TRADITIONAL TO RECENT APPROACHES IN HERBAL MEDICINE THERAPY OF COVID-19

Mohamed S. Refaeyimage, Marwa A.A. Fayed*image

Department of Pharmacognosy, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt.

ABSTRACT 

Coronavirus pneumonia disease (COVID-19) is a newly identified coronavirus strain that causes symptoms ranging from cold-like signs to deaths that reached millions around the world. Until this time, there is no approved vaccine has been invented for clinical use, therefore, developing an effective program for therapy is of high priority to save the lives of patients and protect others from being infected. Nature resembles a huge reservoir of anti-infectious compounds, from which innovative ideas, therapies, and products can be deduced. Chinese herbal medicine had succeeded in the treatment of other coronavirus pneumonia such as SARS, MERS and, H7N9 avian influenza which gives us hope to find the targeted remedy in the traditionally used natural herbs consumed by natives from different regions. This work aims to highlight the use of natural traditional remedies to treat viral pneumonia. This systematic review will include studies of the effects of traditional herbal medicine and its role in the treatment of COVID-19 pneumonia. Although promising results were obtained in many cases, but, only a few studies reported the fractional characterization of bioactive principles and/or mechanisms of action. It is requested that pharmaceutical industries, government agencies, and the scientific community will have a gaze at some of these plants for future research and, to find a potential drug candidates for the development of anti-SARSCoV-2 therapeutics in the near future.

Keywords: COVID-19, influenza, pneumonia, rhinovirus, SARS, traditional medicine.

INTRODUCTION

Viruses are considered as a reason for many ailments that affect humans worldwide. Most of these ailments are very complex and hard to cure, these viruses include (CV), enterovirus 71 (EV71), dengue virus (DENV), coxsackievirus, herpes simplex virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza virus, respiratory syncytial virus (RSV)and measles virus (MV), in addition to coronavirus1. Coronavirus (COVID-19), pandemic 2019, is considered a newly recognized type of coronavirus that causes severe illness varying from symptoms like flu and reaches to be fatal in a considerable percentage of people across the world [1]. This represents a global challenge as cases are increasing rapidly especially critical cases with pneumonia. Recently, over 81,000 cases, with over 2700 deaths have been reported2. The mortality rate is around 2%, most of whom need ICU admission while about 20.1 % have acute respiratory distress syndrome [2]. Therefore, there is an urgent demand to find a quick protocol and strategy for therapy for mild and severe cases. Herbal medicines and purified natural products provide a rich resource for novel remedies where some antiviral drugs have been developed and used in many herbal preparations for therapy. Traditional Chinese medicine has been widely used in China and has already played a major role in the SARS-CoV and SARS-CoV2 outbreaks3. 

In addition, in terms of the composition of herbs for the treatment of paediatric COVID-19, certain herbal formulations adopt the Chinese guidelines4. However, compared to adults, the herbs commonly used in the proposed herbal formulations for the treatment of paediatric COVID-19 lack variety4. The herbs Glycyrrhizae root and rhizome were among the most commonly used herbs in the guidelines for adult treatment of COVID-194. There is also an extensive dependence on traditional medicine in Africa5and India6 and many of them were related to SARS-CoV therapy. The goal of this study was to systematically summarize and examine the herbs commonly used in the treatment of coronavirus and some associated diseases in many regions of the globe to try to participate in finding a suitable therapy for this fatal virus.

In the current review paper, database searches using PubMed, Elsevier, Scopus, Google Scholar and Web of Science were performed until 10 June 2020 to provide up-to - date reported information.


 

Table 1: List of some Formulas used in Traditional Chinese Medicine for COVID-19.

                                                                       

 

 

Table 2: Chinese herbal medicines recommendation for pediatric COVID-19.

                                   

The following MESH terms were used in the databases referred to above for mining results: traditional herbal medicinal plants for COVID-19, antiviral effects of coronavirus, Chinese herbal medicine, natural products for coronavirus, as well as recently reported mechanisms of action were all gathered from the online bibliographical databases. As there are no known therapies for COVID-19 infection and the production of a preventive vaccine is still under investigation. Thus, to try to minimize the mortality it causes, there is an urgent need to develop effective antivirals for prophylaxis and effective COVID-19 infection control. The exploration of already used therapies in the treatment of this epidemic resembles a quick way to overcome this situation. This study will include a wide overall survey for the effects of traditional herbal medicine, some herbal formulae including their ingredients in addition to recent approaches for the herbal treatment of COVID-19. 

 


 

Table 3: Medicinal plants reported in the treatment of COVID-19and their mechanism of action.

  

The use of traditional herbal medicine for the prevention or treatment of this novel viral infection including pneumonia will be investigated. Our research was extended to include most herbs used in this aspect in most regions of the world to provide a collective review with all data required in this field. In searching for the traditionally used therapies some Chinese formulae were found listed in (Table 1) that seem to be effective7.It was found that Glycyrrhizae spp. root and rhizome is considered as one of the most used herbs in several herbal formulas followed by Scutellariae root and rhizome then come Rheum spp. and other herbs listed. These formulas were used for the treatment of several symptoms of some patients of COVID-19 as high fever and diarrhea syndromes7. It was declared at a press conference in April 2020 by a Chinese official that three patent drugs of herbal constituents were approved for the treatment of COVID-19 manifestations. These include Xuebijing injections when the cases are severe in addition to Jinhuaqinggan granules and Lianhuaqingwen capsules indicated for moderate cases. After this approval, these drugs were propagated and widely used in China for the treatment of COVID-19. It was stated that these patents relieve some symptoms as fever, cough, fatigue also it decreases the risk that these cases develop to be severe but no other details were added8. 


 

Table 4: Medicinal plants used in traditional medicine to treat upper respiratory viral infections.

    

Table 5: List of some secondary metabolites against viral respiratory tract infections.

 

Glycyrrhizae rhizoma is considered from the highly effective herbs widely used whatever is the stage of infection. It is approved as an antiviral herbal therapy by the China Food and Drug Administration (SFDA). Its mechanism was reported by many studies as it inhibits attachment, entry, and replication of the virus which was earlier used in treating SARS9,10. In addition, Glycyrrhizae Radix Rhizoma possesses an anti-inflammatory effect which is useful in the treatment of lung inflammatory cases associated with COVID-194,11. A herbal formula called Qingfei Paidu Tang was recommended for the treatment of extreme COVID-19 conditions in the Korean Guidelines, as well as its recommendation in the national Chinese guidelines for diagnosis and treatment. This formula consists of  (Ephedrae Herba 9g, Armeniacae Semen amarum 9g, Glycyrrhizae Rhizoma 6g, Gypsum fibrosum 15~30 g, Alismatis Rhizoma 9g, Cinnamomi ramulus 9g, Polyporus 9g, Poria sclerotium 15g, Atractylodis macrocephalae Rhizoma 9g, Bupleuri Radix 16g, Pinelliae Rhizoma 9g, Scutellariae Radix 6 g, Zingiberis Rhizoma Recens 9g, Farfare Flos 9 g, Asteris Radix 9g, Belamcandae Rhizoma 9g, Dioscoreae Rhizoma 12g, Asari Herba 6g, Aurantii fructus 6g, Agastachis Herba 9 and Citri unshius Pericarpium 6g). Recently, it was reported by12, that this formula boosts immunity and decreases inflammation through its effect on the lung and spleen which are considered the pathways of COVID-19. In addition, the Korean guidelines removed the Farfarae Flos herb due to its safety and toxicity4. Ang et al., presented several herbal formulas used in traditional medicine for pediatric COVID-19 cases (Table 2). They mentioned 13 herbal formulas approved by the Chinese guidelines which consist totally of 56 herbs. According to the authors, clusters of herbal pairs were used Artemisiae annuae herb and Scutellariae root in a cluster, Armeniacae seeds, and Coicis seeds in another and Ephedrae with Gypsum fibrosum.13.


 

 

Table 6: List of Indian medicinal plants and their active compounds as a best therapeutic tool to treat different viral diseases.

                                                               

Traditional medicine plays a major role in supplying communities with treatment in Africa. Medicinal plants such as Artemisia annua are known to be one of the potential therapies for COVID-19, which should be tested for effectiveness and adverse side effects. The WHO suggested testing herbs for their effectiveness and protection before conventional practice through comprehensive clinical trials is crucial [14], In the meantime, conventional medicine continues to be generally used across Africa. President Rajoelina estimated that 80 percent of the population of Madagascar uses 'COVID Organics'15. A biochemist researcher in traditional medicine at North-West University in South Africa, Professor Chrisna Gouws, reported about the use of Artemisia annua in herbal medicine “It’s a very common herbal medicine. In parts of the world, it is one of the most commonly used herbs. The scientific community has been interested in artemisinin, which is a known anti-malarial medication, since it contains”15. Collaborating with Artemi Life Inc., a US-based business and medical researchers in Denmark and Germany, the Max Planck Institute of Colloids and Interfaces, Potsdam (Germany), will be studying Artemisia annua extract and artemisinin derivatives in laboratory cell studies against the novel SARS-CoV-2 coronavirus16.

Furthermore, there are several medicinal plants and many secondary metabolites that were reported effective against viral respiratory tract infections. For example, (Table 3) explains some of medicinal plants that possessed antiviral activity against different coronavirus types and their possible mechanism of actions. While (Tables 4 and Table 5) included various herbal medicines and different secondary metabolites which reported to have activity against causes of viral respiratory infection, specially corona virus. Among these plants, the Lamiaceae family herbs, which have a completely different chemistry, primarily monoterpenoids. According to a previous study17 Salvia apiana (white sage), S. officinalis (garden sage), Thymus vulgaris (thyme), Rosmarinus officinalis (rosemary), and Prunella vulgaris (heal-all) are among the many other mints with antiviral and other beneficial effects relevant to viral respiratory infections. Generally, these are received well by patients based on taste17. Trees from two evergreen families, the Pinaceae and Cupressaceae, make up another family groups of antivirals. Pinus spp. (pine), Abies spp. (true firs), Picea spp. (spruces), Thuja spp. (cedars), and Juniperus spp. (junipers) resin and branch tips are all antiviral and inflammatory modulators with a respiratory tract affinity. All these groups are inflammation modulators, which is important for two reasons. The symptoms of viral respiratory infections are significantly due to immune responses to the infecting virus. More importantly, severe influenza is in part due to what has been dubbed “cytokine storm”: a hyper-reaction of the immune system to certain influenza strains.Thus, inflammation-modulating herbs are significant to decrease symptoms and to prevent severe consequences, at least in the case of influenza infection. Additionally, these herbs considerably have immune-stimulating effects, running the risk of rising symptoms of viral respiratory infections or making cytokine storms worse17. 

Balachandar and his colleagues reported a strategy in India to establish an effective method of viral inactivation by exploiting and infusing active compounds from naturally occurring medicinal plants into respiratory masks based on nanofiber. They listed some of the Indian medicinal plants (Table 6) that could be used as potent antiviral agents18. Moreover, Thangadurai et al., reported that Siddha or Ayurvedha traditional medicine validated a polyherbal formulation Deva chooranam (DC) with proven preclinical safety and activity against HIV and may have possible activity for the prevention and management of 2019-nCoV infection. This herbal formula includes three medicinal herbs: Cedrus deodara (Devadaru), Cinnamomum tamala (Lavanga pathiri) andAlpinia galanga (Arathai)19.

 

RECENT APPROACHES FOR TREATMENT

 

Recently, a study published by Ren et al., showed that 574 prescriptions with the key words "Warm diseases (Wenbing)", "Pestilence (Wenyi or Yibing)" or "Epidemic diseases (Shiyi)" were obtained among 96606 classical prescriptions.7. Meanwhile, among the 574 prescriptions, there were 40 forms of Chinese Medicines (CMs), 36 CMs-pairs, 6 triple-CMs-groups, with high frequency.Also, the primary targets of SARS-COV-2, namely 3CL hydrolase (Mpro) and angiotensin-converting enzyme 2(ACE2), were used to dock the main constituents from the 40 kinds by the Ligand FitDock method. The COVID-19 targets were docked with a total of 66 higher frequency compounds distributed in 26 forms of CMs, of which Gancao (Glycyrrhizae Radix et rhizoma), Dahuang (Rhei radix et rhizome), HuangQin (Scutellariae radix) and Chaihu (Bupleuri radix) contained more potential compounds. In addition, the results of the network pharmacology showed that pairs of Chinese medicines HuangQin (Scutellariae radix)and Gancao (Glycyrrhizae radix et rhizoma) might interact with targets for immune and inflammatory diseases7.

In another study conducted by chen et al., two key proteins, 3C-like protease (3CLpro) and angiotensin-converting enzyme 2 (ACE2), could be used as targets for active constituents in silico screening that stop SARS-COV-2replication and proliferation, profit from rapid SARS-COV-2 sequencing coupled with molecular modelling based on the genomes of associated viral proteins20,21. Owis et al., reported that ten flavonoids that were isolated from Salvadora persica L. aqueous extract showed remarkable binding stability at the N3 binding site of main protease of the COVID-19 to different degrees when compared with darunavir, a COVID-19 main protease inhibitor. The isolated and identified flavonoids were similar in structure which gave the opportunity to deduce the relation between their structure and the affinity to the receptors of the N3 binding site. The findings showed that the fundamental flavonol as a nucleus itself possesses an activity, in addition, the presence of rutinose in position 3 in this nucleus and the absence of O-CH3 group in ring B may be an explanation for improving the binding stability22. According to Khattab et al., cathepsins and furin, may be used for developing broad-spectrum anti-SARS-CoV therapies which target multiple viral and non-viral proteins23. A recent study by Qamar and his colleagues analyzed the 3CLpro sequence of CoV-19, developed its 3D homology model, and screened it against a library of medicinal plant containing 32,297 possible anti-viral phytochemicals/ traditional Chinese medicinal compounds and selected the top nine hits that may inhibit the action of SARS-CoV-2 3CLpro and therefore virus replication24. These compounds were 5,7,3',4'-Tetrahydroxy-2'-(3,3- dimethyl allyl) isoflav -one, myricitrin, methyl rosmarinate, 3,5,7,3',4',5'-hexahydroxy flavanone-3-O-β-D-glucopyranoside, (2S)-eriodictyol 7-O-(6''-O-galloyl)- β- Dglucopyrano-side, calceolarioside B, myricetin 3-O-β-D-glucopyranoside, licoleafol and amaranthin with docking scores ?16.35, ?15.64, ?15.44, ?14.42, ?14.41, ?14.36, ?13.70, ?13.63 and ?12.67, respectively, compared to nelfinavir (?12.20), prulifloxacin (?11.32) and colistin (?11.73).      Higher docking ratings, stronger binding energies, and closer interactions with the retained catalytic dyad residues (Cys-145 and His-41) were seen in the screened phytochemicals than nelfinavir, prulifloxacin, and colistin residues (His-41)24.

 

CONCLUSION

 

From the above reviewed studies, it is evident that different countries around the world have abundance of antiviral plants resources based on scientific findings. There are several medicinal plants traditionally used by the local people of many countries all over the world to treat coronavirus. However, there is a great deficiency to find enough studies considering the chemistry and pharmacological effects of these herbal plants. Therefore, carrying detailed ethnomedicinal studies is of great demand to discover novel active principles with promising activity against this fatal virus. Besides, very few herbs have been screened in vitro and in vivo against viruses including coronavirus, so, pharmaceuti-cal industries and/or government agencies should support more research activities in this area in order to utilize these antiviral medicinal plants for a solution against the global fatal illness (COV-19) or any threaten viral infections.

 

CONFLICTS OF INTEREST

 

The authors have no conflicts to report.

 

AUTHORS’ CONTRIBUTIONS

 

The two authors shared the research ideas, collected data, wrote the article, revised the article grammatical correction and reviewed the whole article. 

 

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