Review Article Usage of Traditional Chinese Herbal Medicine As A

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Review Article

Usage of Traditional Chinese Herbal Medicine as a therapeutic approach against Influenza virus: A review

Accepted 14th May, 2021

ABSTRACT

Traditional Chinese Herbal Medicine (TCHM) has been prevalent in East-Asian countries since long and has been used as a common therapeutic approach to treat various diseases. Influenza virus presents epidemic and pandemic threats in seasonal outbreaks every year. Influenza A viruses (IAVs) has been a major threat of pandemic outbreaks. Influenza viruses utilize the host cellular mechanism to multiply inside the host organism. The existing anti-influenza therapies are limited and there exists a requirement of new therapeutic compounds that possess anti- influenza virus activity. Several TCHMs are used to treat influenza virus infections, whereas some TCHM compounds are undergoing randomized-controlled trials Deepika V1, Sundarrajan S2 and Ramakrishna (RCTs) to prove their safety and efficacy according to international standards. 2 S * Conventional medicine is generally preferred to traditional Chinese medicine

1Institute of Bioinformatics, Saveetha School (TCM) to heal the influenza infection. In this review, TCHM compounds that of Engineering, Saveetha Institute of Medical provide therapeutic effects to treat influenza virus infection were summarized. and Technical Sciences, Thandalam, Chennai The usage of TCHM alongside conventional therapy gives rise to an integrative 602105, Tamil Nadu, India medicinal approach with the benefits from both therapies, minimizing the side- 2 Center for Nanofibers and Nanotechnology Lab, Mechanical Engineering, National effects is also presented. TCHMs used in anti-influenza therapy, along with TCHM University of Singapore, Blk E3 05-12, 2 compounds which have undergone RCTs and TCHMs used in integrative medicinal Engineering Drive 3, Singapore 117581, approach to treat the influenza virus were summarized. Singapore

*Corresponding author. E-mail: Key words: Traditional Chinese Herbal Medicine, influenza virus, pandemic, [email protected] epidemic, anti-influenza therapy.

INTRODUCTION

TCHM is composed of combinations of herbs that are that are personalized to the patient depending on the exclusive, on the basis of TCM (Chen et al., 2006). It is diagnosis performed in consonance with Chinese diagnostic broadly used in Asia and is a rather difficult approach patterns that include checkup, smelling, palpation, inquiry compared to Western medicine. The amalgamation of herbs and listening (Li et al., 2020). WHO claims that most of the utilized in TCHM involves a hierarchy of 4 herbal division world’s population still makes use of traditional medicines namely ministerial (chief), a deputy, assistant, and envoy (TMs) for wellbeing (Parasuraman et al., 2014). The status (Chak et al., 2013). The chief disease pattern is managed by of usage of TMs varies in different places across the world. the ministerial herb. Deputy herbs address the concurrent TCHM has been utilized for treating irresistible infections conditions or assist the ministerial herb. Assistant herbs for a long time. It is used extensively for treating influenza help in decreasing the side effects caused by both and colds in Chinese clinical practice. Influenza viruses, ministerial and deputy herbs. Envoy herbs guide and focus known since the 16th century, cause serious morbidity and the action of the entire drug composition to the targeted fatality and are considered as a major health problem part of the body (Traditional Chinese Herbal Medicine, across the world. 2020). In TCHM therapy, herbalists prescribe Chinese herbs The characteristics of human influenza are sudden Academia Journal of Medicinal Plants; Deepika et al. 136

Figure 1: Publication trend in influenza virus. The literature trend from 2011 to 2021 was retrieved using search hint influenza virus (IV) with traditional Chinese herbal medicine (TCHM) and Traditional Chinese medicine (TCM) as refine keywords. Assessed on 05th March 2021

increase in the temperature of the body, followed by using search hint influenza virus (IV) with traditional headache, fatigue, dry cough and faintness (Blümel et al., Chinese herbal medicine (TCHM) and Traditional Chinese 2009). The major mode of their transmission is via aerosol medicine (TCM) as refine keywords assessed on 05th March infection, followed by direct contact with surfaces 2021. From the last decade, various publications were contaminated with the virus and mouth-nose contact focused on the therapeutic approaches for treating diseases consecutively. Influenza viruses are of two major types: caused by influenza viruses. The publication trend is seasonal and pandemic. Seasonal influenza is prone to plotted by retrieving the data from sci-finder by entering burden of disease every year, and an approximate of the search hint as ‘influenza virus’ and refine word as 500,000 individuals become deceased every year. Pandemic ‘traditional Chinese herbal medicine’, and ‘traditional influenza occurs due to the shift in viral antigens, which Chinese medicine’ which is shown in Figure 1. The graph leave the humans clueless regarding the novel virus. shows that the number of publications does not show a Aforesaid shift occurred 3 times in the previous century: (i) significant variance over the past decade. However, the H1N1-1918 (Jester et al., 2018), (ii) H2N2-1957 and (iii) number increased in 2020 and is expected to rise further in H3N3-1968; and 2 times in the present century: (i) (H1N1) the upcoming years. Influenza viruses are of 4 types, which pdm09 in 2009, (ii) COVID-19 in 2019 (currently ongoing are type A, B, C and D. Every year, the periodic influenza as of May 19, 2020) (Centers for Disease Control and epidemics are instigated by virus type A and B. These types Prevention, 2020). Various efforts are being made for the are further classified into subtypes that combine with improvement of COVID-19 vaccine. WHO says it will take an different types and cause illness in humans. Influenza approximate of 18 months for the vaccines for COVID-19 to pandemics solely occur due to IAVs. Influenza C and D type be released (Li et al., 2008). Safety strategies and disease viruses do not cause epidemics in humans. za A viruses, prevention techniques can be combined to promote hybrid based on the proteins that are present on the virus’ surface, model for organizing social gatherings without health risks such as hemagglutinin and neuraminidase, are sub- (Hanaei et al., 2020). Bio-based face masks such as wheat classified into 2 types namely H and N respectively as seen gluten biopolymer, lanosol, etc. and electrospun ultrafine in Figure 2. There are further 18 diverse H subtypes (H1- fibres can be used in face masks to counter the attack of H18) along with eleven distinctive N subtypes (N1 to N11), virus (Das et al., 2020; Zhang et al., 2021). which are in turn classified into clades and sub-clades. The The literature trend from 2011 to 2021 was retrieved major subclasses of IAVs that circulate among the people Academia Journal of Medicinal Plants; Deepika et al. 137

Figure 2: 2D representation of proteins on IAV’s surface. The picture depicts Hemagglutinin and Neuraminidase proteins that are present on the protein coat of the IAV.

are A(H1N1) and A(H3N2). Influenza B viruses are sub- along with RCTs that evaluate the efficiency of TCHMs and classified into two lineages namely Yamagata and Victoria, explore the interaction between TCHM and conventional which are further classified into clades and sub-groups medicine. similar to type A viruses. These viruses change their genetic and antigenic properties every year and circulate to cause an epidemic, whereas sometimes they change during the MECHANISM OF VIRAL REPLICATION epidemic. TCHM contributed to probable positive results in treating A virus hinges on the cell mechanism and machinery of the influenza A in the course of severe acute respiratory host for its reproduction. The structure of a virus has an syndrome (SARS) (Hsu et al., 2006; Leung, 2006). It has also envelope enclosing the viral capsid. The viral genetic been mentioned in some studies that TCHM has also material along with enzymes integrase and reverse showed promising effect in mollifying symptoms and transcriptase (RT) are enclosed in the capsid. The virus gets minimizing the course of the treatment during the H1N1 attached to the host cell surface and a fusion occurs among outbreak (Xiaoyan et al., 2018). These kinds of studies show the host cell and the virus. The virus then releases its that TCHM is a possible therapeutic method for treating capsid within the host cell. The viral capsid components get various kinds of influenza. Despite the RCTs being released followed by the dissolution of the capsid. The published for the treatment and prevention of influenza, stages of viral replication implement targets for inhibitors. any circumstantial evidence has not been established (Wu Various inhibitors involved are integrase, fusion, protease, et al., 2008). TCHM derivatives possess great reverse transcriptase, integrase and viral pharmacokinetics and bioavailability, making the active polymeraseinhibitors which are allocated as direct antiviral compounds derived from these derivatives better lead agents (Li and Peng, 2013). The RT acts on viral genetic compounds in drug designing. These characteristics of material and synthesizes a complementary strand to viral TCHM pave a way to discover novel ligands for a variety of RNA, to make it viral DNA. The integrase helps the viral receptor molecules. The functions and properties of TCHM DNA integrate with the host DNA. The host DNA undergoes are needed to be interpreted using analytical tools such as transcription and translation mechanisms as usual, but molecular pharmacology, analytical chemistry, animal with the viral genetic material integrated into it. As a result model and computational methods to promote better of this, the viral genetic material gets transcripted and utilization (Li et al., 2008; Lukman et al., 2007; Zhao et al., translated along with the host DNA, resulting in the 2010). The acknowledgement of the operative mechanisms production of viral protein components. These viral of TCHMs is one of the most challenging issues. The proteins and viral RNA arrange together and migrate effectiveness of TCHM against influenza viruses is yet to be towards the cell surface, and get released out of the cell, by certain. Hence, we intend to review various TCHMs that can a process called budding (“Replication of Retroviruses,” be used to treat illnesses caused by influenza viruses n.d.). These newly formed viruses repeat the same pattern Academia Journal of Medicinal Plants; Deepika et al. 138

and multiply in number. treating various ailments. Hypericin, hyperforin, flavonoids rutin, quercetin and kaempferol are the biologically active substances produced by SJW, which possess medical HERBAL DRUGS FOR INFLUENZA activity. Studies indicated that SJW components comprising of catechin and flavonoid are dynamic in contradiction of Ethnobotanicals, herbs and plants are in use from the influenza virus (Shrivastava and Dwivedi, 2015). Hypericin beginning of human race and are in current use around the is active against enclosed viruses and inactive against non- world for preventing and treating various diseases. These enveloped viruses (Diwu, 1995). Enveloped viruses are compounds are being used in the commercial preparation inactivated by the alteration of their viral proteins and also of modern drugs that are manufactured in the present by their ability to fuse with host cell membranes (Cohen, world (Wang et al., 2006). Herbal medicine is a preferred 2016). Tang et al. (1990) described the action of hypericin mode of treatment for some, whereas it is used as adjunct against influenza virus. therapy to conventional medicine in others. Various components such as Cordyceps, ginseng extract, St. John’s wort (SJW), turmeric, etc. are utilized as compounds in Antiviral effects of turmeric herbal medicine to cure influenza (Borrelli and Izzo, 2009). Turmeric is usually used as therapeutic remedy due to its medicinal properties, in many places across the globe Cordyceps as an herbal drug (Ahmad et al., 2020). Bioactive parts of turmeric are responsible for its medicinal properties. The volatile oil of Cordyceps, cultivates on insect larvae. Various active turmeric is one of its important components. Although the components from Cordyceps species have been isolated for dosage was not clear, a slight inhibition of influenza virus their involvement in wide range of bioactivities (Zhong et was observed when the zedoary turmeric oil spray’s al., 2009). Acidic polysaccharides are one among them, antiviral effects were studied in the respiratory region which are isolated from cultured Cordyceps militaris, (Gupta et al., 2020). showed ani-influenza virus activity by reducing virus titers in broncho-alveolar lavage fluid (BALF) and IAVs infested mice-lungs; along with a n bigger survival rate, TNF-α and Kaempferol derivatives IFN-γ levels (Ohta et al., 2007). Cordycepin, otherwise known as 3’-deoxyadenosine, is extracted from naturally Kaempferol, a flavonoid compound extracted from various occurring C. sinensis or from artificially cultured C. militaris. medicinal herbs, is used in treating many illnesses because It is involved in antiviral and immunomodulatory activities of its anti-inflammatory nature. Kaempferol glycosides are (Cao et al., 2020). identified to possess antiviral properties. Kaempferol derivatives containing rhamnose residue seem to be pretty effective against the viral ion channels and might act as Ginseng as an immunomodulator proper objects for the improvement of antiviral agents. These compounds have a great potential to inhibit the 3a Panax ginseng, a medicinal plant is in use in Eastern route of coronavirus, also included in the viral release Countries of Asia for more than 20 centuries due its mechanism (Schwarz et al., 2014). Kaempferol 3-O-α-L- pharmacological benefits (Wee et al., 2011b). Inactivated rhamnopyranoside, a derivative of kaempferol, secluded IAV and aqueous ginseng extract, when co-administered from the Zanthoxylum piperitum leaf inhibits IAV intra-nasally, led to an increase in the virus-specific replication in vitro (Ha et al., 2014). Kaempferol also antibodies levels and neutralizing activities, and also possess antiviral activities on neuraminidase enzymes of contributed to protecting immunity rather than influenza viruses and on H1N1 and H9N2 strains (Jeong et immunization with inactivated IAV alone. This co- al., 2009). administration gave an insight into extract of ginseng which act as both the mucosal adjuvant against influenza and an immunomodulator during the infection, by inducing Other herbal compounds increase of interleukin-4 and interleukin-5 and producing immune cells next to the administration of inactivated IAV Various other herbal compounds are involved in anti- (Wee et al., 2011a). influenza virus activity. Arctigenin is one such compound that exhibits anti-influenza activity in vivo (Gao et al., 2018). Chaenomeles sinesis counterbalances influenza virus by Antiviral properties of SJW stopping hemagglutination activity and also by reppressing nuclear export protein (NS2) synthesis (Sawai et al., 2008). SJW is extensively used in TCM due to their effectiveness in Lianhuaqingwen is a compound that shortens the duration Academia Journal of Medicinal Plants; Deepika et al. 139

of hyperthermia in patients compared to the patients by influenza viruses. The use of TCM for curing many treated with a conventional drug: oseltamivir (Hu et al., endemic and pandemics is mentioned in the TM paperwork 2020). Extracts from Isatis indigitica Fort directly prevent such as Shang Han Lun and Huang Di Nei Jing (Huangdi’s the infection of virus by inhibiting the enzyme activity Canon of Medicine) (He and Hou, 2013). In olden days, only (Xiaoguang and Zejing, 2014). These compounds, along a few compounds listed in traditional medical books were with other herbal compounds that help in treating influenza tested in randomized and placebo-controlled trials, due to virus infection are listed in Table 1. their limited knowledge. So, RCT is the most ideal approach to find their safety and effectiveness. Antiwei capsule was

ACTION OF TCHMS ON INFLUENZA VIRUS identified to have anti-influenza virus activity, multi-centre, randomized, double-blind, placebo-controlled clinical trial A broad spectrum of analysis is required to understand the which was undertaken to find out the safety and efficacy of effects of TCHMs on influenza virus. Various types of it. According to TCM, an antiwei capsule consists of TCHMs and other TCMs are used to cure influenza virus Mahuang (Herba Ephedra), Baimaogeng (Rhizoma (Han et al., 2016). The influenza virus enters the host Imperatae), Gegen (Radix puerariae), Guizhi (Ramulus organism and utilizes its replicative mechanism for its Cinnamoumum), Kuxingren (Semen Armeniacae Amarum.), replication and further invasion as seen in Figure 3 Ganjiang (Rhizoma Zingiberis) and Gancao (Radix (Savarino et al., 2003). The TCHMs target this viral invasion Glycyrrhizae). mechanism inside the host, halting their growth by The results demonstrated the significant decrease in the targeting the viruses at every step of their replication body temperature of the patients infected with influenza process. Various single TCHMs reportedly act on different virus. Studies of antiwei have proved the inhibition of stages of viral replication; Lonicera japonica, also known as growth of influenza A and influenza B viruses (Wang et al., honey suckle, when encoded with atypical micro RNA, 2010). Lian Hua Qing Wen is a traditional Chinese inhibits replication of influenza virus (Zhou et al., 2015); prescription composed of zhimahuang (honey-fried herba- Laggera crispate inhibits the neuraminidase activity, ephedrae), xingren (semen armeniacae amarum), lianqiao suppresses the nuclear factor kappa light chain enhancer of (fructus forsythia), bohe (fructus forsythia), banlangen activated B cells (NF-kB) pathway and viral (radix isatidis), yuxingcao (herba houttuyniae), guanzhong ribonucleoprotein (RNP) complexes, which leads to the (dryopteris setosa), jinyinhua (flos lonicera japonicae), inhibition of replication of the viruses (Guan et al., 2017); shigao (gypsum fibrosum), dahuang (radix et rhizoma rhei), polysaccharides of Houttuynia cordata thunb (HCP) guanghuoxiang (herba pogostemonis), hongjingtian (herba reportedly inhibits the toll-like receptor 4’s (TLR4) rhodiolae), and gancao (radix et rhizoma glycyrrhizae). It expression in the mice lungs, which in turn inhibits the NF- has been approved by the China State Food and Drug kB signaling and reduces the cytokine production (Vaure Administration in 2004. Oseltamivir is a conventional drug and Liu, 2014; Xu et al., 2020); root extracts of Paeonia for anti-influenza activity. After an RCT, Lianhuaqingwen is delavayi Franch. inhibit the neuraminidase activity in confirmed to have improved the symptoms of IAV infection influenza viruses (Li et al., 2016a); HESA-A, a compound in the affected individuals, better than the results compared with herbal-marine origin and Tetradium ruticarpum are to Oseltamivir (Zhao, 2014). reported to hinder the virus-host cell attachment, thus Shuanghuanglian (SHL) is a well-known TCM for treating preventing their penetration and further replication inside fever, cough and sore throat. It has been acknowledged that the host (Lin et al., 2016; Mehrbod et al., 2014); glycyrrhizic injection of SHL, prepared from the extracts of Scutellaria acid and its derivatives prevent the influenza activity baicalensis (honeysuckle) and forsythiae, can treat acute (Baltina et al., 2009; Pompei et al., 1983). It can be observed upper respiratory tract infection (Zhang et al., 2013). On that single TCHM compounds target multiple sites and the other hand, oral liquid of SHL, made from Flos lonicerae various pathways that lead to inhibition of influenza virus (Jinyinhua), Radix scutellariae (Huangqin) and Fructus replication (Figure 4). forsythia (Lianqio), is also used to treat respiratory tract infections (Zhuang et al., 2020). It has been mentioned that SHL has the potential to actively inhibit SARS-CoV-2 (Yang RCTS OF HERBAL COMPOUNDS ACTING AS ANTI- et al., 2020). Various other TCHM compounds which were INFLUENZA DRUGS studied by RCTs are listed in Table 2. The information of these RCTs was obtained from Chinese clinical trials The threat of pandemic influenza remains a constant registry. These TCHM compounds can provide a safe and concern among the public. There is a threat prone for effective way of treating the influenza virus infection, shortcoming of conventional drugs for influenza. This providing an alternative to conventional therapies. opens up new gateways for welcoming new lead compounds for combating influenza viruses. However, one can only be certain of the efficacy of the drug when it goes TCHM COMBINED WITH CONVENTIONAL MEDICINE past the clinical trials phase. This makes it important to find a safe and effective alternative to treat the infection caused Conventional medicine is the mainstream medicine that is Academia Journal of Medicinal Plants; Deepika et al. 140

Table 1: TCHM compounds that provide therapeutic effects to treat influenza virus infection.

TCHM compound Action References Acidic polysaccharide from Anti-influenza virus activity (Ohta et al., 2007) Cordyceps Ginseng extract Immunomodulatory effect (Quan et al., 2007) Flavonoid and catechin-containing Active against influenza virus (Mishenkova et al., fractions of SJW 1975) Hypericin of SJW Inactivates enveloped viruses at different points in the viral life cycle. (Lenard et al., 1993) Inhibits the ability of viruses to fuse with cell membranes. (Degar et al., 1992) Turmeric oil Viral inhibition (Huang et al., 2007) Kurokarin extract Inhibits the plaque formation of influenza virus A and B, and the release of (Knox et al., 2003) (Crude fruit extracts of wild Ribes virus from the infected cells nigrum L.) Extracts from Isatis indigotica Fort Prevention of virus infection, directly inhibit the enzyme activity of 3C-like (Lin et al., 2005) protease (3CLpro) of SARS virus. Extract from Chinese quince Inhibits the activity of influenza virus in vitro. (Hamauzu et al., (Cydonia oblonga Mill.) 2005) Chaenomeles sinensis Neutralizes influenza virus by inhibiting hemagglutination activity and by (Sawai et al., 2008) suppressing (nonstructural protein 2) NS2protein synthesis. Astragalus membranaceus Helps in boosting host defense capacity (Luo et al., 2021) Glycyrrhizin Inhibits replication of the SARS-associated virus (Cinatl et al., 2003) Houttuynia cordata (HC) extract Activates the cell-mediated immunity to prevent viral infection to combat (Lau et al., 2008) SARS Extracts of Cibotium Barometz, inhibits SARS-CoV (SARS-coronavirus) replication (Wen et al., 2011) Gentiana Scabra, Dioscorea Batatas, Cassia Tora, and Taxillus Chinese Maca (Lepidium meyenii) Possesses antiviral activity against flu-A and flu-B viruses (del Valle et al., 2014) Betula papyrifera Antiviral activity against coronavirus was identified and proved from the (Rastogi et al., methanolic plant extract of Betula papyrifera. 2015) Leaf extract of Zanthoxylum Possesses antiviral activities against influenza viruses. (Choi et al., 2008) piperitum Licorice (Glycyrrhiza uralensis Possesses antioxidant activities that inhibits pathogenic H5N1 influenza. It (Wang et al., 2015: Fischer.) is an antiviral compound and acts against SARS coronavirus. Cinatl et al., 2003) Arctigenin from Fructus arctii Inhibits viral replication, possesses anti-influenza activity (Gao et al., 2018) Huajuhong (Exocarpium Citri Prevention and treatment of COVID-19 (Wei-Wei et al., grandis) 2019) Catalpol, extracted from Rehmannia Inhibits inflammatory response in rat alveolar macrophages infected with (Li et al., 2016c) glutinosa influenza virus by downregulating Toll-like Receptor (TLR) 7, Myeloid Differentiation Factor (MyD) 88, Nuclear Factor (NF) -κB, and phospholipase A2 (PLA2). Ginsenoids Protection of human endothelial cells against influenza H9N2-induced (Yung et al., 2011) inflammation and apoptosis. Polysaccharide extract from Radix anti-IAV activity against human seasonal influenza viruses (H1N1 and (Li et al., 2017) isatidis H3N2) and avian influenza viruses (H6N2 and H9N2) in vitro. Kaempferol derivatives Inhibition of viral release mechanism in SARS coronavirus, inhibition of IAV (Zakaryan et al., replication. 2017) Psoralea corylifolia seeds Inhibition of SARS-CoV PLpro (SARS-CoV Papain-Like protease) (Kim et al., 2014) Emodin, derived from Polygonum Inhibits binding of Spike protein of SARS-CoV to angiotensin-converting (Ho et al., 2007) multiflorum enzyme 2 (ACE2). Isolated polyphenols of Broussonetia Non-competitive inhibition of CoV PLpro (Park et al., 2017) papyrifera from ethanol extract Hesperetin, derived from Citri Anti-influenza virus activity (Narkhede et al., Reticulatae Pericarpium (Chenpi) 2020) Academia Journal of Medicinal Plants; Deepika et al. 141

Table 1: Continued

Baicalein, from Scutellaria Inhibition of SARS-CoV-2 3CLpro activity in vitro, replication of SARS-CoV-2 in (Liu et al., baicalensis Vero cells. 2020) Sesquiterpene atractylon, Antiviral activity against H1N1 and H3N2 influenza viruses. (Weng, 2020) isolated from Atractylodes macrocephala

Figure 3: Diagrammatic representation of mechanism of viral replication inside a host. Represented by the permission from Savarino et al. (2003).

accepted by the present society. It is also referred to as to the conventional drug: oseltamivir. Western medicine or modern medicine. This approach sees Conventional antiviral therapeutic agents such as the human body as a bio-chemical model and the lopinavir, ribavirin, favipiravir, remdesivir, oseltamivir, therapeutic compounds are mainly the biomolecules. The chloroquine and interferon α-2b are used for treating approach where the conventional medicine is combinely individuals infected with SARS-CoV-2 and some of them for used with traditional Chinese medicine comes under treating various influenza virus infections as well (Table 3). integrative medicine approach. In this approach, both the Various TCHM compounds have the ability to mimic, traditional and conventional methods are utilized in a increase or oppose the activity of conventional medicines convenient and most effective way in the treatment. A study (Fugh-berman, 2000). Research has shown that the revealed that the span of shedding of virus in IAV in a integrative therapy works better than traditional medicine subgroup treated with integrative Western medicine and or conventional therapy alone. It has also been proven that Chinese medicine has been recorded as lesser than the the use of appropriate TCHMs along with conventional subgroups treated with Western medicine and placebo (Li medicine minimises the side effects as well as adverse et al., 2016b). Same study has also concluded that TCHMs reactions, increasing the immunity. A study which has might have a greater potential in reducing fever compared conducted eight RCTs has concluded that an integrative Academia Journal of Medicinal Plants; Deepika et al. 142

Figure 4: Action of single TCHMs on multiple targets and pathways for the inhibition of influenza virus. Represented by the permission of Xiong et al. (2020).

Table 2: A list of RCTs of TCHM compounds that possess anti-influenza virus activity.

TCHM Sample size Registration number Lian Hua Qing Wen Capsule/Granule 400 ChiCTR2000029434 Shuang Huang Lian Oral Liquid 400 ChiCTR2000029605 Shen Qi Fu Zheng Injection 160 ChiCTR2000029780 Kang Bing Du Granules 160 ChiCTR2000029781 Jin Yin Hua Tang 110 ChiCTR2000029822 Ke Su Ting Syrup /Ke Qing Capsule 72 ChiCTR2000029991 Shen Fu Injection 300 ChiCTR2000030043 Xi Yan Ping Injection 348 ChiCTR2000030117 Jing Yin Granule 300 ChiCTR2000030255 Xue Bi Jing Injection 60 ChiCTR2000030388 Tan Re Qing Capsules 72 ChiCTR2000029813 Liu Gan Shuang Jie Granule 250 ChiCTR-TRC-12004849 Liugan shuangjie heji 100 ChiCTR-IPR-14005358 Antiwei granule 360 ChiCTR-TRC-09000390 Compound Yinhua Jiedu Granule 100 ChiCTR1900027571 Qingfei Xiaoyan Pills 79 ChiCTR1900022903 Kangbingdu Oral Liquid 120 ChiCTR-TRC-10000828

approach of combining Chinese and conventional medicine integrative medicinal approach will contribute greatly to has favourable outcomes such as reduction in death rate, the world and it seems to be the way by which the symptoms and secondary fungal infections in SARS infected traditional medicine will be practiced in other parts of the patients (Liu et al., 2004). Various clinical trials of world. It is crucial to avoid toxicity that can be caused due integrative medicine have been shown in Table 4. The to the interference of both the traditional and conventional Academia Journal of Medicinal Plants; Deepika et al. 143

Table 3: Common conventional drugs used for treating influenza virus infection.

Drug Action of drug References Lopinavir/ritonavir Viral protease inhibitors (Savarino, 2005) Ribavirin RNA polymerase inhibitor (Patel, 2020) Favipiravir (T-705) RNA polymerase inhibitor(selective inhibition of RNA- (Shiraki and Daikoku, 2020) dependent RNA polymerase of influenza virus) Remdesivir neuraminidase inhibitor (Gordon et al., 2020) Oseltamivir neuraminidase inhibitor (Of et al., 1999) Zanamivir neuraminidase inhibitor (Hayden et al., 1997) Peramivir neuraminidase inhibitor (Boltz et al., 2008) Nelfinavir Viral protease inhibitor (in SARS-CoV) (Yamamoto et al., 2004) Amantadine viral M2 proton channel inhibitor (Das, 2012) Rimantadine viral M2 proton channel inhibitor (Das, 2012) Chloroquine Viral entry inhibitor (binds to viral cell surface receptor) (Devaux et al., 2020)

Table 4: RCTs for integrative medicine registered in website of Chinese clinical trial registry.

TCHM compound Conventional medicine Sample size Registration number Reduning Phosphate oseltamivir capsule 120 ChiCTR-TRC-10001082 Chaishi Tuire granules oseltamivir phosphate capsule placebo 120 ChiCTR1900027273 Kangbingdu Granules oseltamivir phosphate capsule Simulator 200 ChiCTR1900027409 Chai-shi-Tui-Re granules Oseltamivir phosphate capsules 85 ChiCTR1900028497 Xiyanping Injection, Danshen Injection Oseltamivir, Zanamivir 222 ChiCTR-TRC-10000814

approaches in integrative approach. January 1990 to December 2012 (John and Shantakumari, 2015). Although, there is a potential for the usage of TCHMs for anti-influenza treatment in children and pregnant TREATING INFLUENZA INFECTED PREGNANT WOMEN women, further RCTs need to be focused on their safety and AND CHILDREN USING TCHMS efficacy.

There exist certain inadequacies with the use of conventional medicine for treating pregnant women, which FUTURE ASPECTS OF TCHMS can be bridged by traditional Chinese medicine, by reducing the symptoms effectively. Children are easily susceptible to As a substitute for conventional therapeutic approach, TCM getting infected by the influenza virus, making them the concentrates on the treatment of the disease through major group of affected individuals. It is crucial to analyse coherence of the relationship between the study of the the effects of medicine used on children before prescribing syndrome and the body of a person. The miraculous them. Ma-huang-tang (maoto in Japanese), which does not curative effect of this is a reason for its popularity exhibit severe adverse effects, has been prescribed widely worldwide (Wang et al., 2014). Various herbal extracts and in the east-asian countries, to treat children affected with compounds have been identified to perform inhibitory influenza (Kubo and Nishimura, 2007; Saita et al., 2011). activities against the influenza virus. However, Observations are recorded regarding to its usefulness in distinguishing and purifying the active compound present new-borns and children who possess low sensitivity to in those extracts or compounds are crucial for interpreting conventional anti-influenza drugs (Nishimura et al., 2009; the mechanism of the effect of these compounds on the Toriumi et al., 2012). According to a study conducted by Hu virus, therapeutically. This in turn will provide us with an et al., Chuan Xin Lian (Andrographis paniculata) has been insight into the field of drug discovery. reported to lower the symptoms of sore throat and cough, Modernization of TCHMs will deliver resourceful as well as the duration of morbidity, compared to information to the world, promote its integration with conventional medicines (Hu et al., 2017). According to the modern biological science and technology, and thus aid for study, usage of herbal medicine among pregnant women the development of TCHM. A TCHM, to meet the ranged from 22.3 percent to 82.3 percent, in the countries international standards for its modernization, must meet of the middle-east, according to the data published from the international standards along with the evidence proving Academia Journal of Medicinal Plants; Deepika et al. 144

its efficacy and safety. This can be achieved by performing M, Jansen, B., Klamm, H., Montag-Lessing, T., Offergeld, R., Pauli, G., Seitz, placebo controlled, randomized, multi-centered and R., Schlenkrich U, Schottstedt V, Willkommen H, Von König CHW, Schweiger B (2009). Influenza virus. Transfus. Med. Hemotherapy 36: double- blind clinical trials (Li and Peng, 2013). Various 32-39. https://doi.org/10.1159/000197314 polymers, metal ions/metal oxides, nanomaterials could be Boltz DA, Ilyushina NA, Arnold CS, Babu YS, Webster RG, Govorkova EA used as antiviral coatings for treating influenza viruses (2008). Intramuscularly administered neuraminidase inhibitor (Pemmada et al., 2020). Modernization of TCHMs can be peramivir is effective against lethal H5N1 influenza virus in mice. Antiviral Res. 80(2): 150-157. achieved through the support of the government by taking Borrelli F, Izzo AA (2009). 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