CN115317468A - Application of terpinen-4-ol in preparing anti-inflammatory medicine or respiratory syncytial virus resisting medicine - Google Patents

Application of terpinen-4-ol in preparing anti-inflammatory medicine or respiratory syncytial virus resisting medicine Download PDF

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CN115317468A
CN115317468A CN202211160092.0A CN202211160092A CN115317468A CN 115317468 A CN115317468 A CN 115317468A CN 202211160092 A CN202211160092 A CN 202211160092A CN 115317468 A CN115317468 A CN 115317468A
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张科
罗语思
郭名扬
沈祥春
陶玲
张晗溪
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Guizhou Medical University
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Abstract

The invention discloses application of terpinen-4-ol in preparation of anti-inflammatory drugs or respiratory syncytial virus drugs, and relates to the technical field of medicines. The invention provides a novel substance for resisting respiratory syncytial virus, namely terpinen-4-ol. The terpine-4-ol has good in-vivo efficacy of resisting respiratory syncytial virus, can relieve lung injury caused by virus infection and reduce the level of lung inflammatory factors, provides experimental basis for developing efficient and safe respiratory syncytial virus resisting medicines, has good prospect for preparing respiratory syncytial virus resisting medicines and anti-inflammatory medicines, and can be used for improving lung tissue injury and/or alveolar structure damage.

Description

Application of terpinen-4-ol in preparing anti-inflammatory medicine or respiratory syncytial virus resisting medicine
Technical Field
The invention relates to the technical field of medicines, in particular to application of terpine-4-ol in preparing anti-inflammatory medicines or respiratory syncytial virus medicines.
Background
Herba houttuyniae is a medicinal and edible Chinese herbal medicine, is also a traditional Chinese medicine with long history in China, is used for treating pneumonia and lung cyst, is known as 'broad spectrum antibiotic in traditional Chinese medicine', and is one of plants officially determined by the Ministry of health of China to be medicinal and edible [1] . It is an edible plant, and the root, stem and flower all have a certain medicinal value, and the whole plant can be used as medicine. The herba Houttuyniae has various chemical components, mainly including volatile oil, alkaloid, flavonoid and phenolic acid [2–4] 。
Many research reports show that the houttuynia cordata has the functions of resisting inflammation, resisting tumor, resisting virus, resisting oxidation and enhancing body immunity [2,5–7] Has obvious effect on respiratory tract system diseases, and the anti-inflammatory activity of the houttuynia cordata plays an indispensable role in relieving lung diseases [8] . Research proves that the houttuynia cordata can remarkably relieve acute lung injury of mice induced by influenza A virus (H1N 1), and the houttuynia cordata has the dual effects of resisting inflammation and virus [9] 。
In addition, research reports that the houttuynia cordata extract is safe and effective for treating pneumonia caused by SARS virus (SARS-CoV), and the houttuynia cordata aqueous extract has obvious inhibiting effect on 3C-like protease (3 CLpro) and RNA dependent RNA polymerase (RdRp) of new coronavirus (SARS-CoV-2) in the aspect of antivirus, thereby slowing down virus replication. On the other hand, oral acute toxicity tests show that the fish has the effect of reducing the toxicity of fishThe raw grass is nontoxic to experimental animals when being orally taken at a dose of 16g/kg [10] . It is one of approved components in SARS preventing preparation, and utilizes molecular model technology of molecular docking and kinetic simulation to research the combination of houttuynia cordata medicine bioactive compound and SARS-CoV-2 replication and transcription related enzyme RdRp and reveal the potential of houttuynia cordata bioactive compound as SARS-CoV-2 resisting candidate medicine [11] . In addition, researches report that the active ingredient of houttuynia cordata has certain inhibition effect on coronavirus and dengue fever virus, and has great potential in the aspect of drug development of the coronavirus and the dengue fever virus [12] 。
Human Respiratory Syncytial Virus (hRSV) is a non-segmented mononegavirale RNA Virus [13,14] . Infection with hRSV can lead to Acute Lower Respiratory Tract Infection (ALRTI) and even death in infants, immunodeficient people, and the elderly [15,16] . Almost all children had been infected with at least one type of hRSV by the age of 2 [17] . The severity of newborn infected with hRSV is more severe than that of older infants, and the newborn is prone to outbreak of infection [18] The ALRTI caused by the drug is one of the main causes of neonatal death [19] . Although the structure and function of hRSV, the infection mechanism and the immune response of infected hosts are researched more widely and deeply, no licensed vaccine is available at present, and the only FDA-licensed therapeutic drug ribavirin has certain therapeutic effect but is not recommended to be used clinically because of the possibility of serious adverse reaction and teratogenicity [20–22] . The only approved monoclonal antibody to palivizumab for passive immunoprophylaxis has a limited range of application due to its high cost and limitation to only high-risk infants [23,24] 。
At present, only a few reports on houttuynia cordata injection for resisting hRSV in vitro [25] No in vivo research report of the houttuynia cordata aromatic water active ingredient (-) -terpinen-4-ol (T-4-ol) against hRSV is available.
At present, an efficient and safe therapeutic drug is urgently needed to be explored to solve the social burden brought by hRSV and relieve the economic pressure.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide application of terpinen-4-ol in preparation of anti-inflammatory drugs or respiratory syncytial virus resistant drugs, so that a novel, efficient and safe treatment drug is provided, social burden caused by hRSV is further solved, and economic pressure is relieved.
The invention is realized by the following steps:
the invention provides an application of terpinen-4-ol in preparing a medicament for resisting human respiratory syncytial virus.
Terpine-4-ol (terpinen-1-ol-4), also known as: 1-methyl-4-isopropyl-1-cyclopentenyl-4-ol, formula C 10 H 18 O, molecular weight 154.249. The inventor finds that the terpine-4-ol has good in-vivo anti-hRSV effect, can relieve lung injury caused by virus infection and reduce the level of lung inflammatory factors, provides experimental basis for developing high-efficiency and safe anti-hRSV medicines, and proves that the terpine-4-ol has good prospect for preparing the anti-hRSV medicines through research of the inventor.
In addition, the terpineol-4-ol can be extracted from houttuynia cordata raw material, has the advantages of easily available source and low cost, can also be obtained by chemical direct synthesis, such as the preparation method provided in the patent CN200910162716.0, and can also be directly obtained on the market.
In a preferred embodiment of the use of the invention, the terpine-4-ol is (-) -terpine-4-ol.
The structural formula of (-) -terpin-4-ol is shown below:
Figure BDA0003859390520000031
the structural formula of (+) -terpinen-4-ol is shown below:
Figure BDA0003859390520000041
the (-) -terpinen-4-ol has better effect on resisting respiratory syncytial virus.
In a preferred embodiment of the invention, the respiratory syncytial virus is human respiratory syncytial virus (hRSV).
The dosage form of the above medicine is tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection, spray or injection.
The invention also provides the application of the terpinen-4-ol in preparing the skin penetration enhancer. The terpine-4-ol is (-) -terpine-4-ol or (+) -terpine-4-ol. Skin penetration enhancers enhance or accelerate the penetration of a drug across the skin.
The invention also provides the application of the terpinen-4-ol in preparing anti-inflammatory drugs. The inventor finds that the terpinen-4-ol has a good effect of inhibiting the level of inflammatory factors and has an anti-inflammatory effect.
In a preferred embodiment of the use of the invention, the anti-inflammatory agent is an anti-pulmonary or anti-mammary inflammatory agent. The terpinen-4-ol provided by the invention can be used for preventing and treating inflammatory diseases. . The inventors have found that it has a particular beneficial effect, especially against inflammation of the lungs.
The lung inflammation is caused by infection with at least one pathogen selected from viruses and bacteria. Especially has better treatment effect on lung infection caused by virus.
In a preferred embodiment of the use of the invention, the virus is selected from the group consisting of human respiratory syncytial virus, novel coronavirus, SARS coronavirus and MERS coronavirus. The (-) -terpinen-4-ol has better effect on resisting human respiratory syncytial virus.
The respiratory syncytial virus is selected, for example, from the group consisting of the human respiratory syncytial virus subtype A or the human respiratory syncytial virus subtype B.
In other embodiments, the virus is further selected from the group consisting of a virus of the gut, such as influenza a, influenza b, influenza a H1N1, influenza a H5N1, human parainfluenza, human metapneumovirus (metapneumovirus), human adenovirus, human enterovirus, and human rhinovirus.
In an alternative embodiment, the bacteria are selected from gram-negative bacteria or gram-positive bacteria.
In an alternative embodiment, the bacteria are selected from the group consisting of mycobacterium tuberculosis, klebsiella pneumoniae (Klebsiella pneumoniae), streptococcus pneumoniae (Streptococcus pneumoniae), moraxella catarrhalis, haemophilus influenzae, legionella, cryptococcus, pseudomonas aeruginosa (Pseudomonas aeruginosa), acinetobacter baumannii (Acinetobacter baumannii), methicillin-resistant staphylococcus aureus.
Bacteria include, but are not limited to: bacteria of the genus Streptococcus (Streptococcus), haemophilus (Haemophilus), moraxella (Moraxella), pseudomonas (Pseudomonas), klebsiella (Klebsiella), pleurotopomonas (Stenotrophoromonas), acinetobacter (Acinetobacter), staphylococcus (Staphylococcus), legionella (Legionella), mycobacterium (Mycobacterium), coxiella (Coxiella), nocardia (Nocardia).
The aforementioned chlamydia is selected, for example, from chlamydia pneumoniae (Chlamydophila pneumoniae) and the Mycoplasma is selected from Mycoplasma pneumoniae (Mycoplasma pneumoniae).
In a preferred embodiment of the use of the invention, the terpine-4-ol is (-) -terpine-4-ol or (+) -terpine-4-ol. The anti-inflammatory effect of the (-) -terpine-4-ol is even better than that of the positive control ribavirin, and the application prospect is good.
The inventor also provides an application of terpinen-4-ol in preparing a medicament with the following application: improve lung tissue damage and/or alveolar structure destruction. Experiments prove that after the terpineol-4-ol is adopted for treatment, a small amount of inflammatory cells infiltrate the lung tissues of the mice around small lung blood vessels and bronchi, but most of alveolar structures are kept intact, and a large amount of alveolar fusion and thrombosis are not generated, while a virus control group shows that lung lesions are serious, a large amount of alveolar fusion damage is generated, a large amount of thrombosis is generated in the lung blood vessels, erythrocyte leakage is obvious, pulmonary interstitial edema is thickened, and a large amount of inflammatory cells infiltrate. The result shows that after the terpine-4-alcohol is treated, the lung injury degree is obviously improved, and the basic structure of the alveoli is maintained.
In a preferred embodiment of the use of the invention, the terpine-4-ol is (-) -terpine-4-ol or (+) -terpine-4-ol.
The invention has the following beneficial effects:
the invention provides a novel substance for resisting respiratory syncytial virus, namely terpinen-4-ol. The terpine-4-ol has good in-vivo efficacy of resisting respiratory syncytial virus, can relieve lung injury caused by virus infection and reduce the level of lung inflammatory factors, provides experimental basis for developing efficient and safe respiratory syncytial virus resisting medicines, has good prospect for preparing respiratory syncytial virus resisting medicines and anti-inflammatory medicines, and can be used for improving lung tissue injury and/or alveolar structure damage.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a graph of infection patterns in mice;
FIG. 2 is a graph showing the statistical results of body weight change and survival rate of mice in the experiment of (-) -terpinen-4-ol anti-lethal GZ08-18 infection; (7.5 mg/kg, 5mg/kg, 2.5mg/kg: different concentrations of T-4-ol treated Group; PBS + GZ08-18 Group: virus control Group;. 7.5mg/kgT-4-ol treated Group is compared with virus control Group;. #. 5mg/kgT-4-ol treated Group is compared with virus control Group;
Figure BDA0003859390520000061
5mg/kg, 2.5mg/kg T-4-ol treatment group compared to 5mg/kgT-4-ol treatment group; * : p<0.05；#：P<0.05；
Figure BDA0003859390520000071
：P<0.05；****：P<0.001)
FIG. 3 shows H & E results of pathological section of lung tissue on day 2 after infection of mice with virulent strain GZ08-18 (PBS + GZ08-18 Group: virus control Group; 7.5mg/kg, 5mg/kg, 2.5mg/kg: T-4-ol treatment Group of different concentrations; 7.5mg/kg Ribavirin: positive control Group; MOCK: blank control Group; A: scale bar = 1000. Mu. M B: scale bar = 50. Mu.m; C: scale bar = 10. Mu.m);
FIG. 4 shows the immunofluorescence-laser confocal results of lung tissues on day 2 after mice are infected with the highly virulent strain GZ 08-18; ( PBS + GZ08-18 Group refers to: a virus control group; 7.5mg/kg, 5mg/kg, 2.5mg/kg: t-4-ol treatment groups with different concentrations; 7.5mg/kg Ribavirin: a positive control group; a: DAPI scale bar =50 μm; b: hRSV F protein (green fluorescence) scale bar =50 μm; c: merge scale bar =50 μm )
FIG. 5 shows the immunofluorescence-confocal laser fluorescence intensity of lung tissue in each treatment group of FIG. 4; (comparison of Ribavirin and each concentration T-4-ol treatment group with a virus control group; #;. Comparison of Ribavirin and each concentration T-4-ol treatment group;. Comparison of A-solidup-5 mg/kg, 2.5mg/kg T-4-ol treatment group with 7.5 mg/kgT-4-ol;)<0.001；****：P<0.0001；#：P<0.05； ###：P<0.001；####：P<0.0001；
Figure BDA0003859390520000072
：P<0.001；
Figure BDA0003859390520000073
：P<0.0001)
FIG. 6 is a statistical chart showing the results of ELISA assay of the expression levels of MIP-1 α, IL-1 β, IL-1 α, IL-6, and TNF- α inflammatory factors in lung homogenate (7.5 mg/kg, 5mg/kg, 2.5mg/kg: T-4-ol treatment groups at different concentrations; PBS + GZ08-18 Group: virus control Group; 7.5mg/kg Ribavirin: positive control Group; T-4-ol and Ribavirin treatment at different concentrations both reduced MIP-1 α, (B) IL-1 β, (C) IL-1 α, (D) IL-6, (E) TNF- α production;. P < 0.05) in lung homogenate.
Detailed Description
Reference will now 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. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment, can be used on another embodiment to yield a still 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 the formulations or unit dosages herein, some are now described. Unless otherwise indicated, the techniques employed or contemplated herein are standard methods. The materials, methods, and examples are illustrative only and not intended to be limiting.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the skill of the art. Such techniques are well explained in the literature, e.g. "molecular cloning: a laboratory Manual (Molecular Cloning: available Manual), second edition (Sambrook et al, 1989); oligonucleotide synthesis (oligonucleotidesin synthesis) (eds. M.j. gait, 1984); animal Cell Culture (Animal Cell Culture), ed.r.i. freshney, 1987; methods in Enzymology (Methods in Enzymology), academic Press, inc. (Academic Press, inc.), handbook of Experimental Immunology (Handbook of Experimental Immunology), D.M.Weir and C.C.Blackwell, gene Transfer Vectors for mammalian Cells (J.M.Miller and M.P.Calos), 1987, methods in Current Molecular Biology (Current Protocols in Molecular Biology), 2015.M.Ausubel, et al, (1987), PCR, polymerase Chain Reaction (PCR) eds: polymerase Chain Reaction (PCR) in polysaccharides, et al, mullis, inc., and Methods in Current Protocols, inc. (Virus J.2015, et al, catalog J.2016, catalog, inc., catalog J.2016, inc., cited in research, inc., 2016 (research, inc., cited in (Clinical research, et al, inc., catalog J.2016, inc., catalog, inc., cited in research).
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Description of the reagents:
(-) -terpin-4-ol (T-4-ol, cas No.:20126-76-5, cat No.:11584, sigma-Aldrich);
ribavirin (Ribavirin, CAS No.:36791-0405, cat No.: R101754, aladdin reagent (Shanghai) Co., ltd.).
Example 1
This example was performed in vivo antiviral experiments to demonstrate the efficacy of (-) -terpine-4-ol against hRSV. GZ08-0 is subtype A hRSV, is separated from Guangzhou children hospital in 2008 and is stored in the laboratory, and GZ08-18 is obtained by passage of GZ08-0 to the 50 th generation in aged BALB/c mice and separation by a plaque purification method.
Referring to FIG. 1, an infection pattern diagram of mice is shown, wherein (-) -terpin-4-ol with different concentrations of 7.5mg/kg, 5mg/kg and 2.5mg/kg, a ribavirin positive control with 7.5mg/kg and a virus control with hRSV high-toxicity strain GZ08-18 are respectively mixed according to a 1:1 system to make the final volume 100 mul, the mixture is placed in an incubator at 37 ℃ to be cultured for 1h, then the mice are challenged with SPF BALB/c female mice for 8 months after being cultured for 3 times every day, the interval is 8 hours every time, the period is 2 days, and the challenged dose is 10 every time 10 TCID 50 。
The day after the completion of virus challenge was defined as day 1 post-infection (D1 post-infection), and the experimental observation endpoint was day 21 post-infection (D21 post-infection). Mice body weight changes and survival were observed and recorded.
The weight change and the survival rate statistical result of the mice are shown in figure 2, figure 2A shows that the weight change of the mice of the T-4-ol treatment groups with different concentrations and the virus control group (n = 7), the weight change of the drug treatment groups shows the rising trend after the weight change is reduced in an observation period taking the 21 st day after infection as an end point, the weight rising of the drug treatment groups with different concentrations is superior to that of the virus control group, the mice of the drug treatment groups with 7.5mg/kg concentration have good state, smooth hair and active spirit, do not have the phenomena of systemic trembling and accelerated heartbeat, do not have the phenomena of tachypnea and dyspnea, have the most obvious rising trend, are recovered to be normal at the observation end point, and have the significant difference (P < 0.05) with the virus control group on the 3 rd day, the 4 th day and the 5 th day; the mice of the drug treatment groups with the concentrations of 5mg/kg and 2.5mg/kg are in good condition, and the body weight of the mice of the drug treatment groups with the concentrations of 5mg/kg is significantly different from that of the virus control group on days 3 and 4 (P < 0.05). However, the virus control mice had poor condition, listlessness, slow movement, prominent hair, accelerated heartbeat, general trembling and poor breathing, and sustained weight loss.
Fig. 2B shows the survival rate statistics, the survival rate of each group was 100% (7 mice in total) for all the 7.5mg/kg drug-treated groups, 42.9% for both the 5mg/kg and 2.5mg/kg drug-treated groups, and 0% for all the virus control groups that died on day 5. Indicating that T-4-ol treatment improves survival and prolongs life span.
Example 2
In the experiment of example 1, lung tissues of mice were collected on day 2 post-infection and stained for hematoxylin-eosin (H & E) staining for pathological changes.
The results of hematoxylin-eosin (H & E) staining of mouse lung tissues show that after treatment with different concentrations of drugs and treatment with the positive control ribavirin, although a small amount of inflammatory cell infiltration occurs around small pulmonary blood vessels and bronchi, most of alveolar structures remain intact, and no large amount of alveolar fusion and thrombosis are observed, while the virus control group shows that lung lesions are severe, a large amount of alveolar fusion damage can be observed, a large amount of thrombosis is observed in pulmonary blood vessels, erythrocyte leakage is obvious, pulmonary interstitial edema is thickened, and a large amount of inflammatory cell infiltration is observed (fig. 3). The results show that the lung injury degree is obviously improved and the basic structure of the alveoli is maintained after the treatment of the medicine.
Example 3
Observing the change of the virus titer of the lung tissues of the mice collected on the 2 nd day after infection by adopting immunofluorescence laser confocal; and detecting the expression level of MIP-1 alpha, IL-1 beta, IL-1 alpha, IL-6 and TNF-alpha inflammatory factors in lung homogenate by an ELISA method.
Lung pathological section immunofluorescence laser confocal reaction shows that the lung hRSV F protein expression (green fluorescence) is remarkably reduced compared with a virus control group after treatment of drugs with different concentrations (P is less than 0.05). Notably, 7.5mg/kg T-4-ol was superior in inhibitory effect on the virus to the positive control ribavirin (FIGS. 4 and 5). The results show that the drugs with different concentrations have the effect of inhibiting the expression of hRSV F protein.
The result of ELISA method for detecting inflammation markers in lung homogenate shows that the expression of MIP-1 alpha, IL-1 beta, IL-1 alpha, IL-6 and TNF-alpha inflammation markers is reduced to a certain extent and is lower than that of positive control ribavirin after treatment by drugs with different concentrations and ribavirin, and the anti-inflammatory effect is optimal when 2.5mg/kg of drugs are used. Notably, 2.5mg/kg drug significantly reduced MIP-1 α, IL-1 β inflammatory factor expression (P < 0.05). Indicating that T-4-ol treatment reduced lung inflammation (FIG. 6). Can be used for developing anti-inflammatory drugs.
In conclusion, the terpine-4-ol provided by the invention has good effects of resisting respiratory syncytial virus and inflammation, can improve the degree of lung injury and maintain the basic structure of alveoli, provides an experimental basis for developing efficient and safe respiratory syncytial virus resisting medicines, and has good prospects in preparing respiratory syncytial virus resisting medicines and anti-inflammation medicines.
Reference documents
[1] The study on the chemical components and pharmacological action of houttuynia cordata has been advanced in An Ping and Zhang Nianfeng of Xiaojuan (J) the modern J.Med.Western J. 2022,31 (11): 5).
[2]WU Z,DENG X,HU Q,et al.Houttuynia cordata Thunb: an ethnopharmacological review[J].Frontiers in Pharmacology,2021, 12:714694.
[3]MULUYE R A,BIAN Y,ALEMU P N, Anti-inflammatory and antimicrobial effects of heat-clearing Chinese herbs:A current review[J].Journal of Traditional and Complementary Medicine,2014,4(2):93-98.
[4]CHOU S C,SU C R,KU Y C,et al.The constituents and their bioactivities of Houttuynia cordata[J].Chemical and Pharmaceutical Bulletin,2009,57(11):1227-1230.
[5]SHINGNAISUI K,DEY T,MANNA P,et al.Therapeutic potentials of Houttuynia cordata Thunb.against inflammation and oxidative stress:A review[J].Journal of Ethnopharmacology,2018, 220:35-43.
[6]XU Y Y,ZHANG Y Y,OU Y Y,et al.Houttuynia cordata Thunb.polysaccharides ameliorates lipopolysaccharide-induced acute lung injury in mice[J].Journal of Ethnopharmacology,2015, 173:81-90.
[7] Liu Fangzhou, shihan, shiyujing, et al, research on pharmacodynamics of anti-influenza virus in houttuynia cordata injection [ J ] pharmaceutical press, 2010, (3): 4.
[8]LEE J H,AHN J,KIM J W,et al.Flavonoids from the aerial parts of Houttuynia cordata attenuate lung inflammation in mice[J].Archives of Pharmacal Research,2015,38(7):1304-1311.
[9]LING L J,LU Y,ZHANG Y Y,et al.Flavonoids from Houttuynia cordata attenuate H1N1-induced acute lung injury in mice via inhibition of influenza virus and Toll-like receptor signalling[J].Phytomedicine,2020,67:153150.
[10]LAU K M,LEE K M,KOON C M,et al. Immunomodulatory and anti-SARS activities of Houttuynia cordata[J].Journal of Ethnopharmacology,2008,118(1):79-85.
[11]BAHADUR GURUNG A,AJMAL ALI M,LEE J,et al. Identification of SARS-CoV-2inhibitors from extracts of Houttuynia cordata Thunb.[J].Saudi Journal of Biological Sciences,2021, 28(12):7517-7527.
[12]CHIOW K H,PHOON M C,PUTTI T,et al.Evaluation of antiviral activities of Houttuynia cordata Thunb.extract,quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection[J].Asian Pacific Journal of Tropical Medicine,2016,9(1): 1-7.
[13]NAM H H,ISON M G.Respiratory syncytial virus infection in adults[J].BMJ,2019:l5021.
[14]BAWAGE S S,TIWARI P M,PILLAI S,et al.Recent advances in diagnosis,prevention,and treatment of human respiratory syncytial virus[J].Advances in Virology,2013,2013: 1-26.
[15]WANG X,LIU Z.Prevention and treatment of viral respiratory infections by traditional Chinese herbs[J].Chinese Medical Journal,2014(7):1344-1350.
[16]RUSSELL C D,UNGER S A,WALTON M,et al.The human immune response to respiratory syncytial virus infection[J]. Clinical Microbiology Reviews,2017,30(2):481-502.
[17]BAKER K A,RYAN M E.RSV infection in infants and young children:What’s new in diagnosis,treatment,and prevention？[J].Postgraduate Medicine,1999,106(7):97-111.
[18] Huang Xiaoxi, du research on different subtypes of neonatal respiratory syncytial virus [ J ] contemporary medicine, 2022,29 (15): 31-35.
[19] Xiwei, wei Gong neonatal respiratory syncytial virus infection and prevention study status [ J ] pediatric journal of pharmacy 2022,28 (3): 56-58.
[20]SHANG Z,TAN S,MA D.Respiratory syncytial virus: from pathogenesis to potential therapeutic strategies[J].International Journal of Biological Sciences,2021,17(14):4073-4091.
[21]COULTAS J A,SMYTH R,OPENSHAW P J.Respiratory syncytial virus(RSV):a scourge from infancy to old age[J].Thorax, 2019,74(10):986-993.
[22]MAZUR N I,MARTINóN-TORRES F,BARALDI E,et al.Lower respiratory tract infection caused by respiratory syncytial virus:current management and new therapeutics[J].The Lancet Respiratory Medicine,2015,3(11):888-900.
[23]GAREGNANI L,ROSON RODRIGUEZ P,ESCOBAR LIQUITAY C M,et al.Palivizumab for preventing respiratory syncytial virus(RSV)infection in children[J].Cochrane Database of Systematic Reviews,2020.
[24]DOMACHOWSKE J B,ANDERSON E J,GOLDSTEIN M.The future of respiratory syncytial virus disease prevention and treatment[J].Infectious Diseases and Therapy,2021,10(S1):47-60.
[25] Zhao Yugong, shen Kunling, liu Yayi in vitro experimental study of houttuynia cordata injection for the treatment of respiratory syncytial virus infection [ J ] proceedings of the university of capital medical, 2005, 26 (005): 571-573.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. 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 (10)

1. Application of terpinen-4-ol in preparing medicine for treating respiratory syncytial virus is disclosed.
2. Use according to claim 1, characterized in that the terpine-4-ol is (-) -terpine-4-ol.
3. The use according to claim 1, wherein the respiratory syncytial virus is a human respiratory syncytial virus.
4. Application of terpinen-4-ol in preparing skin penetration enhancer is provided.
5. Application of terpinen-4-ol in preparing anti-inflammatory medicine is disclosed.
6. The use according to claim 5, wherein the anti-inflammatory drug is an anti-pulmonary or anti-mammary inflammatory drug;
preferably, the lung inflammation is caused by infection with at least one pathogen selected from the group consisting of viruses and bacteria.
7. The use according to claim 6, wherein the virus is selected from the group consisting of respiratory syncytial virus, novel coronavirus, SARS virus and MERS coronavirus;
preferably, the bacteria are selected from gram-negative bacteria or gram-positive bacteria;
preferably, the bacteria are selected from the group consisting of mycobacterium tuberculosis, klebsiella pneumoniae (Klebsiella pneumoniae), streptococcus pneumoniae (Streptococcus pneumoniae), moraxella catarrhalis, haemophilus influenzae, legionella, cryptococcus, pseudomonas aeruginosa (Pseudomonas aeruginosa), acinetobacter baumannii (Acinetobacter baumannii), methicillin-resistant staphylococcus aureus.
8. Use according to claim 5, characterized in that the terpine-4-ol is (-) -terpine-4-ol or (+) -terpine-4-ol.
9. The application of the terpinen-4-ol in preparing the medicines with the following applications is characterized in that the application comprises the following steps: improve lung tissue damage and/or alveolar structure destruction.
10. The use of claim 9 wherein the terpine-4-ol is (-) -terpine-4-ol or (+) -terpine-4-ol.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020018757A1 (en) * 2000-06-30 2002-02-14 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Cosmetic skin care compositions and containing gum mastic
WO2012014244A1 (en) * 2010-07-26 2012-02-02 Istituto Superiore Di Sanita' USE OF TERPINEN-4-ol AS ANTIMICROBIAL AGENT AGAINST BACTERIA OF LEGIONELLA GENUS
CN102762218A (en) * 2009-09-29 2012-10-31 雷斯蒙农业合作社联盟 Compositions of botanical extracts and their use
CN112075459A (en) * 2020-07-03 2020-12-15 张卓 Antiviral and antibacterial respiratory tract compound essential oil and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020018757A1 (en) * 2000-06-30 2002-02-14 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Cosmetic skin care compositions and containing gum mastic
CN102762218A (en) * 2009-09-29 2012-10-31 雷斯蒙农业合作社联盟 Compositions of botanical extracts and their use
WO2012014244A1 (en) * 2010-07-26 2012-02-02 Istituto Superiore Di Sanita' USE OF TERPINEN-4-ol AS ANTIMICROBIAL AGENT AGAINST BACTERIA OF LEGIONELLA GENUS
CN112075459A (en) * 2020-07-03 2020-12-15 张卓 Antiviral and antibacterial respiratory tract compound essential oil and preparation method thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
VALERIA CAGNO ET AL.，: "In vitro anti-herpes simplex virus-2 activity of Salvia desoleana Atzei & V. Picci essential oil", 《PLOS ONE》, vol. 12, no. 2, pages 1 - 12 *
庞雪威等: "植物性食品原料中单萜类化合物形成机理及生物活性综述", 《中国酿造》, vol. 35, no. 6, pages 24 - 29 *
蔡旭玲;黄晓晖;周俊立;邹志辉;陈思东;: "甘草醇沉淀物有效部位对RSV作用的体外实验研究", 中国热带医学, vol. 13, no. 07, pages 793 - 796 *

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