Application of antitussive agent in preparation of anti-influenza virus drugs

Abstract

The invention belongs to the field of medicines, and particularly relates to application of a cough relieving agent in preparation of an anti-influenza virus medicine. Through the synergistic effects of resisting viruses, resisting inflammation, regulating mucus secretion and inhibiting nerve sensitization, the antitussive agent relieves influenza symptoms and promotes recovery from the source, has the advantages of being stable in curative effect, small in toxic and side effect, not prone to generating drug resistance, not capable of promoting virus variation and the like, is wider in application stage and application crowd, and can intervene in the early stage of influenza infection. Due to the fact that the antitussive agent can treat influenza caused by exogenous cold and influenza viruses, the antitussive agent can be used in time to relieve symptoms when cough, excessive phlegm and other symptoms are found in the early stage of a patient, the antitussive agent can relieve the exogenous cold for a non-influenza patient, and the antitussive agent can prevent influenza from being converted into severe influenza from mild influenza for an influenza patient. And the reduction of the treatment effect caused by definite diagnosis delay and oseltamivir treatment delay is also avoided.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medicine, and particularly relates to application of Zhi-Ke-Bao in preparation of anti-influenza virus drugs. BACKGROUND

[0002] Influenza is an acute respiratory infection caused by influenza virus, and has the characteristics of strong infectivity and fast transmission. Influenza virus is a ribonucleic acid (RNA) virus, and is divided into three types of A, B and C, and the first two types are mainly pathogenic. Influenza A virus can be divided into many subtypes according to the structure of surface proteins hemagglutinin and neuraminidase and their genetic characteristics (B and C types have no subtypes), and 16 subtypes (H1-16) of hemagglutinin and 9 subtypes (N1-9) of neuraminidase have been found so far, and many subtypes are formed by different combinations of the two, such as H1N1, H3N2, H5N1, etc. Influenza A viruses mainly of H1N1 and H3N2 and influenza B viruses cause seasonal influenza, which causes heavy burden to social economy and human health. According to statistics, influenza epidemic every year can cause three to five million serious cases, and cause 300,000-500,000 deaths.

[0003] After human infection with influenza A virus, early symptoms are similar to common influenza, including fever, cough, sore throat, body aches, headache, chills and fatigue, and some patients also have diarrhea or vomiting, muscle pain or fatigue, red eyes, etc. In addition, influenza can also cause a series of complications, such as pneumonia, bronchitis, sinus infection and ear infection, etc.

[0004] In terms of prevention of influenza, vaccine is still the main means at present. However, there are certain limitations in vaccination. On the one hand, the vaccinated population is selective, and not everyone can be vaccinated; on the other hand, the protection rate of influenza virus vaccine is limited, and the protection time is relatively short, usually only 3-6 months. Therefore, in the prevention and control of influenza A H1N1 influenza pandemic, antiviral drugs become the main choice.

[0005] At present, oseltamivir (oseltamivir), that is, Tamiflu, is commonly used to treat influenza A. Oseltamivir is a neuraminidase inhibitor and has specific inhibitory effect on influenza virus entering cells. However, there are many problems in the use of oseltamivir. First, a series of side reactions occur in some patients after taking oseltamivir, including vomiting, nausea, insomnia, headache, abdominal pain, diarrhea, dizziness, fatigue, nasal congestion, sore throat and cough. Second, oseltamivir is converted into an active metabolite in the liver and intestine in the body to exert the inhibitory effect on neuraminidase. If the liver and intestinal organ function of the patient is abnormal, the drug efficacy will be affected. In addition, oseltamivir should be used with caution in patients with renal dysfunction. In addition, with the wide application of oseltamivir, oseltamivir-resistant influenza A viruses carrying H275Y NA mutations have appeared worldwide. In view of the above situation, WHO does not recommend the use of oseltamivir for the treatment of mild influenza A H1N1 patients in order to prevent the increase of drug-resistant strains caused by the overuse of oseltamivir. Since the early symptoms of influenza are similar to those of common influenza, and considering the cautious use of oseltamivir, many patients have the problems of delayed diagnosis and delayed oseltamivir treatment, which further reduces the treatment effect.

[0006] Therefore, it has become an important issue to develop a low-toxicity, high-efficiency, safe, non-drug-resistant or low-drug-resistant antiviral drug for early intervention in influenza infection, to avoid the transformation from mild to severe or critical illness, and to reduce the risk of adverse outcomes. SUMMARY

[0007] Based on this, the purpose of the present application is to overcome the defects or deficiencies of the prior art, and to provide a low-toxicity, high-efficiency, safe, non-drug-resistant or low-drug-resistant antiviral drug, which can be used for early intervention in influenza infection, to avoid the transformation from mild to severe or critical illness, and to reduce the risk of adverse outcomes.

[0008] The present application is realized by the following technical scheme: application of Zhikebao in preparation of an anti-influenza virus drug Compared with the prior art, the Zhikebao provided by the present application can relieve the symptoms of influenza and promote recovery from the root by the synergistic effect of antiviral, anti-inflammatory, mucus secretion regulation and inhibition of nerve sensitization, and has the advantages of stable curative effect, small toxic and side effects, non-drug resistance and non-virus variation, etc. It is suitable for a wider stage and a wider population and can be used for early intervention in influenza infection. Since Zhikebao can treat influenza caused by exogenous wind-cold and influenza virus, it can be used in time to relieve symptoms when the patient is found to have early symptoms such as cough and excessive sputum. For non-influenza patients, Zhikebao can relieve exogenous wind-cold. For influenza patients, Zhikebao can avoid the transformation from mild to severe influenza, and also avoid the decline of treatment effect caused by delayed diagnosis and delayed oseltamivir treatment.

[0009] In one embodiment, the influenza virus comprises an H1N1 influenza virus.

[0010] In one embodiment, the drug is a drug that inhibits replication of the influenza virus.

[0011] In one embodiment, the drug is a drug that inhibits infection of the influenza virus.

[0012] In one embodiment, the drug is a drug that inhibits lung tissue inflammation, lung pathology, and lung index elevation caused by infection of the influenza virus.

[0013] In one embodiment, the drug is a drug that inhibits vagus nerve tissue inflammation and / or bronchial inflammation caused by infection of the influenza virus.

[0014] In one embodiment, the drug is a drug that inhibits cough sensitivity elevation caused by infection of the influenza virus.

[0015] In one embodiment, the inhibiting infection of the influenza virus comprises inhibiting expression of proinflammatory cytokines IL-6 and TNF-α; and / or, inhibiting expression of chemokine CXCL-10; and / or, inhibiting expression of mucin MUC5AC; and / or, inhibiting expression of SP and NGF.

[0016] In one embodiment, the pharmaceutical composition is formulated into a pharmaceutical preparation with a pharmaceutically acceptable carrier or excipient.

[0017] In one embodiment, the pharmaceutical preparation is a decoction, a powder, a tablet, a capsule, a pill, an oral liquid, a granule, an injection, or a suppository.

[0018] For better understanding and implementation, the present application is described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 ZKB's inhibitory effect on lung index elevation caused by H1N1 infection.

[0020] Figure 2 ZKB's improvement effect on cough sensitivity elevation caused by H1N1 infection.

[0021] Figure 3 ZKB's inhibitory effect on H1N1 proliferation in lung tissue of mice.

[0022] Figure 4 ZKB's inhibitory effect on cytokine expression in lung tissue caused by H1N1 infection.

[0023] Figure 5 ZKB's inhibitory effect on cytokine expression in vagus nerve caused by H1N1 infection.

[0024] Figure 6 Improvement of lung pathological changes caused by ZKB to H1N1 infected mice. DETAILED DESCRIPTION

[0025] Compared with western medicine such as oseltamivir, traditional Chinese medicine is made by combining various Chinese medicinal materials, and has the advantages of stable curative effect, less side effects, and less resistance to drugs, and does not promote virus mutation, but its purchase and taking are relatively troublesome. Chinese patent medicine is a kind of traditional Chinese medicine product made of Chinese medicinal materials according to the prescribed prescription and preparation process. Compared with traditional Chinese medicine, it is more convenient to take, has a shorter treatment course, and is cheaper, and has the potential to become a low-toxicity, high-efficiency, safe, non-resistant or low-resistant antiviral drug. However, at present, many Chinese patent medicines claim to have antiviral effect, but they are not directed against influenza virus, and the antiviral mechanism is not clear. At the same time, many Chinese medicine prescriptions for treating exogenous wind-cold (i.e. cold in western medicine) do not have a direct effect on influenza virus, that is, not all Chinese medicine prescriptions for treating cold have a clear effect on inhibiting influenza virus. Therefore, the present scheme focuses on exploring the effect and mechanism of existing Chinese patent medicines against influenza virus, in order to screen out Chinese patent medicines with low toxicity and high efficiency and with the effect of resisting influenza virus.

[0026] Most patients infected with influenza virus will have cough symptoms, and their early symptoms are similar to those of exogenous wind-cold. However, compared with patients who only show influenza-like symptoms but are not infected with influenza virus, influenza patients are more likely to have cough. In addition, oseltamivir, as the most commonly used anti-influenza virus drug, has been proven to be able to shorten the duration of cough. Based on this, the present application considers screening Chinese patent medicines with good cough-relieving effect from Chinese patent medicines that can treat exogenous wind-cold, such as Dongguan Cough-Relieving Granules, Cough-Relieving and Asthma-Relieving Capsules, and Cough-Relieving Treasure, etc., for further research. It is found that Cough-Relieving Treasure not only shortens the duration of cough, but also significantly inhibits the replication of influenza virus and the complications such as pneumonia and bronchitis caused by influenza virus infection.

[0027] The principle of Cough-Relieving Treasure in relieving influenza virus infection is described in detail below through specific examples and drawings.

[0028] 1. Drug and its preparation Cough-Relieving Treasure (ZKB) is provided by Teiyao Pharmaceutical Group Co., Ltd. ASM is purchased from First Three Gorges Pharmaceutical (Shanghai) Co., Ltd. Oseltamivir (OSE) is purchased from Shanghai Roche Pharmaceutical Co., Ltd. Among them, ASM is a strong antitussive drug, and oseltamivir is an antiviral drug.

[0029] Cough-Relieving Treasure, oseltamivir and ASM are all diluted with PBS to obtain a series of doses for in vivo experiments.

[0030] 2. Establishment of influenza mouse model and intervention with Zhibo Bao To study the protective effect of Zhibo Bao on cough and lung injury caused by H1N1 infection in mice, the mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were randomly divided into normal group (Sham), placebo group (Placebo), oseltamivir group (80 mg / kg / d, OSE-80), asmetrexate group (18.4 mg / kg / d, ASM-18.4) and high, medium and low dose groups of Zhibo Bao (ZKB-380, ZKB-190 and ZKB-95 mg / kg / d).

[0031] After the mice were anesthetized with isoflurane, the mice in the placebo group, the OSE group, the ASM group and the different dose ZKB groups were infected with 50 μL of influenza A virus A / Puerto Rico / 8 / 34 (PR8, H1N1) containing 1.5 LD50 by nasal instillation, and the mice in the Sham group were infected with the same volume of PBS by nasal instillation. The body weight of the mice was recorded every day. The ZKB group, the OSE group and the ASM group received corresponding drug gavage treatment 2h after infection, the normal group was gavaged with the same volume of PBS, the placebo group was gavaged with the same volume of placebo, once a day for 5 consecutive days.

[0032] On the 6th day, the cough frequency was determined. Then the mice were sacrificed, and the lung tissue, vagus nerve tissue and the like were collected for subsequent study.

[0033] 3. Cough frequency determination The whole body plethysmography system (Shanghai Ta Wang Intelligent Technology Co., Ltd.) was used to detect the cough frequency of the mice. The mice were placed in a 500 mL transparent closed glass jar, and 25% ammonia water was atomized for 45 seconds to induce cough, and the cough frequency within 3 minutes was recorded.

[0034] Referring to Figure 2 and Table 1, the significant increase in cough sensitivity of mice caused by H1N1 infection (p<0.001, Sham vs Placebo). OSE (p<0.01), ASM (p<0.01) and ZKB (p<0.05) all reduced the cough frequency of infected mice, and had obvious antitussive effect.

[0035] Table 1 Improvement of ZKB on the increase of cough sensitivity caused by H1N1 infection (X±SD, n=6)

[0036] Note: compared with the placebo group, *, p<0.05; **, p<0.01; ***, p<0.001.

[0037] 4. Lung index determination The lung was weighed and the lung index (lung weight / body weight x 100) was calculated.

[0038] Referring to Table 2 and Figure 2 , the lung index of H1N1 infected mice was significantly increased (p<0.001) (Sham vs Placebo). Three doses of ZKB (p<0.05, 0.001), OSE (p<0.001) and ASM (p<0.05) can significantly inhibit the increase of lung index of infected mice (ZKB, OSE, ASM vs Placebo), among which the effect of medium and high doses of ZKB is close to OSE, and is significantly better than ASM.

[0039] Table 2 Inhibition of ZKB on the increase of lung index caused by H1N1 infection (X±SD, n=6)

[0040] Note: compared with placebo group, *, p<0.05; **, p<0.01; ***, p<0.001.

[0041] 5. Virus titer determination After the lung tissue was weighed, half of the lung tissue was homogenized to determine the virus titer and cytokine expression.

[0042] The TCID50 of lung homogenate supernatant was detected by CPE method. The method is as follows: the sample to be tested is diluted by 10 times gradient in DMEM medium, from 10 -1 to 10 -8 , then inoculated into monolayer MDCK (dog kidney epithelial) cells (purchased from ATCC) in 96-well plates, and placed in a CO2 incubator at 37℃ for 48 hours. The CPE was recorded under a microscope, and the TCID50 value of the virus was calculated according to the Reed-Muench method.

[0043] Table 3 Inhibition of ZKB on the proliferation of H1N1 in lung tissue of mice (X±SD, n=6)

[0044] Note: compared with placebo group, *, p<0.05; ***, p<0.001.

[0045] Referring to Table 3 and Figure 3 , three doses of ZKB and OSE can significantly inhibit the proliferation of virus in lung tissue (ZKB, OSE vs Placebo) (p<0.001) (ZKB, OSE vs Placebo). Figure 3( Table 4 ), in contrast, ASM showed a poor inhibitory effect on viral proliferation, which indicates that ASM mainly treats symptoms such as cough, and does not directly inhibit influenza viruses that cause cough, i.e., an antitussive does not necessarily have a superior antiviral effect.

[0046] 6. Cytokine assay of lung tissue and vagus nerve tissue After the virus enters the respiratory tract, its surface protein binds to the receptor on the surface of the respiratory epithelial cells, invades the cells, and replicates in large quantities in the cells, thereby destroying the integrity of the respiratory mucosa, causing cells to fall off, exposing the underlying nerve endings, leading to increased nerve sensitivity. At the same time, the respiratory tract cilia are destroyed, causing secretions and pathogens to be retained, stimulating the nerve endings and triggering cough.

[0047] Secondly, viral infection can trigger inflammation, activate the immune system to release various inflammatory mediators, which directly stimulate nerve endings to trigger cough. Immune cells such as macrophages also gather in the infected part, exacerbate the inflammatory response by phagocytizing viruses or releasing cytokines (such as IL-6, TNF-a), and indirectly stimulate cough. In addition, pro-inflammatory cytokines can enhance the cough reflex through central sensitization mechanisms. In addition, the immune response can cause increased secretion of respiratory gland, forming mucus, which stimulates the respiratory mucosa and triggers cough to expel foreign matter.

[0048] An important pathophysiological feature of lung injury includes mucus hypersecretion. Mucin in mucus secretions in mice is mainly MUC5AC, which is one of the main components of airway and lung tissue mucus, and its expression is up-regulated in inflammatory response, which is closely related to mucus hypersecretion, inflammation, and cough. In acute lung injury, MUC5AC enhances lung inflammation and promotes the invasion of inflammatory cells. MUC5AC indirectly promotes cough by enhancing inflammation and mucus barrier function.

[0049] In addition, nerve mediators such as nerve growth factor (NGF) and substance P (SP) also play an important role in the neuropathological mechanism of cough. NGF can enhance cough reflex and airway sensitivity to stimuli by activating TrkA and transient receptors (such as TRPV1) in the airway. SP is a sensory nerve peptide, and its level is elevated in the nasal secretions of patients with cough, which is related to neurochemical abnormalities.

[0050] In order to study the anti-tussive principle of Zhibo, the expression levels of the above cytokines were determined in the present example: the lung tissue and vagus nerve tissue of the mice were taken into EP tubes, Trizol and magnetic beads were added for homogenate lysis. 200 μL chloroform was added to each tube, and after oscillation and mixing, it was left to stand at room temperature for 10 minutes. After centrifugation, the upper aqueous phase was taken into a new EP tube, 500 μL of isopropyl alcohol was added to the new EP tube, mixed, and left to stand at room temperature for 10 minutes. After centrifugation, the supernatant was discarded and the lower precipitate was retained. 1 mL of anhydrous ethanol was added to wash the precipitate, which was repeated twice. The lower precipitate was retained after the last time, and the EP tube was inverted and air-dried at room temperature for 10 minutes. 20 μL of enzyme-free water was added to each tube to resuspend the precipitate, and total RNA was extracted.

[0051] The reverse transcription kit (Novozyme, R323-01) was used for reverse transcription to obtain cDNA, and the program was set according to the kit instructions: 37°C, 15 min; 85°C, 5 s.

[0052] SYBR dye method fluorescence quantitative PCR amplification was performed using the qPCR kit (Novozyme, Q711-02), and the primer sequences are shown in Table 1. The amplification program is: 95°C, 30 s, pre-denaturation; 95°C, 5 s, melting; 60°C, 30 s, annealing. Dissociation curve: 95°C, 15 s; 60°C, 60 s; 95°C, 15 s; cycle number: 40.

[0053] The corresponding mRNA expression amount was calculated by 2 ΔΔCT Calculation, set GAPDH group as internal reference. The primers of each inflammatory factor are shown in Table 4.

[0054] Table 4 Inflammatory factor primer sequences of mouse lung tissue and vagus nerve tissue

[0055] Referring to Table 5, in the lung tissue, ZKB effectively inhibited the expression of TNF-α (380 mg / kg / d, p<0.001), MUC5AC (95, 190, 380 mg / kg / d, p<0.001), NGF (95, 380 mg / kg / d, p<0.05) and SP (95, 190 mg / kg / d, p<0.001) (Placebo vs ZKB) Figure 4 A- Figure 4 D). OSE effectively inhibited the expression of TNF-α (p<0.001) and MUC5AC (p<0.001) (Placebo vs OSE) Figure 4 A, Figure 4 B). ASM effectively inhibited the expression of MUC5AC (p<0.001), NGF (p<0.05) and SP (p<0.01) (Placebo vs ASM)Figure 4 B- Figure 4 D)。

[0056] Table 5 Inhibitory effect of ZKB on cytokine expression in lung tissue caused by H1N1 infection (X±SD, n=6)

[0057] Note: compared with placebo group, *, p<0.05; **, p<0.01; ***, p<0.001.

[0058] Referring to Table 6, in the vagus nerve, three doses of ZKB were effective in inhibiting the expression of IL-6 and NGF (ZKB vs Placebo, p<0.05, 0.001) Figure 5 A, Figure 5 C), high and medium doses of ZKB had a significant inhibitory effect on CXCL-10 / IP-10 (ZKB vs Placebo, p<0.05) Figure 5 B).

[0059] Table 6 Inhibitory effect of ZKB on cytokine expression in vagus nerve caused by H1N1 infection (X±SD, n=6)

[0060] Note: compared with placebo group, *, p<0.05; **, p<0.01; ***, p<0.001.

[0061] In combination with the results of lung tissue and vagus nerve, Amsin mainly achieves the effect of relieving cough by expectorating and reducing nerve sensitivity, and its anti-inflammatory effect is poor. Oseltamivir mainly reduces the stimulating source of cough by inhibiting the expression of pro-inflammatory factors and airway mucin, thereby achieving the effect of relieving cough. In contrast, the cough-relieving treasure of the present embodiment has multiple action targets, and achieves the effect of relieving cough through the synergistic effect of inhibiting the expression of inflammatory factors, reducing the content of mucus, and reducing nerve sensitivity.

[0062] 7. Preparation of pathological sections (1) Fixation: place the lung tissue of the mouse in the tissue fixing solution containing 4% paraformaldehyde for 24 hours.

[0063] (2) Dehydration: after fixation, wash with running water, and then place in an automatic dehydration machine for dehydration overnight.

[0064] (3) Embedding: after dehydration, place the tissue in 60°C paraffin for immersion, and then take out the tissue and place it in a pre-cooled embedding mold. After cooling, trim the wax block type to be neat and flat.

[0065] (4) Slicing: Adjust the angle of the knife holder of the paraffin slicer, select the thickness of the slice as 3 μm, install the wax block to the sample holder, shake the slicing handle at a constant speed to continuously slice, carefully take the slice and put it into the slice spreader to spread, then use the glass slide to take the slice and put it into the oven at 60 °C to dry for 1 hour, and firmly adhere to the glass slide.

[0066] (5) HE staining: first, put the dried slice into xylene for deparaffinization. Then, gradually hydrate the slice with 100%, 95%, 90%, 80%, and 70% alcohol, respectively, for 5 minutes each time. Soak the slice in hematoxylin dye for 5 minutes to stain the cell nucleus. Slightly differentiate with 1% hydrochloric acid alcohol solution until the cell nucleus appears blue. Soak the slice in eosin dye for 3 minutes to stain the cytoplasm and extracellular matrix. Dehydrate the stained slice with 100%, 95%, 90%, 80%, and 70% alcohol, respectively, for 5 minutes each time. Put the slice into xylene for transparency treatment, repeat twice, 5 minutes each time. Then, drop neutral gum sealing solution on the slice, and seal with a cover glass.

[0067] (6) Result analysis: the bronchial and lung tissue structure of the normal group of mice (Sham) is normal, and no obvious pathological changes are observed Figure 6 A). The H1N1 infected mice (Placebo) have obvious interstitial pneumonia, including bronchial epithelial shedding and karyopyknosis, lymphocytes and a small amount of macrophage infiltration in the bronchial lumen, alveolar epithelial hyperplasia, and a large amount of lymphocyte infiltration in the lung interstitium Figure 6 B).

[0068] The ASM slightly improves the interstitial pneumonia of the infected mice Figure 6 C). The lung interstitium of the OSE group and the high and medium dose ZKB groups (380 mg / kg / d, 190 mg / kg / d) is significantly improved, the inflammation of the lung interstitium and the bronchial periphery is also significantly improved, and the inflammatory cell infiltration in the bronchial lumen is also improved Figure 6 D, Figure 6 E, Figure 6 F). The low dose ZKB (95 mg / kg / d) has no significant improvement on the lung pathological changes of the infected mice Figure 6 G).

[0069] In summary, the Zhi Fei Bao provided by the application can relieve the symptoms of influenza and promote recovery from the root by the synergistic effect of antiviral, anti-inflammatory, mucus secretion regulation, and inhibition of nerve sensitization.

[0070] In terms of antiviral, Zhi Fei Bao significantly inhibits the replication of H1N1 virus in lung tissue, and reduces the viral load from the source.

[0071] In terms of anti-inflammatory and reducing lung injury, Cough Relief can significantly reduce the expression of TNF-α in lung tissue, IL-6 and CXCL-10 in vagus nerve, thereby reducing the inflammatory state of lung tissue and vagus nerve. Moreover, Cough Relief can significantly improve viral-induced interstitial pneumonia, reduce inflammatory cell infiltration and tissue hyperplasia in bronchus and lung interstitium. In addition, Cough Relief can significantly reduce the increase of lung index caused by infection, indicating that it can effectively relieve pulmonary inflammatory edema and consolidation.

[0072] In terms of regulating mucus secretion, Cough Relief can significantly reduce the gene expression of mucin MUC5AC, thereby reducing the generation of mucus from the source, reducing airway obstruction and irritation, and thus reducing the symptoms of cough.

[0073] In terms of inhibiting nerve sensitization, Cough Relief can effectively inhibit the expression of key factors of nerve sensitization, NGF (nerve growth factor) and SP (substance P) in lung tissue and vagus nerve, thereby reducing the sensitivity of cough reflex and alleviating the symptoms of cough.

[0074] Compared with pure antitussive drugs (such as Asmetin ASM), Cough Relief not only has the effect of relieving cough and expectorant, but also has direct antiviral ability and systemic anti-inflammatory effect. It directly targets the cause (virus) and symptoms (inflammation, cough sensitivity, etc.) rather than just suppressing the symptoms. Therefore, it is superior to ASM in improving lung tissue pathological injury, reducing lung index and other indicators.

[0075] Compared with pure antiviral drugs (such as oseltamivir OSE), Cough Relief can directly target the prominent symptom of cough while effectively resisting viruses, and through the inhibition of key pathways such as NGF and SP, it can more quickly and directly alleviate the symptoms of cough and other symptoms in patients.

[0076] In addition, compared with Asmetin and oseltamivir, Cough Relief has the advantages of stable curative effect, less side effects, less resistance to drug resistance, and no promotion of virus mutation. This makes Cough Relief more widely applicable to a wider range of people and can intervene in the early stages of influenza infection. Since Cough Relief can treat both exogenous wind-cold and influenza virus-induced influenza, it can be used to relieve symptoms such as cough and excessive sputum in patients in the early stages. For non-influenza patients, Cough Relief can effectively relieve discomfort caused by exogenous wind-cold; for influenza patients, Cough Relief can not only prevent influenza from becoming more severe, but also prevent the decline in treatment effect caused by delayed diagnosis and delayed treatment with oseltamivir.

[0077] The above examples only express several embodiments of the present application, and the description is more specific and detailed, but it should not be understood as limiting the scope of the patent. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application.

Claims

1. Application of Zhikebao in the preparation of anti-influenza virus drugs.

2. The application according to claim 1, characterized in that, The influenza viruses mentioned include the H1N1 influenza A virus.

3. The application according to claim 2, characterized in that, The drug in question is a drug that inhibits the replication of the influenza virus.

4. The application according to claim 2, characterized in that, The drug in question is a drug that inhibits influenza virus infection.

5. The application according to claim 4, characterized in that, The drug is used to inhibit lung tissue inflammation, lung pathological changes, and elevated lung index caused by influenza virus infection.

6. The application according to claim 4, characterized in that, The drug is an agent that inhibits inflammation of the vagus nerve tissue and / or bronchus caused by influenza virus infection.

7. The application according to claim 4, characterized in that, The drug is used to suppress increased cough sensitivity caused by influenza virus infection.

8. The application according to claim 4, characterized in that, The inhibition of influenza virus infection includes: inhibiting the expression of pro-inflammatory cytokines IL-6 and TNF-α; and / or, inhibiting the expression of chemokine CXCL-10; and / or, inhibiting the expression of mucin MUC5AC; and / or, inhibiting the expression of SP and NGF.

9. The application according to any one of claims 1-8, characterized in that, The pharmaceutical composition is formulated into a pharmaceutical preparation with a pharmaceutically acceptable carrier or excipient.

10. The application according to claim 9, characterized in that, The pharmaceutical preparations are decoctions, powders, tablets, capsules, pills, oral liquids, granules, injections, or suppositories.

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