the virus. Based on the difficulty of prevention and control and the restriction of immunity, the development of drugs capable of inhibiting and killing IBRV is one of the hot spots of many researchers.

Cabotegravir is a potent HIV integrase inhibitor drug used as an orally deliverable tablet and depot injection for the treatment and prevention of HIV infection. So far, no report is available on the application of the composition in preventing and treating the infectious bovine rhinotracheitis virus.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the application of Cabotegravir in preparing the medicine for resisting the infectious bovine rhinotracheitis, and the invention firstly proves that the Cabotegravir compound can effectively inhibit the proliferation of the infectious bovine rhinotracheitis virus and has small toxicity to cells, so the Cabotegravir compound has the prospect of being developed into the medicine for resisting the infectious bovine rhinotracheitis.

One of the purposes of the invention is to provide the application of Cabotegravir in preparing the medicine for resisting infectious bovine rhinotracheitis.

The second purpose of the invention is to provide a medicine for resisting the infectious bovine rhinotracheitis.

In order to achieve the purpose, the invention relates to the following technical scheme:

in a first aspect of the invention, there is provided the use of Cabotegravir in the manufacture of a medicament for the treatment of infectious bovine rhinotracheitis. And thus Cabotegravir is effective for preventing and/or treating infectious bovine rhinotracheitis virus-associated diseases.

According to the present invention, the concept "prevention and/or treatment" means any measure suitable for the treatment of infectious bovine rhinotracheitis virus-related diseases, either for prophylactic treatment of such manifested diseases or manifested symptoms, or to avoid recurrence of such diseases, e.g. after the end of a treatment period or treatment of symptoms of diseases that have already occurred.

In the sense of the invention, the anti-infectious bovine rhinotracheitis medicine is a substance which has obvious inhibiting and killing effects on infectious bovine rhinotracheitis viruses, mainly acts on the early stage of the life cycle of the infectious bovine rhinotracheitis viruses, and has better direct killing effect on the viruses than adsorption blocking effect and replication blocking effect.

According to the present invention, not only is the use of Cabotegravir for the preparation of a medicament against infectious bovine rhinotracheitis disclosed, but it is also disclosed that such an effect can be enhanced when Cabotegravir is administered in combination with at least one other pharmaceutically active ingredient. Alternatively or in addition to other pharmaceutically active ingredients, Cabotegravir can also be used in combination with other non-pharmaceutically active ingredients.

In view of the above, the second aspect of the present invention provides a pharmaceutical composition for treating infectious bovine rhinotracheitis, which comprises Cabotegravir and at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient.

Wherein Cabotegravir is not less than half the Effective Concentration (EC)₅₀) The drug concentration of (a), half the effective concentration of Cabotegravir against bovine infectious rhinotracheitis virus (EC)₅₀) 1.419. mu.M;

the other pharmaceutical active ingredients can be used for preventing and/or treating infectious bovine rhinotracheitis virus-related diseases, preferably infectious bovine rhinotracheitis.

Other non-pharmaceutically active ingredients pharmaceutically acceptable carriers, excipients and/or diluents.

The pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection.

The medicine composition is tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar coated preparation, granule, dry powder, oral solution, small water injection for injection, freeze-dried powder injection for injection, large transfusion or small transfusion.

Compared with the prior art, the invention has the following effects and advantages:

the invention discovers for the first time that the compound Cabotegravir can effectively inhibit the proliferation of infectious bovine rhinotracheitis virus, has low toxicity to cells, and experiments prove that the Cabotegravir has half toxicity concentration (CC) to MDBK cells₅₀) Greater than 100. mu.M, and a concentration (EC) that is half as effective against infectious bovine rhinotracheitis virus₅₀) 1.419. mu.M; the therapeutic index of Cabotegravir to the infectious bovine rhinotracheitis virus is more than 70.47, which shows that the Cabotegravir has the prospect of being developed into an anti-infectious bovine rhinotracheitis drug, opens up new drug application for Cabotegravir, lays an experimental foundation for developing high-efficiency and specific anti-IBRV drugs and provides a new visual field.

Drawings

FIG. 1 is a graph showing the effect of Cabotegravir of the present invention on IBRV-damaged cells;

wherein: wherein FIG. 1A is a MDBK normal cell group; FIG. 1B is a control group of MDBK-infected viruses; FIG. 1C is a drug test group of infected cells (40. mu.M Cabotegravir administered);

FIG. 2 is a Cabotegravir sample of example 2half-Cytotoxic Concentration (CC) against MDBK cells₅₀) A drawing;

FIG. 3 is a graph of the half-Effective Concentration (EC) of Cabotegravir against IBRV in example 3₅₀) A drawing;

FIG. 4 is a graph of the effect of Cabotegravir administration at various time points on IBRV inhibition in example 4;

FIG. 5 is a graph showing the effect of Cabotegravir on IBRV direct killing in example 5.

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

The present invention is further illustrated by reference to specific examples, which are intended to be illustrative only and not limiting. If the experimental conditions not specified in the examples are specified, they are generally according to the conventional conditions, or according to the conditions recommended by the sales companies; the present invention is not particularly limited, and may be commercially available.

As described in the background, there has been no report on the use of the prior art for preventing and treating infectious bovine rhinotracheitis virus.

In view of the above, in one embodiment of the present invention, Cabotegravir is used for preparing a medicament against infectious bovine rhinotracheitis. And thus Cabotegravir is effective for preventing and/or treating infectious bovine rhinotracheitis virus-associated diseases.

The HIV integrase inhibitor drug developed by Cabotegravir from Kulanin Schker (GSK) of UK has the following chemical structural formula (CAS No.1051375-10-0), and is proved to be used for treating and preventing HIV infection as an oral lead-in tablet and a long-acting injection, but the effect of the drug on other purposes, especially on infectious bovine rhinotracheitis virus, is not studied.

The Cabotegravir also comprises pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts of the Cabotegravir are salts formed by a Cabotegravir compound and an inorganic acid or salts formed by the Cabotegravir compound and an organic acid;

preferably, the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid; the organic acid is methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.

Wherein, in the medicine for resisting infectious bovine rhinotracheitis, Cabotegravir is not less than half Effective Concentration (EC)₅₀) The drug concentration of (a), half the effective concentration of Cabotegravir against bovine infectious rhinotracheitis virus (EC)₅₀) 1.419. mu.M;

In the sense of the present invention, "anti-infectious bovine rhinotracheitis drug" means a substance which contains Cabotegravir having an obvious inhibitory effect on infectious bovine rhinotracheitis virus and mainly acts on the early stage of the life cycle of infectious bovine rhinotracheitis virus, and specifically, the direct killing effect on virus is better than the adsorption blocking effect and the replication blocking effect.

In a further embodiment of the invention, a pharmaceutical composition against infectious bovine rhinotracheitis is provided, said pharmaceutical composition consisting of Cabotegravir and at least one further pharmaceutically active ingredient and/or at least one further non-pharmaceutically active ingredient.

In yet another embodiment of the invention, the Cabotegravir is taken at a concentration not less than half the Effective Concentration (EC)₅₀) The drug concentration of (a), half the effective concentration of Cabotegravir against bovine infectious rhinotracheitis virus (EC)₅₀) 1.419. mu.M;

the Cabotegravir also comprises pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts of the compound are salts formed by the compound and inorganic acid or salts formed by the compound and organic acid;

in yet another embodiment of the present invention, the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, or hydrobromic acid; the organic acid is methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.

Other non-pharmaceutically active ingredients pharmaceutically acceptable carriers, excipients and/or diluents. Such as pharmaceutically compatible inorganic or organic acids or bases, polymers, copolymers, block copolymers, monosaccharides, polysaccharides, ionic and non-ionic surfactants or lipids, pharmacologically innocuous salts such as sodium chloride, flavoring agents, vitamins such as vitamin a or vitamin E, tocopherols or provitamins, antioxidants such as ascorbic acid, and stabilizers and/or preservatives for extending the use and shelf life of the pharmaceutically active ingredient or formulation, and other common non-pharmaceutically active ingredients or adjuvants and additives known in the art, and mixtures thereof.

The technical solution of the present invention is further described with reference to the following specific examples.

Example 1 Virus TCID₅₀Measurement of (2)

MDBK cells were digested at 1X 10 per well⁵Cell density of one/mL was seeded into 96-well cell culture plates and placed at 37 ℃ in 5% CO₂Culturing the cells in the cell culture box to form monolayer cells, discarding the cell growth liquid in the holes, and continuously diluting the IBRV by 10 times to obtain virus diluent (the dilution is 10 respectively)^-1-10^-10) The cells were seeded in 96-well plates filled with a monolayer of cells at 100. mu.L per well. Adding 5% CO at 37 deg.C₂The culture was continued in the incubator, and the cells were observed day by day for CPE and the number of cytopathic wells was recorded in detail. And setting a normal cell control group and a blank control group at the same time, setting 8 repeats in each group, and judging the result when the cytopathic effect is not continued. The cell lesion hole is a cell hole corresponding to the above cell lesion, and virus TCID is calculated by Karber method₅₀。

TABLE 1 TCID₅₀of IBRV-F9

As a result: the morphological observation under a microscope shows that the concentration is different at 48hViral dilutions of different degrees cause cytopathic effect, the refractive index of cells changes, the monolayer structure is destroyed, cells are necrotized in a circular shape, gradually become a net shape and form vacuoles, some cells are cracked and fall off into fragments, cytopathic effect of each hole is not continued after 5 days, the number of CPE holes with different concentrations is counted, the CPE ratio with different concentrations is calculated, and the TCID of IBRV is calculated according to the Karber method₅₀The value:

LgTCID₅₀L-D (S-0.5) (L: log of highest dilution; D: difference between logs of dilutions;

s: positive aperture ratio sum

LgTCID₅₀＝L-D(S-0.5)＝-1-1×(5.5-0.5)＝-6

TCID₅₀＝10^-6/0.1mL

I.e. diluting the virus 10⁶Inoculation with 100. mu.L resulted in 50% of the cells being diseased.

Example 2 toxicity test of Cabotegravir on MDBK cells:

MDBK cells are susceptible cells to IBRV. Therefore, the cytotoxicity of Cabotegravir to MDBK cells was first tested by the following specific experimental procedures:

(1) 100 μ L of cells (MDBK 5000 per well) were seeded in 96-well plates.

(2) After about 12h of incubation, the next dosing analysis was performed. Media was discarded and 100 μ L of 2% FBS DMEM containing different drug concentrations were added to each well, 3 replicates for each concentration. At the same time, control wells: 100 μ L of 2% FBS DMEM medium containing 0.9% DMSO was added. Zero setting hole: cells were not plated.

(3) At 37 ℃ 5% CO₂After culturing for 48h under the conditions, the medium in the wells was discarded. Two washes with 100 μ L PBS were performed to exclude the effect of drug on MTT response. Each well was supplemented with 100. mu.L of DMEM medium + 10. mu.L of MTT.

(4)37℃，5％CO₂After further culturing for 4h under the conditions, 100. mu.L of Formazan lysis solution was added to each well. 37 ℃ and 5% CO₂Incubation was continued until the Formazan purple crystals were completely dissolved.

(5) The absorbance was measured at 570 nm. A570nm of 0.9% DMSO treated cells was set as a 100% cell control.

(6) Data were analyzed and half the Cytotoxic Concentration (CC) of Cabotegravir calculated using GraphPad Prism5₅₀) The value is obtained. The results are shown in FIG. 2.

As a result: the Cabotegravir shows a dose-dependent relationship, namely, cytopathic effect is more obvious along with the increase of the concentration of the drug. Statistical analysis shows that the half poisoning concentration of Cabotegravir is more than 100 mu M, which indicates that the Cabotegravir has small toxic effect on cells.

Example 3 inhibition experiment of Cabotegravir on IBRV:

(1) 1X 10 inoculations in each well of a 96-well plate⁴MDBK cells, 37 ℃, 5% CO₂Culturing in an incubator overnight;

(2) the medium was discarded and 100. mu.L of 100TCID was added to each well₅₀The IBRV virus diluent (virus diluent is added after 2% FBS DMEM cells are full, the virus diluent is diluted and added according to 50 mu M initial concentration and double concentration gradient, and 5% CO is added₂Culturing in an incubator;

(3) after 48h, the OD at 450nm was measured with a microplate reader, following the instructions of the CCK-8 kit.

(4) The data were analyzed, and the rate of virus inhibition (%) (drug-treated D450nm value-virus control D450nm value)/(normal cell control D450nm value-virus control D450nm value) × 100%, half the effective concentration of the compound (EC) was obtained using GraphPad Prism5 software₅₀) The value is obtained. The results are shown in FIG. 3. Then according to the formula TI ═ CC₅₀/EC₅₀And calculating the corresponding therapeutic index TI value.

As a result: the CCK-8 kit is used for detecting the cell viability, so that the effective inhibition rate of the medicament on the IBRV can be calculated. From the results, it can be seen that the Cabotegravir has a certain dose-effect relationship in that the effective inhibition rate increases with the increase of the drug concentration within the safe concentration range. Half Effective Concentration (EC) of infectious bovine rhinotracheitis virus by analytical software₅₀) It was 1.419. mu.M. The therapeutic index of Cabotegravir to infectious bovine rhinotracheitis virus is greater than 70.47.

EXAMPLE 4 preliminary investigation of the mechanism of action

The compound to be tested is added into MDBK cells inoculated with the infectious bovine rhinotracheitis virus through different administration time, namely corresponding time points of firstly administering and then infecting the virus (before 0h), firstly infecting the virus and then administering (after 0h), and simultaneously adding the virus and the medicine into the cells (0h), thereby preliminarily judging the action period of the Cabotegravir. The specific experimental steps are as follows:

(1) 1X 10 inoculations in each well of a 96-well plate⁴MDBK cells, 37 ℃, 5% CO₂Culturing in an incubator.

(2) According to the measured pharmacodynamic evaluation result of the related medicine, the concentration of the medicine required by the experiment is determined, and the medicine is diluted to the required concentration by using a maintenance medium.

(3) After overnight incubation, the cell supernatants from the second three duplicate wells of the 96-well plate were aspirated and the cells were washed 2 times with phosphate buffer. Then 50. mu.L of the drug to be tested was added, and the time was recorded as-2 h.

(4) After 2h, the cell supernatants from the other wells were aspirated off, and the diluted bovine infectious rhinotracheitis virus dilutions were added to each well of columns 2-11 at a loading volume of 50 μ L per well. At the same time, 50. mu.L of the corresponding analyte was added to the three duplicate wells in column 3, which was recorded as 0 h.

(5) And adding corresponding compounds to be detected into the three compound holes in the next row at regular intervals, and marking the corresponding time. MDBK cells from column 11 were used as virus control.

(6) After 48 hours of incubation, OD measurements were performed. The data were analyzed and concluded, the results of which are shown in fig. 4.

As a result: according to the analysis of the administration experiment results at different time points, the Cabotegravir has obvious inhibition effect on viruses when the viruses infect cells for 0h and 2h, which indicates that the Cabotegravir may be mainly acted on the early stage of the life cycle of the IBRV.

EXAMPLE 5 Effect of different time addition of Compounds on IBRV replication

The screened Cabotegravir with good effect and low toxicity is further researched on the action mechanism. The in vitro antiviral inhibition test is carried out by 3 different action modes of adding medicine first and then adding virus, adding virus first and then adding medicine, and pre-acting medicine and virus.

(1) Direct killing effect of medicine on virus

Equal amount of 100TCID₅₀Mixing the virus solution with the medicinal diluent at different concentrations, and standing at 37 deg.C with 5% CO₂Pre-acting in an incubator for 4h, adding into a 96-well cell culture plate with a monolayer, allowing each liquid medicine to have a gradient of 100 μ L/well, acting in the incubator for 2h, discarding the supernatant, and adding cell maintenance liquid to continue culturing. The test simultaneously sets a normal cell control group, a virus control group and a blank control group, each concentration is set to be 3 times, cell viability detection is carried out for 48 hours, and GraphPad Prism5 software is used for obtaining EC of the compound₅₀。

As a result: under the administration mode of the Cabotegravir and the IBRV acting in advance, the cytopathic effect of the experimental drug-adding group with each concentration is slight compared with that of a virus control group, the pathological phenomena of cell rounding, cell shedding, vacuolation and the like are reduced to some extent, and the effect of the Cabotegravir on the IBRV is shown in figure 5 through analysis software. As can be seen from the figure, under the action formula, the Cabotegravir shows an inhibition effect on the IBRV, and the effective inhibition rate of the drug is increased along with the increase of the drug concentration within a safe concentration range, and has a certain dose-effect relationship. Indicating that Cabotegravir has direct inactivation effect on IBRV.

(2) Blocking effect of drug on IBRV adsorption

Inoculating the digested cells into a pore plate according to the cell density of each pore, removing the supernatant after the cells grow into a monolayer, adding the drug diluents with different concentrations into a 96-pore cell culture plate with the monolayer, removing the supernatant after the drug diluents with different concentrations act for 4 hours in an incubator in advance, washing twice with PBS, adding 100TCID with the same amount₅₀Placing the virus liquid at 37 ℃ and 5% CO₂Culturing in an incubator. The test is simultaneously provided with a normal cell control group, a virus control group and a blank control group, each concentration is set for 3 times, cell activity detection is carried out after 48 hours, and the antiviral effective rate of the drugs with different concentrations under the action mode is calculated.

As a result: CPE observations showed that there was no significant change in the extent of cytopathic effect in the drug pre-treated group compared to the virus control group. Cell viability detection results show that the effective inhibition rate of the drug on IBRV is below 20%, which indicates that Cabotegravir cannot prevent IBRV from adsorbing cells.

(3) Blocking of IBRV replication by drugs

Inoculating the digested cells into a well plate according to the cell density of each well, removing the supernatant after the cells grow into a monolayer, and adding 100TCID (total dissolved solids)₅₀Adding virus solution into 96-well cell culture plate, and standing at 37 deg.C under 5% CO₂Pre-acting in an incubator for 2h, removing supernatant, washing cells for 2 times with PBS, adding drug diluents with different concentrations, each drug solution gradient being 100 μ L/well, setting a normal cell control group, a virus control group and a blank control group at the same time in the test, setting 3 repeats for each concentration, placing at 37 ℃ and 5% CO₂Culturing in an incubator, detecting cell viability after 48h, analyzing data and obtaining a conclusion.

As a result: CPE observations showed that there was no significant change in the extent of cytopathic effect in the virus pretreatment group compared to the virus control group. The detection result shows that the effective inhibition rate of Cabotegravir on IBRV is lower than 20%, which indicates that Cabotegravir can not block the replication effect in cells.

In the application embodiment of the invention, the bovine kidney cells (MDBK) are used as a carrier, and 3 different action modes of adding medicine first and then adding virus, adding medicine first and then adding medicine, and pre-acting virus and then adding medicine are adopted on a cytopathogenic model to carry out in-vitro antiviral inhibition research. The novel antiviral effect of Cabotegravir is found to have a certain inhibiting effect on IBRV, and the direct killing effect on viruses is better than the adsorption blocking effect and the replication blocking effect.

Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

The use of Cabotegravir or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of infectious bovine rhinotracheitis, the Cabotegravir having the structure:

。
2. the use according to claim 1, wherein the anti-infectious bovine rhinotracheitis medicament has a medicament concentration of Cabotegravir of not less than 1.419 μ M.
3. The use of claim 1, wherein the pharmaceutically acceptable salt of Cabotegravir is a salt of a Cabotegravir compound with an inorganic acid, or a salt with an organic acid.
4. The use of claim 3, wherein the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, or hydrobromic acid; the organic acid is methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.
5. Use of a Cabotegravir pharmaceutical composition for the manufacture of a medicament against infectious bovine rhinotracheitis, said pharmaceutical composition consisting of Cabotegravir or a pharmaceutically acceptable salt of Cabotegravir and at least one other pharmaceutically active ingredient and/or at least one other non-pharmaceutically active ingredient, wherein Cabotegravir has the structure:

。
6. the use of claim 5, wherein the Cabotegravir is present in a drug concentration of not less than 1.419 μ M.
7. The use of claim 5, wherein the pharmaceutically acceptable salt of caboteravir is a salt of a caboteravir compound with an inorganic acid or a salt with an organic acid.
8. Use according to claim 5, wherein the other pharmaceutically active ingredient is an ingredient for the prevention and/or treatment of infectious bovine rhinotracheitis.
9. The use of claim 5, wherein the other non-pharmaceutically active ingredients comprise a pharmaceutically acceptable diluent; the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection.
10. The use according to claim 9, wherein the pharmaceutical composition is a dispersible tablet, an enteric tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, a dry powder, an oral solution, a small injectable water needle, a lyophilized injectable powder, a large or small infusion solution.