CN114796189B - Pharmaceutical composition for treating and preventing respiratory tract pathogen infection and application thereof - Google Patents
Pharmaceutical composition for treating and preventing respiratory tract pathogen infection and application thereof Download PDFInfo
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- CN114796189B CN114796189B CN202210223547.2A CN202210223547A CN114796189B CN 114796189 B CN114796189 B CN 114796189B CN 202210223547 A CN202210223547 A CN 202210223547A CN 114796189 B CN114796189 B CN 114796189B
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention discloses a pharmaceutical composition for treating and preventing respiratory pathogen infection and application thereof, and relates to the technical field of respiratory diseases. The inventors have found a new use of rotenone. In vitro and in vivo experiments prove that the rotenone can reduce the virus titer of human laryngeal cancer epithelial cells infected by Human Respiratory Syncytial Virus (HRSV), improve the survival rate of animals, and promote the weight of infected animals to gradually rise from a low level. The rotenone has good effect of resisting respiratory pathogens (especially respiratory infection virus), has good application prospect when being used for treating and/or preventing respiratory pathogen infection, and can be used for developing corresponding medicaments for treating or preventing respiratory pathogen infection. Brings good news to patients with pneumonia such as viral pneumonia.
Description
Technical Field
The invention relates to the technical field of respiratory diseases, in particular to a pharmaceutical composition for treating and preventing respiratory pathogen infection and application thereof.
Background
Rotenone (Rotenone) is a natural compound derived from the roots and stems of the genus Rotenone, herba Dendrobii, agave, and mung bean. Rotenone has been widely used as an insecticide for controlling insects, ticks and lice since the end of the 19 th century, and as a fish insecticide for managing fish in lakes and reservoirs. Betarset et al in 2000 reproduced most of the behavioral, biochemical and pathological features of Parkinson's disease in rotenone-treated rats. Since then, rotenone has received much attention as an environmental neurotoxin involved in the pathogenesis of parkinson's disease. In addition, researchers have now constructed a common experimental model for studying the underlying mechanisms leading to parkinson's disease and evaluating new underlying treatments for the disease.
The existing research shows that: mitochondria produce ATP via oxidative phosphorylation complexes present in their inner membranes, these complexes are known as NADH ubiquinone oxidoreductase (complex I), succinate dehydrogenase (complex II), ubiquinone cytochrome c oxidoreductase (complex III), cytochrome c oxidase (complex IV) and ATP synthase (complex V). The oxidative phosphorylation process begins with the oxidation of NADH by complex I enzymes. It is currently known that rotenone can cause a significant decrease in cellular mitochondria through oxidative phosphorylation of complex formation ATP by inhibiting complex I, while electrons leaking at complex I can reduce unreduced oxygen at complex IV to Reactive Oxygen Species (ROS), resulting in increased ROS.
At present, the report of the human virus infection resistance of rotenone is as follows: in 2020, dihydrorotenone was investigated as a novel anti-Hepatitis C Virus (HCV) compound by its inhibitory effect on autophagy (Liao W, X Liu, yang Q, et al Deguelin inhibits HCV replication through suppressing cellular autophagy via down regulation of Beclin1 expression in human hepatoma cells, anti-viral Research,2020, 174:104704); in 2018, dihydrorotenone was used for studies against human cytomegalovirus (HMCV) infection through its inhibition of viral replication (Nukui M, O' Connor, christine, murphy E.the Natural Flavonoid Compound Deguelin Inhibits HCMV Lytic Replication within fibriplasts. Viruses,2018,10 (11)).
Human Respiratory Syncytial Virus (HRSV) is the most important pathogen causing viral pneumonia in children, and is one of the important pathogens for lower respiratory tract infection in long-term patients, and severe pneumonia caused by the viral infection can cause death in hundreds of thousands of children or long-term patients every year, so that no vaccine is marketed.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for treating and preventing respiratory pathogen infection and application thereof, and aims to provide a pharmaceutical scheme for treating and preventing respiratory pathogen infection.
The invention is realized in the following way:
the invention provides an application of rotenone in preparing a medicament for treating and/or preventing respiratory pathogen infection.
The inventors have found a new use of rotenone. In vitro and in vivo experiments prove that the rotenone can reduce the virus titer of animal cells infected by Human Respiratory Syncytial Virus (HRSV), improve the survival rate of animals, and promote the weight of infected animals to gradually rise from a low level. The rotenone has good effect of resisting respiratory pathogens (especially respiratory infection virus), has good application prospect when being used for treating and/or preventing respiratory pathogen infection, and can be used for developing corresponding medicaments for treating or preventing respiratory pathogen infection. Brings good news to patients with pneumonia such as viral pneumonia.
Such treatments include, but are not limited to: the respiratory tract of the patient is obviously smoother in breathing, or the cough symptom is relieved, or the swelling and pain of the throat and the lung are relieved or eliminated, or the inflammation of the respiratory tract is eliminated compared with the respiratory tract before the medicine provided by the invention is applied. The respiratory tract can achieve a certain curative effect after the medicine provided by the invention is used, and the invention belongs to the protection scope of the invention.
Rotenone, CAS accession number 83-79-4, also known as rotenone, toxic rotenone.
In a preferred embodiment of the invention, the respiratory pathogens include, but are not limited to: human respiratory syncytial virus, influenza a virus, influenza b virus, influenza a virus H1N1, influenza a virus H5N1, human parainfluenza virus, human metapneumovirus (metapneumovirus), human adenovirus, human enterovirus, human rhinovirus, bordetella pertussis (Bordetella pertussis), chlamydia pneumoniae (Chlamydophila pneumoniae), mycoplasma pneumoniae (Mycoplasma pneumoniae) and other microorganisms from the genera: streptococcus (Streptococcus), haemophilus (Haemophilus), moraxella (Moraxella), pseudomonas (Pseudomonas), klebsiella (Klebsiella), euphoria (stenotophomonas), acinetobacter (Acinetobacter), staphylococcus (Staphylococcus), mycoplasma (mycoplasm), legionella (Legionella), chlamydia (Chlamydophila), mycobacterium (mycobabacterium), kochia (Coxiella), nocardia (Nocardia), pneumocystis (Pneumocystis), nocardia (Nocardia) and Aspergillus (Aspergillus).
The antiviral effect of rotenone results from the induction of apoptosis of cells in the internal initiation pathway, i.e. apoptosis of mitochondrial pathway. In theory, it is possible to treat the infection with rotenone as long as it is early in the infection by a virus or bacteria that inhibits apoptosis of the host cell.
In a preferred embodiment of the present invention, the human respiratory syncytial virus is selected from the group consisting of human respiratory syncytial virus subtype a and human respiratory syncytial virus subtype B.
In a preferred embodiment of the present invention, the human parainfluenza virus is selected from human parainfluenza virus type 1, human parainfluenza virus type 2, human parainfluenza virus type 3 or human parainfluenza virus type 4.
In a preferred embodiment of the invention, the human adenovirus is selected from the group consisting of human adenovirus subtype B, human adenovirus subtype C and human adenovirus subtype E.
The present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of respiratory pathogen infection, the pharmaceutical composition comprising:
the rotenone or the extract containing the rotenone derived from the plant, or the pharmaceutical composition contains the synthetic compound of the rotenone or the synthetic derivative thereof, or the pharmaceutical composition contains the rotenone compound selected from the dehydrocompound or the crystalline compound of the rotenone.
The rotenone extract comprises all or part of the components obtained by extraction.
In a preferred embodiment of the present invention, the dehydrogen compound of rotenone is dehydrorotenone and the crystalline compound is rotenone.
In a preferred embodiment of the use of the invention, the plant is selected from leguminous plants;
in an alternative embodiment, the leguminous plant is selected from the group consisting of plants of the family Papilionaceae, genus Boehmeria, genus Zuioia, genus Derrichthys, genus Ipomoea or genus Adinandra.
In an alternative embodiment, the genus thuja is selected from the group consisting of spatholobus stem.
The genus yam is selected from the group consisting of ground melon seeds;
the Papilionaceae is selected from Pterocarpus Indicus.
Plants of the genus yu include, but are not limited to: huntis mountain, derris henyi Thoth, large She Yuteng Derris latifolia, derris florida, isoptera mountain Derris malaccensis, derris margarita, derris marginata, derris lanuginosa, palm She Yuteng Derris palmifolia, derris robusta, derris crudels Derris scabricaulis, miquel mountain Derris thyrsiflora, tokyo mountain Derris tonkinensis, royal mountain Derris trifoliata, yunnan mountain Derris yunnanensis, bettus albo-rubra hemsl, brevibacterium Derris breviramosa, tail She Yuteng Derris caudatilimba, guigu mountain Derris cavaleriei, ding mountain Hu mountain Derris dinghuensis P.Y. Chen, derris eiptica, derris macrocarpa, purpura mountain Derris ferruginea, derris norrisdii powder She Yuteng Derris mountain, derris glauca Derris hainanensis, kadsura pepper Derris harrowiana, and Darbur mountain.
In a preferred embodiment of the application of the invention, the pharmaceutical composition contains rotenone or rotenone compounds as the active ingredients in a mass percentage concentration of 10-90%.
In a preferred embodiment of the present invention, the pharmaceutical composition is in the form of a tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection, spray or injection.
Optionally, the pharmaceutical composition further includes a pharmaceutically acceptable salt, and the "pharmaceutically acceptable salt" includes a pharmaceutically acceptable inorganic acid salt or organic acid salt.
Alternatively, the inorganic acid salt may be a sulfate, sulfite, hydrochloride, hydrobromide, nitrate, phosphate or dihydrogen phosphate salt.
Alternatively, the organic acid salt may be acetate, maleate, fumarate, succinate, citrate, p-toluenesulfonate, tartrate, formate, propionate, heptanoate, oxalate, benzoate, malonate, succinate, maleate, hydroxybutyrate, citrate, methanesulfonate, benzenesulfonate, lactate or mandelate.
Alternatively, the organic acid salt may be an organic acid salt compound having a functional group such as a carboxyl group, a sulfonic acid group, a sulfinic acid group, or a thiocarboxylic acid group.
In other alternatives, the above-described inorganic acid salts and organic acid salts are not limited in scope by the present invention.
The modes of use of the above pharmaceutical composition include, but are not limited to: injection, oral administration, nasal inhalation (aerosol).
The invention has the following beneficial effects:
the inventors have found a new use of rotenone. In vitro and in vivo experiments prove that the rotenone can reduce the virus titer of human laryngeal cancer epithelial cells infected by Human Respiratory Syncytial Virus (HRSV) and the pulmonary virus load of animals, improve lung lesions, improve the survival rate of animals and promote the weight of infected animals to gradually rise from a low level. The rotenone has good effect of resisting respiratory pathogens (especially respiratory infection virus), has good application prospect when being used for treating and/or preventing respiratory pathogen infection, and can be used for developing corresponding medicaments for treating or preventing respiratory pathogen infection. Brings good news to patients with pneumonia such as viral pneumonia.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing statistics of viral titers and viral gene copy numbers of rotenone treated groups at different concentrations in cell pellet and cell supernatant, respectively, 48 hours post-infection;
FIG. 2 is a graph showing statistics of viral titers and viral gene copy number of rotenone treated groups at various concentrations in cell pellet and cell supernatant, respectively, 72 hours post-infection;
FIG. 3 is a graph comparing body weight (A) and survival (B) of mice in the saline-treated group after HRSV infection and mice in the rotenone-treated group at different concentrations;
FIG. 4 is a graph showing the statistical results of survival rates of mice treated with physiological saline after HRSV infection, mice treated with rotenone at different concentrations after HRSV infection and mice treated with rotenone at different concentrations;
FIG. 5 is a graph showing the results of the determination of pneumovirus titers in HRSV-infected mice in physiological saline-treated groups at days 4, 5 and 6 after HRSV infection and in mice in rotenone-treated groups at 1.0mg/kg after HRSV infection;
FIG. 6 is a graph showing the results of H & E staining of pulmonary pathological sections of HRSV post-infection normal saline treated mice, HRSV post-infection 1.0mg/kg rotenone treated mice, 1.0mg/kg rotenone treated mice and blank control mice at day 5 post-infection HRSV.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
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 disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of formulations or unit doses herein, some methods and materials are now described. Unless otherwise indicated, techniques employed or contemplated herein are standard methods. The materials, methods, and examples are illustrative only and not intended to be limiting.
Unless otherwise indicated, practice of the present invention will employ conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the ability of a person skilled in the art. This technique is well explained in the literature, as is the case for molecular cloning: laboratory Manual (Molecular Cloning: A Laboratory Manual), second edition (Sambrook et al, 1989); oligonucleotide Synthesis (Oligonucleotide Synthesis) (M.J.Gait et al, 1984); animal cell culture (Animal Cell Culture) (r.i. freshney, 1987); enzymatic methods (Methods in Enzymology) (Academic Press, inc.); manual of experimental immunology (Handbook of Experimental Immunology) (D.M.Weir and C.Blackwell et al, 1991), vector for gene transfer for mammalian cells (Gene Transfer Vectors for Mammalian Cells) (J.M.Miller and M.P.Calos, 1987), method of contemporary molecular biology (Current Protocols in Molecular Biology) (F.M.Ausubel et al, 1987), PCR: polymerase chain reaction (PCR: the Polymerase Chain Reaction) (Mullis et al, 1994), and contemporary immunological methods (Current Protocols in Immunology) (J.E.Coligan et al, 1991), fields Virology (David M.Knife et al, 2013), principles of Virology (J Flint, V Racanielo, et al, 2015), introduction to Modern Virology en (Nigel J.Dimm, et al, 2016, essential Human Virology, 2016) and 2016 (J.E.Coli.2016, 2016, each of which is incorporated by reference herein in its entirety.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The present example provides an in vitro antiviral validation experiment of rotenone.
The HRSV low strain HRSV-A-GZ08-0 and high strain HRSV-A-GZ08-18 used were referenced to Zhang K, li C, luo Y S, et al, estabishiment of Sup>A lethal aged mouse model of human respiratory syncytial virus in isolation, anti-viral Research,2019,161:125-133.
In vitro antiviral experiments: HEp-2 cells were infected with HRSV low strain HRSV-A-GZ08-0 and high strain HRSV-A-GZ08-18, respectively, for 1 hour, and then the culture was continued with cell culture mediSup>A (DMEM-F12/GlutaMax-I, 10565, gibco;2% FBS;1% P/S) containing rotenone at 1. Mu.M, 0.75. Mu.M, 0.5. Mu.M, 0.25. Mu.M and 0.125. Mu.M concentrations, followed by TCID at 48 hours and 72 hours after infection, respectively 50 And determining the virus titer in the cell pellet and the cell supernatant by a real-time fluorescent quantitative PCR method and comparing the virus titer.
The results are shown in FIGS. 1 and 2, and it can be seen that 48 hours after infection (FIG. 1), in the cell pellet, the virus titers of the 1. Mu.M, 0.75. Mu.M, 0.5. Mu.M and 0.25. Mu.M rotenone treated groups were all lower than the virus control group, most of which were statistically significant; in the cell supernatant, the virus titers of the rotenone treatment groups of 1. Mu.M, 0.75. Mu.M, 0.5. Mu.M and 0.25. Mu.M were all lower than that of the virus control group, and most of the virus titers were statistically significant.
The real-time fluorescence quantitative PCR results show that in the cell sediment, the virus copy numbers of the rotenone treatment groups of 1 mu M, 0.75 mu M, 0.5 mu M and 0.25 mu M are lower than those of the virus control group; in the cell supernatant, the virus copy numbers of the rotenone treatment groups of 1 mu M, 0.75 mu M, 0.5 mu M and 0.25 mu M are lower than those of the virus control group, and most of the virus copy numbers are statistically significant.
72 hours post infection (FIG. 2), 1. Mu.M, 0.75. Mu.M, 0.5. Mu.M, 0.25. Mu.M and 0.125. Mu.M rotenone treated groups had lower viral titers than the control group, most of which were statistically significant; in the cell supernatants, the virus titers of the 1. Mu.M, 0.75. Mu.M, 0.5. Mu.M, 0.25. Mu.M and 0.125. Mu.M rotenone treated groups were all lower than that of the virus control group, most of which were statistically significant.
The real-time fluorescence quantitative PCR results show that in the cell pellet, the virus copy numbers of the rotenone treatment groups of 1 mu M, 0.75 mu M, 0.5 mu M, 0.25 mu M and 0.125 mu M are lower than those of the virus control group; in the cell supernatants, the virus copy numbers of the 1. Mu.M, 0.75. Mu.M, 0.5. Mu.M, 0.25. Mu.M and 0.125. Mu.M rotenone treated groups were all lower than that of the virus control group, and most of them were statistically significant.
***：p<0.001。
Example 2
In this example, an in vivo antiviral validation experiment of rotenone was performed.
After BALB/c mice were infected with HRSV high strain HRSV-A-GZ08-18 (same source as in example 1), rotenone was dissolved in physiological saline at different concentrations, and the mice were subcutaneously injected with 1.5mg/kg, 1.0mg/kg and 0.5mg/kg of rotenone for 3 days, while setting the HRSV-A-GZ08-18 virus control group and 1.5mg/kg, 1.0mg/kg and 0.5mg/kg of rotenone subcutaneously injection control group.
FIG. 5 shows physiological saline after HRSV infection on days 4, 5 and 6 after HRSV infectionThe test result graph of the pneumovirus titer of the mice in the treatment group and the mice in the HRSV treatment group with 1.0mg/kg rotenone after infection is that the test method is TCID 50 A method of manufacturing the same. The results show that the pulmonary viral load of the mice treated with physiological saline on the 4 th day and the 5 th day after HRSV infection is obviously higher than that of the mice treated with rotenone (p) of 1.0mg/kg after HRSV infection<0.05)。
FIG. 6 is a graph showing the results of H & E staining of pulmonary pathological sections of HRSV post-infection normal saline treated mice, HRSV post-infection 1.0mg/kg rotenone treated mice, 1.0mg/kg rotenone treated mice and blank control mice at day 5 post-infection HRSV. As can be seen from fig. 6, on day 5 after HRSV infection, acute interstitial pneumonia of mice in the group treated with normal saline after HRSV infection is marked, and is mainly manifested by interstitial edema around bronchioles and small blood vessels, loosening, increased aggregation of inflammatory cells at alveolar spaces, thickening of alveolar walls, and neutrophil-based inflammatory cells, erythrocytes and a large amount of pink protein exudates and edema fluid in alveolar spaces. After HRSV infection, 1.0mg/kg rotenone is treated to thicken the alveoli wall of mice, a small amount of inflammatory cells mainly comprising neutrophils are oozed out of the alveoli space, the inflammatory cells at the alveoli space have a small amount of aggregation, the general acute interstitial pneumonia is not obvious, and obvious bronchioles, perivascular interstitial oedema and inflammatory cell aggregation are not seen. 1.0mg/kg rotenone treated mice and blank control mice have clear pulmonary bronchioles, surrounding small blood vessels and alveolar spaces, and no inflammatory cell infiltration. The results show that compared with the mice treated with rotenone at 1.0mg/kg after the HRSV infection, the lung lesions of the mice treated with physiological saline after the HRSV infection are obvious.
Mice were then observed for mortality to 21 days post infection, and mice were counted for body weight and survival.
As a result, 1.5mg/kg, 1.0mg/kg and 0.5mg/kg of rotenone control mice were found to have no death; survival rates of the HRSV-A-GZ08-18 post-infection 1.5mg/kg, 1.0mg/kg and 0.5mg/kg rotenone treated groups were 44.44%, 41.67% and 33.33%, respectively, with weight loss to about 70% on day 6 post-infection followed by slow rebound; the survival rate of the HRSV-A-GZ08-18 virus control group is 16.67%, and the weight is continuously reduced. The results are shown in figures 3 and 4.
Experimental results show that rotenone can effectively improve survival rate of infected mice and recover weight loss caused by virus infection.
The safety evaluation of rotenone can be described by http:// extoxnet. Orst. Edu/pips/rotenone. Htm, LD of rotenone taken orally by rats 50 LD of rotenone in white rat body of 132mg/kg to 1500mg/kg 50 350mg/kg. Reference Kidd, h.and James, d.r., eds.the Agrochemicals Handbook, third edition.royal Society of Chemistry Information Services, cambridge, UK,1991 (as updated). 2-13.
In conclusion, the rotenone has good effect of resisting respiratory pathogens (especially respiratory infection virus), has good application prospect when being used for treating and/or preventing respiratory pathogen infection, and can be used for developing corresponding respiratory pathogen infection treatment or prevention medicines. Brings good news to patients with pneumonia such as viral pneumonia.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (2)
1. Use of rotenone for the preparation of a medicament for the treatment and/or prophylaxis of human respiratory syncytial virus infection.
2. The use according to claim 1, wherein the human respiratory syncytial virus is selected from the group consisting of human respiratory syncytial virus subtype a and human respiratory syncytial virus subtype B.
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