2019year12Months, covid-19（coronavirus disease 2019，COVID-19）It has spread rapidly in China, and as of2020year2month16day24According to31Provinces (autonomous regions and municipalities directly under the central government) and the Xinjiang production and Construction Corps reported a total of confirmed cases70 548Cases, a total of confirmed cases were notified from Hong Kong, Macao and Taiwan87example^[1].2020year2month11day, the International Committee on classification of viruses officially named the novel coronavirus as severe acute respiratory syndrome coronavirus2（severe acute respiratory syndromecoronavirus 2，SARS-CoV-2）COVID-19At present, there is no clinically confirmed specific drug for the virusCOVID-19The diagnosis and treatment plan is still being optimized and improved in combination with the treatment of the disease.

Based on the current epidemiological survey,COVID-19The clinical symptoms of the patients were mainly fever, fatigue and dry cough, and a few patients were accompanied by nasal congestion, runny nose, sore throat and diarrhea. About half of the patients were in1Weeks later, dyspnea and/Or hypooxia, which can rapidly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis that is difficult to correct, blood viscosity rise, and bleeding and coagulation dysfunction. Integrated traditional Chinese and Western medicine treatmentCOVID-19Clinical experience shows that traditional Chinese medicine has significant effects in improving disease symptoms, controlling disease progression, improving patients' mood, and promoting the rehabilitation process, which can play a full course of treatment and all-round role^[2]。

The National Health Commission issued5According to the progress of the disease course, the new version of the diagnosis and treatment plan for covid-19 pneumonia (Trial) (hereinafter referred to as the diagnosis and treatment plan) willCOVID-19The treatment period was divided into cold dampness stagnation of lung, lung closure by epidemic virus, internal closure and external detachment, lung and spleen qi deficiency4Type. Diagnosis and treatment plan No4edition^[3]And P5edition^[4]In the part of traditional Chinese medicine treatment, Xiyanping injection (raw material: andrographolide total sulfonate) is recommended to be used in the middle of the clinical treatment period (epidemic toxin closes the lung). At the same time, in Shaanxi Provincial Health Commission^[5](mild disease: heat toxin attacking the lung and external cold and internal heat; severe disease: heat toxin obstructing the lung), Shanghai Municipal Health Commission^[6](heat poison closes the lung), Ningxia Hui Autonomous Region Administration of traditional Chinese Medicine^[7](mid term: closed lung with epidemic virus) and Henan Provincial Health Commission^[8](middle stage: lung closure due to heat toxin and large intestine dryness) and Wuhan Tongji Hospital^[9](Critical/It is also recommended in the diagnosis and treatment plans or guidelines issued by the Ministry of health of the people's Republic of China.

This article reviews the literature of andrographolide and its derivatives, the raw material of Xiyanping injection, and summarizes its relationship with anti -COVID-19Related pharmacological effects and clinical applications, and analyze its treatmentCOVID-19And speculate the possible mechanism of action, in order to provide reference for clinical application.

1  Andrographolide preparations

Andrographis paniculataGraphis Paniculata (Burm. f) NessBitter in taste, cold in nature, homing to the heart, lung, large intestine, bladder meridian, good at clearing heat and detoxification, cooling blood, detumescence, dryness and dampness, mainly treating exogenous wind heat, early onset of febrile disease, lung heat, cough and asthma, etc^[10]Andrographolide is a diterpene lactone extracted from the whole herb or leaves of Andrographis paniculata, which is one of the main effective components of Andrographis paniculata.

Andrographolide and its derivatives are the main raw materials of andrographolide preparations. The commonly used clinical dosage forms include oral solid preparations and injections. Andrographolide is the raw material of oral solid preparations, and the dosage forms include pills, tablets, capsules, etc. The raw material of the injection is andrographolide derivatives, and the main products are Xiyanping injection, Lianbizhi injection, andrographolide injection and Yanhuning injection.

Andrographolide preparations are mainly effective in clearing heat and detoxification, antibacterial and anti-inflammatory, cough and dysentery^[11](table1）. At present, andrographolide preparations are widely used in the treatment of inflammation related diseases in China and other Asian countries, such as respiratory tract infection, viral pneumonia, bacterial dysentery, etc. 2015Included in the annual edition, and entered into the guidelines for the diagnosis and treatment of hand, foot and mouth disease, type AH1N1There are many clinical medication guidelines and consensus, such as the influenza diagnosis and treatment plan, the prevention and treatment guide for fever with thrombocytopenia syndrome, and the traditional Chinese medicine diagnosis and treatment guide for the common cold, whose efficacy has been widely recognized in clinic.

2  Andrographolide vsCOVID-19Related pharmacological effects

Andrographolide and its derivatives have a wide range of biological activities. Studies have shown that andrographolide has antipyretic and anti-inflammatory, antiviral, antibacterial, hepatoprotective and cholagogic, immune regulation, anti cardiovascular disease, anti-tumor and other effects.

2.1  Antipyretic and anti-inflammatory effects

Andrographolide has good antipyretic and anti-inflammatory effects. Du Hong et al^[12]The effect of andrographolide microemulsion on3The anti-inflammatory effects of three inflammatory models (acetic acid-induced peritoneal capillary permeability enhancement mouse model, carrageenan gasbag inflammation rat model, cotton ball granuloma mouse model) showed that its anti-inflammatory effect on the capillary permeability increased in various stages of inflammation. Shan min et al^[13]By observing20The therapeutic effect of andrographolide injection combined with andrographolide in the treatment of children with acute bronchopneumonia proved that andrographolide injection can directly act on the mediators of the central body temperature regulation to achieve the effect of stabilizing body temperature.

Unlike corticosteroids and non steroidal anti-inflammatory drugs, andrographolide is a specific nuclear transcription factor-κB（NF-κB）Inhibitors,NF-κBAndrographolide is involved in the gene regulation of various physiological and pathological processes, such as inflammation, immunity, and apoptosis. Andrographolide exerts anti-inflammatory effects by inhibiting its signal transduction pathway^[14]In addition, the anti-inflammatory mechanism of andrographolide also includes^[15-22]: ① inhibition of multiple mitogen activated protein kinases（MARK）signaling pathway， Including extracellular signal regulated protein kinases（ERK1/2）Accessc-JunN-terminal kinase/Stress activated protein kinase（JNK/SAPK）Accessp38 MAPKPathways; ② Regulation of non receptor tyrosine protein kinases-Signaling and transcriptional activator proteins（JAK-STAT）signaling pathway； ③ Inhibition of cyclooxygenase-2（COX-2）Expression of; ④ Reduced vascular endothelial growth factor（VEGF）Vascular cell adhesion molecule-1（VCAM-1）, hypoxia inducible factor-1（HIF-1α）And endothelin-1（ET-1）Generation of; ⑤ Downregulation of interleukin-6（IL-6）、IL-1β, tumor necrosis factor-α（TNF-α）（NO）, prostaglandinsE₂（PGE2）And other inflammatory factors.

The structure-activity relationship study revealed that^[23]The diterpene bicycles and five membered lactone rings in andrographolide structure are the necessary structures for its antipyretic and anti-inflammatory activity, and the position and number of double bonds determine the strength of its anti-inflammatory activity. The anti-inflammatory effect of compounds with double bonds inside the ring is stronger than that of compounds with double bonds outside the ring. At the same time, the structural modification of hydroxyl group also has a great impact on the anti-inflammatory activity.

2.2  Antiviral effect

Andrographolide and its derivatives have inhibitory effects on a variety of viruses, such as influenza virus, severe acute respiratory syndrome（SARS）Virus, Ebola virus, respiratory syncytial virus, herpesvirus, rotavirus, Coxsackie virusA16Type A, human immunodeficiency virus（HIV）Et al.

stay2003yearSARSWhen the virus broke out on a large scale, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, found that African green monkey kidney cellsVero E6Under the influence ofSARSAccompanied by virus infectionNF-κBInhibition of protein kinasesα（IκBα）Protein degradationAnd andrographolide can very effectively protectE6Cells protected fromSARSVirus infection, and the titer of inhibiting virus replication^[24]。An in vitro experiment of andrographolide and its sulfonate against various types of influenza viruses showed that andrographolide could inhibit apoptosis, increase the survival rate of infected animals, reduce lung pathological changes, reduce viral load and inflammatory cytokine expression induced by infection^[17,25]。

The antiviral mechanisms of andrographolide compounds mainly include^[26-27]：① Occupy virus replicationDNAWith the protein binding site, preventing the protein fromDNAThe encapsulation of fragments, which makes the virus unable to replicate normally; ② Inhibit the cleavage of glycosyl protein fluorescent peptide on the surface of virus envelope, and prevent the virus from invading cells; ③ Affecting virus induced retinoic acid inducible gene proteinsILike receptor（RLRs）signaling pathway。

2.3  Hepatoprotective effect

Several studies have confirmed that andrographolide and its derivatives have a clear liver protective effect, and have a protective effect on liver injury caused by a variety of factors^[28-32]，It can inhibit liver apoptosis and reduce the activation of hepatic stellate cells, thereby alleviating the degree of liver fibrosis^[33-34]In addition, it can also increase the amount of bile flow, bile salt, cholic acid and deoxycholic acid, thus playing an effective protective role against cholestatic liver injury^[35]。

Its mechanism of action is mainly anti lipid peroxidation through phosphatidylinositol3-Kinases（PI3K）/protein kinaseB（Akt）And extracellular signal regulated kinase（ERK）Up regulation of antioxidant protein glutathione thiotransferase（GST）, glutathione peroxidase（GSH- Px）And glutathione reductase（GR）Expression, activationNrf2, upregulatedHO-1Expression, inhibitionTNF-αAnd reduce the generation of oxygen free radicals in tissues, thereby reducing oxidative stress injury^[29-31,36]。At the same time, by downregulatingNF-κBInflammatory pathways inhibit the inflammatory response to reduce liver injury and fibrosis^[37]。

2.4  Immunomodulatory effect

. Yang Liang'an et al^[38]The therapeutic effect of andrographolide on bronchiolitis, which is closely related to immunity, was studied. Studies have shown that andrographolide can reduce theTh17andTh2Type I cells (helperTCells) levels, thereby inhibiting their secreted cytokinesIL-17(it is closely related to airway hyperresponsiveness and can inhibit the immune response of the body) and so on to play an immunomodulatory role. In addition, andrographolide can also activate macrophages^[39], promoting lymphokine activated killer cellsLAKAnd prolong its killing effect time^[40], improve intestinal flora^[41]Et al., is considered to be a non-specific regulator of immune function.

2.5  Anti cardiovascular effects

Andrographolides have the effects of anti atherosclerosis, regulating blood lipids, anti myocardial ischemia, anti myocardial hypertrophy, and anti platelet aggregation^[39]Its mechanism of action includes^[42-47]: ① inhibit inflammation; ② Induction of cholesterol efflux and inhibition of acyl CoenzymesA-Cholesterol acyltransferase（ACAT）, thereby reducing plasma cholesterol levels; ③ Inhibition of hydroxymethylglutaryl coenzymeA（HMG-CoA）Reductase, regulate cholesterol synthesis; ④ Improve the body's antioxidant capacity, regulate the production capacity of cardiomyocytes, and affect the balance of vasoactive substances; ⑤ Inhibit coagulation factor and thrombin activity, reduce fibrinogen content, and enhance fibrinolytic activity.

3  Clinical application of andrographolide preparation

Over the years, a variety of preparations with andrographolide or its derivatives as raw materials have accumulated a lot of clinical experience. Its application range is wide, and it can be used to treat diseases of the respiratory system, digestive system, cardiovascular system and other diseases. The applicable population covers adults, children and infants.

3.1  Respiratory diseases

3.1.1  Upper respiratory diseases  Andrographolide dropping pills have a significant effect on upper respiratory tract infection symptoms such as sore throat, can relieve symptoms, improve immune function, and have a low recurrence rate^[48]Xiyanping and Yanhuning combined with ribavirin have good therapeutic effects on viral upper respiratory tract infection and influenza^[49-50]。

3.1.2  Lower respiratory tract diseases  Andrographolide injections are widely used in the treatment of pneumonia. In the clinical study of viral pneumonia^[51]The total effective rate of Xiyanping injection was higher than that of ribavirin, and the improvement time of clinical symptoms and signs (fever, cough, pulmonary rales) was significantly shortened. The incidence of adverse reactions was also significantly lower than that of ribavirin, and all were mild reactions. For pneumonia caused by mycoplasma infection, Xiyanping injection combined with azithromycin can significantly improve the curative effect and reduce the level of early inflammatory factors^[52]。

Chronic obstructive pulmonary disease（COPD）It is a common chronic disease that seriously endangers human life and health. Clinical studies have shown that^[53-54], Xiyanping injection and Yanhuning injection onCOPDPulmonary hypertension and its complications（PAH）It can reduce the level of inflammatory factors, regulate the function of vascular endothelial cells, improve multiple indicators of the lung and heart of patients, and improve the quality of life without obvious adverse reactions.

Sunmenghua et al^[55]The systematic evaluation method of evidence-based medicine was used to prove that Xiyanping injection, when used alone or in combination with chemical drugs, has a good therapeutic effect on children with acute bronchitis. It has a significant effect in the defervescence time, the disappearance time of cough and sputum, and the disappearance time of pulmonary rales. It can also improve the overall curative effect, and no serious adverse reactions were observed.

3.2  Digestive system diseases

The clinical study of andrographolide combined with tea polyphenols in patients with chronic gastritis showed that the efficacy of the combination of the two drugs was significantly better than that of omeprazole control group, and the incidence of adverse reactions was significantly lower than that of the control group^[56]Rotavirus enteritis is a common infectious diarrhea in infants. When Xiyanping injection is combined with related drugs, the effect is significant, which is related to its antiviral effect^[57]。

3.3  Cardiovascular and cerebrovascular diseases

Chenxinghua^[58]Chuanhuning Injection Combined with astragalus injection was used to treat viral myocarditis. The results showed that Chuanhuning could improve the curative effect. Feizhongting^[59]It was also found that Xiyanping injection can effectively improve the symptoms, signs and myocardial enzymology of acute viral myocarditis, and promote the recovery of electrocardiogram.

3.4  Other diseases

Andrographolide preparations have also been reported in the clinical application of hand foot mouth disease, mumps, sepsis, and children's acute rash^[60-63]。

4  Andrographolide preparations againstCOVID-19The theoretical basis and functional characteristics of

faceCOVID-19The most direct treatment is antiviral therapy. spike（SProtein inhibitorsACE2Binder)RdRp、3Clpro、MproandPlproThe study of isoprotein targets is in full swing, but its antiviral activity remains to be verified clinically.SARS-CoV-2Is a new strain of coronavirus, which is associated with2003SARS coronavirus in（SARS-CoV）Yes80%The left-right similarity, which is similar to that found in batsSARSSimilar coronaviruses have90%The above similarity, its effect onACE2Strong binding force^[64]Andrographolide vsSARSThe virus has a certain inhibitory effect, combined with the antiviral mechanism of andrographolide, suggesting that andrographolide may have potential anti -SARS-CoV-2Viral activity.

,COVID-19The main treatment method is symptomatic treatment, including reducing the inflammatory response, improving immunity, alleviating the symptoms of fatigue, fever, cough, sore throat, dyspnea, etc., improving blood oxygen saturation, and protecting the damaged organs (lung, heart, liver, kidneyViscera, etc.), to control secondary bacterial infection, etc. According to the team of academician Zhongnanshan^[65]Recently published1 100exampleCOVID-19The results of the clinical analysis of the patients were87.9%and67.7%Twenty five percent of the patients reported fever and cough symptoms during hospitalization. In addition, common symptoms of pneumonia such as expectoration, fatigue, shortness of breath, headache, and sore throat were also common.76.4%Of patients were admitted to the hospitalCTPneumonia was present on examination. In addition, relevant clinical studies have also found that^[66-67], inCOVID-19Cytokine storm syndrome can be seen in critically ill patients（CSS）The occurrence of.CSSIt refers to the extreme immune attack that the virus attacks the human body, causing the disorder of the human immune system, causing the rapid and massive production of a variety of cytokines in body fluids, and then damaging the host. In the early99individualCOVID-19Among the cases, there are17Cases developed acute respiratory distress syndrome（ARDS）, which also includes11Deaths.CSSIs caused byARDSThe main reason is that the patient's condition can worsen in a short time and eventually die of multiple organ failure. Therefore, before the advent of effective antiviral drugs, appropriate anti-inflammatory treatment can effectively reduce the mortality of patients.

. It is reported in the literature^[68], in128exampleCOVID-19Among the patients, there were45%Of the patients received glucocorticoid treatment, but did not receive results. Glucocorticoids forCOVID-19There is limited evidence for treatment of^[69]。

Andrographolide preparations have clear antipyretic and anti-inflammatory effects, and can be used in the treatment of upper respiratory tract infection, viral pneumoniaCOPDRich clinical experience has been accumulated in the treatment of diseases such as bronchitis, which can reduce the level of inflammation, improve the signs of cough, fever and pulmonary rales, and delay the pathological changes of the lungs. And its anti-inflammatory mechanism is different from corticosteroids, which will not bring the immunosuppressive effect of hormone drugs, and the incidence of adverse reactions is low. At the same time, andrographolide preparations have antibacterial and immunomodulatory effects, which can inhibitCOVID-19Concurrent bacterial infection, enhance the body's immunity.

Retrospective single center study^[70]Pointed out that many patients were complicated with organ function damage, about43%,13%The patient had elevated creatine kinase,76%The patient had elevated lactate dehydrogenase, suggesting cardiac injury. ^[71]，COVID-19The liver injury caused bySARS-CoV-2Viral infection causes the body inflammatory response, and the virus will also cause cholestasis, further stimulate the inflammatory response, thus causing liver injury, and even trigger a cytokine storm, leading to organ failure. In addition, the treatments currently in clinical useCOVID-19Of chemical drugs (lopinavir/Ritonavirα-Interferon, ribavirin, glucocorticoid) have certain effects on liver injury^[72]Andrographolide and its derivatives have both anti-inflammatory and hepatoprotective effects, especially for cholestatic liver injury. At the same time, he also has some clinical experience in the treatment of cardiovascular diseases, such asTreatment of viral myocarditis, etc. It is suggested that it may have some protective effects on liver injury and heart injury, but it needs further clinical verification.

Analysis from the perspective of traditional Chinese Medicine^[73-74]，COVID-19It has the characteristics of rapid onset, rapid transmission, strong infectivity, similar main symptoms, seasonality, etc. combined with its clinical manifestations, infectious source, transmission route, infection scope and other judgment, this disease belongs to the epidemic evil gas that feels dampness as the main nature, which can be called "dampness epidemic". The pathogenesis should be "dampness stagnation in the lung". The disease is due to "fierce Qi and Pandora gas", and has the characteristics of "dampness, heat, poison, blood stasis and deficiency". ,COVID-19Divided into4Stage (early stage, middle stage, severe stage and recovery stage), and the middle stage is divided into cold dampness stagnation of the lung, epidemic toxin blocking the lung (heat toxin attacking the lung, heat toxin blocking the lung, heat toxin blocking the lung, cold outside and heat inside), internal closure and external detachment, lung spleen qi deficiency4Type. . Common treatment methods include resolving turbidity and dispersing lung, clearing heat and detoxification, sweating and relieving exterior symptoms, clearing lung and resolving phlegm, etc. Andrographis paniculata is bitter and cold in nature, and its main effects are to clear away heat, detoxify and cool blood. Therefore, it can be applied to all diseases and syndromes caused by the pathogen of warm heat. It is also good at clearing lung fire, cooling blood and reducing swelling, and is good at treating lung heat cough and asthma, lung carbuncle vomiting pus, sore throat. Therefore, Xiyanping injection for the treatment of mid-term is in line with the requirements of traditional Chinese medicine forCOVID-19The dialectics and treatment of can be targeted atCOVID-19Symptomatic treatment of "heat" and "poison" can also cooperate with other drugs to exert curative effect.

5  epilogue

Andrographolide preparations forCOVID-19The theory of traditional Chinese medicine and modern research results are the theoretical basis for the treatment of this disease, which is applicable toCOVID-19It is speculated that the main role of the treatment in the advanced stage (early and middle stage of treatment), severe stage and recovery stage is to reduce the level of inflammation, improve the signs of cough, fever, pulmonary rales and so on, and play a role in inhibiting virus replication and infection, inhibiting concurrent bacterial infection, improving the immune ability of the body, and improving the liver function and cardiovascular injury degree of patients, without adverse reactions of hormone drugs.
 

References (omitted)  

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