key: cord-0932422-ns4jmxgn
authors: Pan, Xiaoqi; Dong, Lan; Yang, Nian; Chen, Dayi; Peng, Cheng
title: Potential drugs for the treatment of the novel coronavirus pneumonia (COVID-19) in China
date: 2020-06-09
journal: Virus Res
DOI: 10.1016/j.virusres.2020.198057
sha: fc42f5385bd73a8731f4e70da3ea8148002aeb25
doc_id: 932422
cord_uid: ns4jmxgn

The fight against the novel coronavirus pneumonia (namely COVID-19) that seriously harms human health is a common task for all mankind. Currently, development of drugs against the novel coronavirus (namely SARS-CoV-2) is quite urgent. Chinese medical workers and scientific researchers have found some drugs to play potential therapeutic effects on COVID-19 at the cellular level or in preliminary clinical trials. However, more fundamental studies and large sample clinical trials need to be done to ensure the efficacy and safety of these drugs. The adoption of these drugs without further testing must be careful. The relevant articles, news, and government reports published on the official and Preprint websites, PubMed and China National Knowledge Infrastructure (CNKI) databases from December 2019 to April 2020 were searched and manually filtered. The general pharmacological characteristics, indications, adverse reactions, general usage, and especially current status of the treatment of COVID-19 of those potentially effective drugs, including chemical drugs, traditional Chinese medicines (TCMs), and biological products in China were summarized in this review to guide reasonable medication and the development of specific drugs for the treatment of COVID-19.

The novel coronavirus pneumonia (coronavirus disease 2019, is caused by a novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) infection . SARS-CoV-2 that seriously endangers human health has been found throughout China and around the world, including America, Brazil, Russia, India, Peru, England, and other countries (Zhang et al., 2020a) . As of April 14, 2020, a total of 83700 confirmed cases and 3351 deaths in China, and more than 1.85 million of COVID-19 confirmed cases in other countries were reported. According to the speed of SARS-CoV-2 infection, the number of confirmed and deaths of COVID-19 in the world is still increasing. The prevention and treatment of COVID-19 is undoubtedly one of the biggest challenges in the history of human development. Chinese government formulated quickly strict prevention and control mechanism, issued the "Guidelines for the diagnosis and treatment of novel coronavirus pneumonia (the seventh trial version)", and encouraged the front-line clinical workers to try to use the marketed medicines for COVID-19 treatment (National Health Commission et al., 2020) . Fortunately, as of April 14, 2020, more than 78000 of patients had been successfully cured in China. A number of drugs exhibit certain inhibitory effects on SARS-COV-2 in China, which are expected to be specific drugs for the treatment of COVID-19. Meanwhile, a large number of clinical and fundamental studies on these potentially effective drugs are being carried out. Some drugs that have been clinically tested in advance have good curative effects, and some drugs also have shown certain antiviral effects in vitro experiments. However, most of these drugs have not yet been tested in standardized clinical studies, especially large sample randomized controlled trials (RCTs).

In the face of the battle between human health and viruses, Chinese scholars should share these potential drugs to cooperate with other countries and regions for resisting this virus attack.

This review lists current clinical trial drugs and potential drugs against SARS-CoV-2 in China, including chemical drugs, traditional Chinese medicines (TCMs), and biological products, which is beneficial to promote researchers around the world to discover specific drugs for COVID-19 treatment as soon as possible.

clinical trials to verify the efficacy and safety. The chemical structures, pharmacological actions, indications, adverse reactions, and general usage of these chemical drugs for COVID-19 treatment were listed in Table 1 .

Kaletra consists of two kinds of protease inhibitors lopinavir and ritonavir, which both can block the division of Gag-Pol polyproteins and generate non-infectious virus particles to specifically inhibit retroviral infection (van der Laan et al., 2018) . Initially, this drug is mainly used to treat human immunodeficiency virus (HIV) infection in adults and children over 2 years of age. Studies in vitro experiments showed that lopinavir and ritonavir could reduce the levels of SARS-CoV and MERS-CoV (Chu et al., 2004) . Based on the results of substantial clinical benefits of lopinavir and ritonavir in patients with SARS-CoV infection, scientists speculated that this drug might be effective in patients with SARS-CoV-2 infection . The team in Zhongshan

University constructed a structural model of two new coronavirus proteases-coronavirus endopeptidase C30 and papain-like protein through homology modeling, and docked lopinavir/ritonavir with protease models, respectively. Results showed that lopinavir and ritonavir more easily combined with coronavirus endopeptidase C30 compared with papain-like enzymes, which expressed excellent anti-SARS-CoV-2 effects (Lin et al., 2020) . However, after using lopinavir/ritonavir tablets in 40 patients diagnosed with COVID-19, 29 cases had adverse reactions related to lopinavir/ritonavir, such as the elevated triglycerides, nausea, and diarrhea (Liang et al., 2020) . Therefore, larger clinical trials of this drug should focus on its safety.

Ribavirin, a broad-spectrum antiviral drug, can be phosphorylated in red blood cells to produce ribavirin monophosphate, diphosphate, and triphosphate. Ribavirin monophosphate is a strong inhibitor of inosine monophosphate dehydrogenase, which can inhibit cellular guanylate synthesis, reduce cellular guanylate triphosphate, and block viral nucleic acid synthesis. Ribavirin triphosphate inhibits influenza virus RNA polymerase, thereby interfering with virus μmol/L in A549 cells (Chang et al., 2011) . When ribavirin was used in combination with IFN-α2b, anti-MERS-CoV activity of ribavirin was significantly enhanced in rhesus macaques (Falzarano et al., 2013) . Ribavirin was shown to inhibit SARS-CoV replication in five different cell types derived from animals or humans at therapeutically achievable concentration (Morgenstern et al., 2005) . However, some adverse reactions should be noted during ribavirin application. For example, 61% of patients developed hemolytic anemia, 58% hypocalcemia, and 46% hypomagnesemia in 110 SARS patients treated with ribavirin (Knowles et al., 2003) . Given the efficacy of ribavirin in the treatment of diseases caused by SARS-CoV and MERS-CoV, it is expected to become an effective drug for COVID-19 treatment. However, the efficacy of ribavirin for the treatment of COVID-19 is still controversial, which are needed to further confirm in clinical trials.

Chloroquine is an anti-malarial and anti-inflammatory drug, which is widely used in the treatment of malaria and rheumatoid arthritis for more than 70 years. Anti-malarial effect of chloroquine may interfere with the replication and transcription of the plasmodium schizont DNA or hinder its endocytosis, thereby leading to the parasite to die due to amino acids deficiency. Chloroquine also has immunomodulatory activity, which can synergistically enhance antiviral effects (Wang et al., 2020a) . Chloroquine phosphate and hydroxychloroquine destroy the terminal glycosylation of angiotensin converting enzyme II (ACE2) in vitro. Therefore, chloroquine may be potent inhibitors of SARS-CoV-2 infection. Based on the results of previous studies, chloroquine phosphate has a therapeutic effect on COVID-19 in vitro (Wang et al., 2020a) . At present, several clinical trials were successively announced. The results of an open-label non-randomized clinical trial revealed that hydroxychloroquine was significantly associated with viral load reduction or disappearance in patients with COVID-19 (Philippe et al., 2020) . Similarly, another randomized clinical trial also confirmed the efficacy of hydroxychloroquine on COVID-19, which are manifested with the shortening of the body temperature recovery time and the cough remission time of patients with COVID-19 . Preliminary evidence from a multicenter prospective observational study showed that the median time to undetectable viral RNA was shorter in chloroquine than in non-chloroquine, and no serious adverse reactions were observed in the chloroquine group . In contrast, the results of some clinical studies showed J o u r n a l P r e -p r o o f negative for the treatment of COVID-19 with chloroquine or hydroxychloroquine. For example, an open-label, randomized, controlled trial indicated that hydroxychloroquine did not result in a higher negative conversion probability than standard-of-care alone in mild to moderate COVID-19 patients, and adverse events, especially diarrhea, were higher after receiving hydroxychloroquine (Tang et al., 2020) . Another randomized, double-blinded, phase Ⅱb clinical trial showed that the high dosage chloroquine phosphate group (total 12 g) presented more QTc>500 ms and higher mortality rate (17%) than the low dosage group (total 2.7 g) (Mayla et al., 2020) . Hence, the safety and efficacy of chloroquine for the treatment of COVID-19 still need to be testified by more and bigger clinical trials.

Arbidol inhibits the fusion between viral envelope and cell membrane of the target cells, thereby preventing the virus from entering the target cells (Teissier et al., 2011) . Arbidol is often used to resist influenza viruses in Russia and China, which has not yet been approved for marketing in other countries. In vitro and in vivo studies have shown that arbidol has antiviral activity against influenza virus, RSV, rhinovirus, coxsackie virus, coxsackie virus B5, and adenovirus (Shi et al., 2007; Zhong et al., 2009) . Previous studies have shown that arbidol can inhibit RNA viruses and filoviridae, such as SARS-CoV and MERS-CoV(Guan et al., 2018; Hulseberg et al., 2019) .

Chinese scientists found that arbidol could effectively inhibit the pathological effects of SARS-CoV-2 at a concentration of 10~30 μmol/L with 60 times of viral load in vitro through screening a variety of antiviral drugs. At present, two RCTs have been initiated to evaluate the efficacy and safety of arbidol in the treatment of COVID-19 in China.

Favipiravir is a viral RNA polymerase inhibitor, which can be mediated by its metabolite ribofuranosyl-5'-triphosphate (RTP) that inhibits influenza virus RNA polymerase activity.

Favipiravir was urgently used and presented good inhibitory effects on Ebola virus in 2014 (Nagata et al., 2015) . Despite of fairly modest antiviral activity, favisiravir could completely inhibit murine norovirus (MNV) replication at a concentration of 100 μg/mL with little or no side effects on cells (cell survival rate> 80%) (Rocha-Pereira et al., 2012) . Favipiravir is proven to protect mice from lethal infection with various influenza viruses (Furuta et al., 2013) . However, previous reports showed that favipiravir might have a prolonged QT interval during treatment, which should be paid attention to monitoring during medication (Kumagai et al., 2015) . Favipiravir has been J o u r n a l P r e -p r o o f officially approved by Chinese Medical Products Administration for marketing and formally put into production in China. Favipiravir is the first approved drug with the potential curative effect on COVID-19 in China, which will play an important role in prevention and control of SARS-CoV-2 infection.

Remdesivir produced by Gilead Sciences Inc. is mainly used as a test drug against Ebola virus.

One review suggested that remdesivir might be more suitable against coronaviruses (John, 2020) .

Remdesivir has a strong anti-filovirus effect in vitro and a certain anti-coronavirus effect through inhibiting RNA-dependent RNA synthetase in animal experiments (Wang et al., 2020b; Zumla et al., 2016) . Subsequent research found that remdesivir was not only effective against Ebola virus, but also inhibits respiratory syncytial virus, coronavirus, nipah virus, and hendra virus (Warren et al., 2016) . Researchers reported that the first COVID-19 patient in the United States recovered after receiving remdesivir treatment (Holshue et al., 2020) . In November 2019, the results of a phase II clinical trial showed that 175 of 681 Ebola patients were treated with remdesivir, following 29 serious adverse reactions, only one of which was related to remdesivir (Mulangu et al., 2019) . Research showed that giving remdesivir could prevent rhesus macaques from getting sick before MERS-CoV infection and improve their symptoms after being infected (de Wit et al., 2020) . Furthermore, remdesivir treatment initiated early during infection had a clear clinical benefit in SARS-CoV-2-infected rhesus macaques, which predicted that early remdesivir treatment initiation in COVID-19 patients might prevent progression to severe pneumonia (Brandi et al., 2020) . Chinese scientists have found that EC50 of remdesivir against SARS-CoV-2 is 0.77 μmol/L in Vero E6 cells, and the selection index SI is greater than 129, indicating that this drug can effectively inhibit SARS-CoV-2 infection in vitro (Wang et al., 2020a) . Preliminary results from a clinical trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID) in USA showed that the patients who received remdesivir had 31% faster time to recovery than those who received placebo, indicating that remdesivir has a significant positive effect in reducing recovery time for patients with COVID-19. In addition, Gilead Sciences Inc. also announced that similar clinical improvements after the 5-day and 10-day remdesivir administration in patients with severe COVID-19 were found even without a placebo control. However, a randomized, double-blinded, placebo-controlled, multicentre clinical trial conducted by Chinese scientists J o u r n a l P r e -p r o o f revealed that remdesivir did not accelerate recovery or reduce the mortality in patients with severe COVID-19 compared with the placebo group. The rate of early discontinuation due to adverse events, including nausea, vomiting, and cardiopulmonary failure, was higher in the group receiving remdesivir than that in the placebo group (11.6% versus 5.1%). Although this is the first high-quality clinical trial of remdesivir in the treatment of COVID-19 so far, only 237 samples are included in the clinical trial . Therefore, the antiviral efficacy and safety of remdesivir still need to be supported by more high-quality and larger sample clinical studies.

In China, the practice of fighting against SARS-CoV-2 in the past four months has fully confirmed that TCMs play an important role in prevention and treatment of COVID-19 before successful development of specific medicines and vaccines. The combination treatment methods of TCMs and chemical drugs improved clinical efficacy, shortened the length of hospital stay, and reduced the critical mortality rate . Therefore, those TCMs, including Chinese herbal compound prescriptions, injection preparations, and active ingredients of TCMs, with certain effects for prevention and treatment of COVID-19 should be summarized and shared. Chinese herbal compound prescriptions and injection preparations that were tried to prevent and treat COVID-19 in China were listed in Table 2 .

Glycyrrhizic acid (GA) is the principal bioactive ingredient isolated from Chinese herb University and the University of Hong Kong proved that GA could bind to ACE2, which testified that GA preparation might have potential value in preventing SARS-CoV-2 infection. Studies have shown that GA can not only exert antiviral effects by regulating immune function, but also has a clear anti-inflammatory mechanism (Li et al., 2017) . A number of experts in Hubei province of China said that patients with severe COVID-19 could trigger an inflammatory storm, leading to multiple organ failure. GA derivatives also presented the antiviral activity against SARS-CoV (Hoever et al., 2005) . A clinical retrospectively analysis of 73 SARS patients showed J o u r n a l P r e -p r o o f that compound glycyrrhizin could improve the symptoms of dry cough, chest tightness, shortness of breath, and other symptoms, which is believed that compound glycyrrhizin has a certain effect on SARS-CoV (Lu et al., 2003) . At present, the commonly used oral GA+vitamin C for the treatment of COVID-19 has been approved in a clinical trial in China.

In addition, a study revealed that several active natural products and TCMs might have therapeutic effects on COVID-19 through screening the self-built "Highly Pharmaceutical 

Chinese herbal compound prescription refers to a prescription consisting of two or more components for the treatment of a relatively certain disease and syndrome, which has a relatively prescribed processing method and usage method. Each herb in Chinese herbal compound prescription has specific curative effect, which cooperates with each other to increase the curative effect or reduce toxicity and adverse reactions. Chinese herbal compound prescriptions are widely applied in clinical practice, which has overall comprehensive effects of broad-spectrum antibacterial, antiviral, and immune function regulation.

Huoxiang Zhengqi (HXZQ) is used as a common Chinese herbal compound prescription to improve the symptoms of headache, dizziness, nausea and vomiting, fatigue, and gastrointestinal discomfort in Chinese families. There are different dosage forms on the market, such as water, capsule, and pill. Clinical reports showed that HXZQ powder treated 22 cases of infectious diarrhea caused by Norwalk virus, with the results of 100% effective rate (Wang, 2010) . HXZQ oral solution could bind to ACE2 to target PTGS2, HSP90AB1, AR, CAMSAP2, and other targets through the network pharmacology and molecular docking, thus playing a role in prevention and control of COVID-19 (Deng et al., 2020) . Adverse reactions caused by HXZQ preparations are diverse, such as skin damage being the most, followed by circulatory system, respiratory system, and nervous system symptoms (Fang et al., 2015) . and IFN-γ levels in patients with influenza, thus improving the immune function (li et al., 2013; Qi et al., 2016) . 300 major active ingredients of JHQG for COVID-19 treatment were predicted through network pharmacology analysis, involving 414 target proteins, 47 of which are potential targets for COVID-19 treated with JHQG (Mao et al., 2020) . Lianhua Qingwen Capsule (LHQW) are applied to relieve fever or high fever and cough caused by influenza, which can inhibit the proliferation of various influenza viruses and reduce IL-6, IL-8, and TNF-α levels, thereby exerting antiviral effects (Ding et al., 2017; Dong et al., 2014) . LHQW significantly enhanced the efficacy of conventional antiviral drugs, and improved fever, cough, and fatigue symptoms in a clinical study of 63 suspected COVID-19 cases . In addition, a retrospective clinical study of LHQW combined with conventional treatment patients, LHQW could significantly improve fever, fatigue, cough, sputum, shortness of breath, chest tightness, and appetite in patients with common COVID-19, and reduce the proportion of common to severe . Clinical study of 42 patients with common COVID-19 treated with LHQW found that compared with the control group, the disappearance rate of fever symptoms increased from 57.1% to 85.7%, and the disappearance rate of cough symptoms increased from 5.6% to 46.7%. The duration of fever was shortened by 1.5 days, the disappearance rate of expectoration increased from 9.1% to 64.3%, and the disappearance rate of shortness of breath symptoms increased from 0 to 77.8% . LHQW prescription for the treatment of mild and common COVID-19 has been approved to be added to drug instruction in China.

has good curative effects on fever, cough, and headache. Studies showed that SFJD significantly reduced the serum levels of PGE2, IL-1β, and TNF-α in rats with acute pharyngitis (Qian, 2019) .

SFJD combined with arbidol could significantly improve clinical symptoms, including the increased white blood cells and lymphocytes, and the absorption of chest CT image in 100 patients with mild COVID-19 . Fangfeng Tongsheng Pill (FFTS) can effectively reduce serum TNF-α level, thus exerting anti-inflammatory, anti-allergic and immune-regulating effects (Jin et al., 2017; Wang et al., 2018) . SARS-CoV-2 infection is easy to cause symptoms, such as fatigue, gastrointestinal upset, and fever during the observation period. Chinese herbal J o u r n a l P r e -p r o o f compound prescriptions can reduce the levels of related inflammation-related factors, exert anti-inflammatory and improve immunity, and ultimately alleviate the symptoms of patients with COVID-19 (Zhang et al., 2020b) .

Qingfei Paidu Decoction (QFPD) is mainly used to control lung infection in clinical practice.

The active ingredients of QFPD for the treatment of COVID-19 were predicted by network pharmacology methods, including quercetin, luteolin, kaempferol, naringenin, and isorhamnetine . QFPD combined with antiviral drugs could significantly shorten Huashi Baidu Prescription (HSBD) that is developed by Chinese academician Huang Luqi's team can improve fever, promote blood circulation to remove blood stasis, and improve the immunity function. An analysis of 44672 confirmed cases with COVID-19 by Chinese Center for Disease Control and Prevention showed that the crude mortality rate of critical cases was 49% (Epidemiology working group for NCIP epidemic response et al., 2020). Severe COVID-19 is easy to develop into critical illness, which greatly increases the mortality rate. Clinical studies have confirmed that the application of HSBD following the guidance of traditional theories can effectively relieve the symptoms of severe COVID-19 and reduce the conversion rate and mortality rate of critical illness. However, the dosage of HSBD needs to be adjusted according to is mainly related to combating viral infection and repairing lung injury (Wang et al., 2020b) .

Forsythiae Fructus, which has been used to prevent infection for more than 2000 years in China.

The common formulations on the market include granule, oral solution, and injection.

Shuanghuanglian has multiple pharmacological activities, including antibacterial, antiviral, and immune-enhancing functions. Previous studies have shown that Shuanghuanglian injection has obvious antiviral effects against influenza A virus H5N1 in vivo and in vitro (Tang et al., 2018) . A systematic review of RCTs suggested that Shuanghuanglian could be applied for the treatment of acute upper respiratory tract infection (Zhang et al., 2013) . Preliminary studies in vitro found that Shuanghuanglian oral solution inhibited SARS-CoV-2. But whether Shuanghuanglian is effective against COVID-19 requires a large number of clinical trials to confirm. At present,

Hospital affiliated to Huazhong University of Science and Technology. Shanghai Institute of Materia Medica has negotiated and reached a cooperation agreement with relevant companies to jointly conduct in-depth research on the antiviral efficacy of Shuanghuanglian.

Chinese medicine injection preparation is a sterilized solvent, powder or concentrated solution, which can be applied for injecting into the body through extracting the active ingredients from J o u r n a l P r e -p r o o f TCMs by the modern techniques and methods. The active component of Xiyanping injection is andrographolide total ester sulfonate. Xiyanping injection that is commonly used clinically for respiratory infections, pneumonia, and gastroenteritis has anti-inflammatory, blood coagulation regulation, vascular endothelial protection, immunity-enhancing and other functions through the "multi-components, multi-targets, and multi-pathways" mechanism (Ma et al., 2009; Ma et al., 2015) . Xuebijing injection is mainly used for anti-infective treatment, which can antagonize endotoxin and inflammatory mediators and improve lung and systemic inflammation in the treatment of coronavirus (Li et al., 2020a) . In clinical application, Xuebijing injection had a significant effect on inflammation storm and low blood oxygen saturation caused by SARS-CoV-2 infection. A retrospective analysis of 44 patients with common COVID-19 found that Xuebijing treatment could promote the absorption of lung infection lesions, thereby improving the efficacy.

But Xuebijing had no obvious efficacy on inflammatory indexes, including white blood count, lymphocyte count, percentage of lymphocytes, CRP, and ferritin . Few patients may experience itchy skin after injecting Xuebijing injection. The incidence of Xuebijing injection is reported differently, probably between 2.68% and 4% (Lu et al., 2013) . The components of Shenfu injection that is used clinically to treat septic shock include Ginseng Radix et Rhizoma rubra and Aconiti lateralis Radix praeparata extract, which contain the active ingredients ginsenosides and water-soluble alkaloids. Occasionally, allergic reactions may occur after Shenfu injection treatment. An analysis on 23 RCTs containing 1804 participants showed that the combination of Shengmai injection and chemical drugs could achieve a better effect than drugs alone in terms of improving the clinical total effective rate, pulmonary function, blood gas index, immunoglobulin and CRP levels, and the lung rale disappearance time of chronic obstructive pulmonary disease (COPD) (Huang et al., 2019) . But Shengmai injection may cause adverse reactions, such as allergic rash and severe back pain. The ingredients of Reduning injection are Artemisiae annuae Herba, Lonicerae japonicae Flos, and Gardeniae Fructus, which are used for relieving symptoms caused by upper respiratory tract infection, such as high fever, headache, and cough. Reduning injection rescued death triggered by Enterovirus 71 infection in Vero cells and in mice (Cao et al., 2015) . Severe pneumonia induced by H1N1 influenza a virus could be reversed by the combination of ribavirin and Redunning administration (Ma et al., 2016) . Tanreqing injection is mainly used for the treatment of acute and chronic bronchitis, pneumonia, and upper J o u r n a l P r e -p r o o f respiratory tract infections caused by bacteria or viruses. Xingnaojing injection is well known for treating stroke in Chinese clinic. Animal experiments showed that Xingnaojing injection improved cerebral ischaemia/reperfusion injury through inhibiting inflammatory response (Zhang et al., 2020c) . A study revealed that Xingnaojing had a positive effect on patients with fever, poisoning, and stroke-induced consciousness disturbance (Wu et al., 2016) . Shenmai injection is increasingly used in tumor therapy, which can obviously improve the immune function of tumor patients. For example, Shenmai injection improved the postoperative immunological function of papillary thyroid carcinoma patients by inhibiting differentiation into Treg cells (Fang et al., 2018) . When combined with chemotherapeutic drugs, Shenmai injection reduces adverse reactions caused by chemotherapeutic drugs. At present, these Chinese medicine injection preparations are mainly tried to treat middle and severe COVID-19 cases in clinical trials.

As the global epidemic situation of COVID-19 becomes more and more serious, many countries and regions have begun to develop biological products for the treatment of COVID-19. Biological products mainly stimulate immune system to produce immune substances that presents antiviral efficacy. As one of the first countries to conduct the prevention and treatment of COVID-19, China has launched the development of biological products against SARS-CoV-2, such as IFN, vaccines, stem cells, and convalescent plasma (CP).

Recombinant human interferon-α (IFN-α), including IFN-α1b and IFN-α2b, exerts broad-spectrum antiviral, antitumor, cell proliferation inhibition, and immunity improvement on patients. IFN-α binding to cell surface receptors induces cells to produce a variety of antiviral proteins, which inhibits viral proliferation in cells and improves immune ability through enhancing the phagocytosis of macrophages, the cytotoxicity of lymphocytes to target cells, and the vitality of natural killer (NK) cells Sugita et al., 1987) . IFN-α2b is widely used to treat some viral diseases, such as acute and chronic viral hepatitis, shingles, and genital warts. However, IFN may have adverse reactions, such as fever, fatigue, headache, myalgia, arthralgia, loss of appetite, and nausea at the early stage of medication (Wang et al., 2020c) . Study showed that IFN-α2b and ribavirin for the treatment of MERS-CoV infected rhesus macaques reduced virus replication, moderated the host response, and improved clinical outcome(Falzarano J o u r n a l P r e -p r o o f et al., 2013) . In vivo studies also showed that IFN-α played an effective role in promoting prognosis of MERS-CoV infection (Momattin et al., 2013) . By comparing the clinical effects of combined IFN-α with glucocorticoid alone in treating patients with SARS-CoV infection, the results showed that lung image remission time was reduced by 50%, and oxygen saturation was significantly improved in IFN-α treatment group (Loutfy et al., 2003) . At present, IFN-α nebulized inhalation combined with other antiviral drugs, such as ribavirin, has been clinically tested for the treatment of COVID-19, which achieved a good therapeutic effect. However, it is necessary to be alert to the microbial aerosols that may be generated during IFN-α nebulized inhalation due to the possibility of aerosol transmission in SARS-CoV-2 infection . Some medical protection and disinfection should be done to reduce the risk of infection by medical staff. Chinese Clinical Trial Registry announced that clinical trial comparing the efficacy of new recombinant high-efficiency compound IFN and IFN-α for the treatment of COVID-19 has been registered.

Vaccines treatment is an effective method to prevent infection or improve the severity of diseases . Previous evidence showed that various vaccines were designed (Ju, 2020) . Although stem cell therapy presents certain advantage against COVID-19, more data and results are still needed to support the safety and efficacy of COVID-19 treatment.

CP therapy is applied for treating patients with infectious diseases through extracting the cured J o u r n a l P r e -p r o o f patients' plasma, serum or immunoglobulin, which was widely used in infectious diseases outbreaks in recent years, such as pandemic influenza, SARS, and MERS (Arabi et al., 2015; Cheng et al., 2005; Leider et al., 2010) . A systematic review showed that early treatment with CP might be more effective than late treatment with that (Mair-Jenkins et al., 2015) . In theory, most of the patients with COVID-19 will produce specific antibodies against SARS-CoV-2 after the recovery, which can kill and clear the virus. Preliminary clinical studies also confirmed that CRP and IL-6 levels in 3 severe COVID-19 patients after plasma exchange therapy were significantly reduced, lymphocytes and prothrombin time were improved, but inflammatory factors in patients treated with tocilizumab did not decrease .The clinical symptoms improved significantly, oxygen saturation and oxygenation index tended to improve, and inflammation indicators also improved within 72 hours after CP infusion for a severe COVID-19 patient (Li et al., 2020b) . Severe illness is the leading cause of COVID-19-induced death. Therefore, CP therapy may be an effective method to reduce mortality of severe COVID-19 patients with serious inflammatory response in the absence of specific treatments. In China, CP therapy has been added to the "Diagnosis and Treatment Plan for the Novel Coronavirus Infected Pneumonia (trial edition 7)", which is applicable to the treatment of cases with rapid progression, severe or critically ill.

However, CP must be collected at an appropriate time and has a higher neutralizing antibody titer(Bai et al., 2020).

At present, a worldwide outbreak of COVID-19 seriously affects people's health and economic development. SARS-CoV-2 infection has been widely caused in the general population and medical staff. Development of specific medicines or vaccines for the treatment of COVID-19 is quite urgent. Chinese scientists tried various marketed drugs, especially chemical drugs and TCMs, for the treatment of COVID-19. A number of drugs with good effects against SARS-COV-2 in vitro or preliminary clinical trials have emerged. However, there is still insufficient evidence to support the efficacy and safety of these drugs against SARS-CoV-2. Some shortcomings exist in previous studies, such as unreliable in vitro results, non-standard clinical trials, small sample size.

Hence, it is necessary to summarize these potential therapeutic drugs to ensure clinical medication safety and guide further standardized clinical research. compared with the absence of any antiviral drugs. In contrast, the incidence of adverse reactions in the lopinavir and ritonavir groups was higher than that in the control group without antiviral drugs.

Chloroquine and remdesivir are regarded as the promising chemical drugs against SARS-CoV-2.

However, the dosage and cycle of chloroquine need further clinical trials to confirm. The clinical pharmacokinetic reports indicated that the oral half-life of chloroquine was as long as 5-60 days, the median half-life is 21-30 days, and the clinical lethal dose is 3-5g. Therefore, the clinical dosage of chloroquine needs to be adjusted according to individual differences of body weight and age. The efficacy and safety of remdesivir for COVID-19 treatment still lack more high-quality evidence. Therefore, the application of these chemicals in the treatment of COVID-19 should pay special attention to the latest clinical trials and drug safety studies.

TCM has been practiced clinically in China for thousands of years to relieve the symptoms of diseases and regulate immunity. TCM is of great value in prevention and treatment of COVID-19.

The therapeutic effects of TCMs, including active ingredients of TCMs, Chinese herbal compound prescriptions, and Chinese medicine injection preparations, on COVID-19 have been extensively studied. Currently, active ingredients of TCMs against SARS-CoV-2 are only studied in vitro or by computer simulation. Some studies have pointed out that GA can bind to ACE2 by the molecular docking methods, suggesting that GA preparations have potential application value for preventing J o u r n a l P r e -p r o o f SARS-CoV-2 infection. There was a study that screened several TCMs ingredients with anti-SARS-CoV-2 activity through virtual screening and enzymatic testing, including emodin, polydatin, chalcone, and shikonin. However, these active ingredients of TCMs need to pass clinical trials to further confirm their efficacy against COVID-19. HXZQ, JHQG, LHQW, SFJD, FFTS, TJQW, and QFPD suggested by Chinese health authorities have all been tried in clinical trials, all of which have shown good curative effects, such as shorten the time for the patient to heal and relieve the development from mild to severe . HXZQ can alleviate fatigue and gastrointestinal discomfort in patients with COVID-19. JHQG, LHQW, and SFJD have similar effects, which can improve the symptoms of fatigue and fever in COVID-19 patients.

JHQG has a definite effect on the treatment of mild and common patients with COVID-19, which can shorten the time of fever, improve the normalization rate of lymphocytes and leukocytes, and promote immunological function. LHQW also shows good curative effect on mild and common patients with COVID-19, which is manifested with relieving fever, cough, fatigue and other symptoms, and effectively reducing the conversion rate of mild/common to severe.

QFPD has a total effective rate of more than 90% in the early clinical treatment of COVID-19, which is suitable for mild, common, and severe patients (He et al., 2020) . QFPD Xiyanping, Reduning, and Tanreqing injections that all have anti-inflammatory and antibacterial effects can be used to treat patients with viral infection and mild bacterial infection. Xingnaojing injection has the effects of reducing fever, resuscitating and refreshing the brain, which is mainly aimed at patients with high fever following unconsciousness. Xuebijing injection can improve the cure rate and discharge rate of patients with COVID-19, reduce the chance of conversion from J o u r n a l P r e -p r o o f severe to critically ill, and promote the elimination of inflammatory factors. Shenmai injection can provide the immunity of patients, which is mainly used to treat the immunosuppressed patients.

Shenfu injection has the effect of resurrecting for patients with shock. Arachidonic acid metabolism pathway is involved in cytokine production (Xiao et al., 2005) . The latest research showed that serum levels of inflammatory factors in patients with SARS-CoV-2 infection significantly increased, suggesting that SARS-CoV-2 infection may involve "cytokine storm" (Alimuddin et al., 2020) . Studies have screened 338 active ingredients of TCMs that have potential inhibitory effects on the arachidonic acid metabolism pathway through the pharmacophore technology . Interestingly, the above active ingredients existed in HXZQ, JHQG, LHQW, QFPD, Xuebijing injection, Reduning injection, and Tanreqing injection, which suggested that the above TCMs may resist SARS-CoV-2 infection by inhibiting the "cytokine storm". Although TCMs are effective and relatively safe for prevention and treatment of COVID-19, clinical medication needs to be administered under the guidance of an experienced physician, thereby avoiding adverse reactions due to overdose or misuse of TCMs. Moreover, clinical medication based on different symptoms and the severity of the disease is an important principle during the treatment of COVID-19 with TCMs. For example, preliminary clinical studies showed that LHQW was effective for the treatment of mild or common patients with SARS-CoV-2 infection, which is manifested with the improvement of fever, cough, and diarrhea.

Xuebijing had a wonderful effect on the treatment of severe and critically ill patients with COVID-19.

Both TCMs and chemical drugs can complement each other rather than replacing each other, which has been fully demonstrated in prevention and control of this outbreak of COVID-19. TCM with a relatively wide range of treatment can improve the immunity and relieve symptoms in mild cases with COVID-19, such as fever, cough, fatigue, and sore throat. In terms of severe COVID-19, TCM can also reduce the progression from severe to critical illness, thereby reducing the mortality rate. Chemical drugs have clear chemical composition and significant antiviral effect, which can quickly inhibit SARS-CoV-2 infection. The latest clinical evidence showed that the integrated traditional and western medicine for the treatment of COVID-19 could significantly reduce the clinical symptoms of patients, shorten the course of disease, and improve the clinical cure rate . A retrospective analysis of 71 discharged patients with COVID-19 J o u r n a l P r e -p r o o f showed that the combination therapy of IFN-α, arbidol, high-dose of vitamin C, and TCMs was effective against SARS-CoV-2 . A systematic review showed that LHQW combined with western medicines significantly improved fever symptoms with good clinical safety (Qi et al., 2020) . Zhang Boli's team observed the clinical effect of integrated traditional Chinese and western medicine in the treatment of COVID-19. The results showed that compared with the pure western medicine group (13 cases of commonl type, 4 cases of severe, and 1 case of critically ill), the average days of treatment in the integrated traditional Chinese and western medicine treatment group (27 cases of common type, 6 cases of severe, and 1 case of critically ill) was shortened from 7.15 days to 5.15 days, the average recovery time of body temperature was shortened from 4.38 days to 2.64 days, the average time of hospital stay was shortened from 9.59 days to 7.38 days, the improvement rate of CT imaging was increased from 68.8% to 88.2%, clinical cure rate was increased from 61.1% to 94.1%, the conversion rate of common to severe and critically ill was reduced from 35.3% to 5.9% .

Biological products are currently an important means for treating severe COVID-19, which can effectively relieve patients' symptoms to reduce mortality. Development of biological products mainly includes IFN-α, vaccines, stem cells, and CP. Although the theoretical incidence of adverse events induced by IFN-α nebulized inhalation may be lower than that of traditional administration routes, the relevant medication monitoring should still be done . IFN-α is often used clinically in combination with other antiviral drugs to treat COVID-19, such as ribavirin and favipiravir. The dosage, drug stability, adverse reactions, and the risk of secondary infection should be fully considered during IFN aerosol inhalation. Vaccine treatment is an effective method to prevent and treat COVID-19, but the development of vaccines needs to take a long time. The safety and effectiveness of drugs in vaccine development process require sufficient clinical data to verify. Fortunately, the adenoviral vector vaccine that is independently developed by China's team has entered the phase Ⅱ clinical trials. Stem cell therapy also shows certain potential for COVID-19 treatment. The application of MSCs will give new clinical plan for COVID-19 treatment. Preliminary clinical studies have shown that CP therapy has good efficacy for severe COVID-19 treatment, but CP with high-quality antibody titers is difficult to obtain. In the absence of specific drugs, CP therapy can become a first-aid method for COVID-19 patients with severe or critically ill.

China has accumulated a bit of experience during the prevention and treatment of SARS-CoV-2 infection with the above drugs, including chemical drugs, TCMs, and biological products.

Although these drugs are expected to be specific drugs for the treatment of COVID-19, the adoption of these drugs without adequate evidence of efficacy and safety must be careful.

Nowadays, these potential drugs have been used to treat COVID-19 by many countries and regions due to the outbreak of COVID-19. The basic characteristics of these drugs, including pharmacological effects, indications, and adverse reactions, and especially advance on the treatment of COVID-19, should be understood to promote reasonable medication and guide further basic research and clinical trials.

The authors have no conflict of interest. Note: Drugs with similar efficacy can be selected according to individual conditions, or can be used in combination with another TCM. Injections should be used following the principle of starting with low doses and adjusting gradually according to clinical symptoms, which can be in combination with decoctions. Clinical application of the above TCMs requires special attention to drug contraindications, especially allergic constitution. The above usage of TCMs is for reference only, which should be adjusted appropriately according to the patient's symptoms.

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