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Traditional medicine preparations and particular plant metabolites in COVID-19 clinical trials

In December 2019, a new type of virus COVID-2019 first broke out in Wuhan, China, and currently the pandemic events have been reported in many countries. The NIH has declared a public health emergency for COVID-19 and is doing their part to help the scientific community to continue their research.

Patients with severe COVID-19 (or SARS-CoV-2) have rapid disease progression and high mortality rate. This may be attributed to the excessive immune response caused by "cytokine storm". Strategies based on antiviral drugs and treatments against symptoms have now been employed, however, these managements can't effectively treat the lethal lung injury and uncontrolled immune responses. Globally, all available adjuvant treatments designed to help reach the ultimate goal of recovery are currently being considered and applied. They often include Traditional Medicine means, which treat the disease from alternative perspectives and achieve satisfactory results, particularly in combination with standard Western medicine practices. Multiple NIH sources provide information on a series of policies and new research aimed to enhance the administration of traditional medicine prescriptions. They include ongoing and future clinical trials related to COVID-19. A number of research strategies are aimed to evaluate the efficacy of traditional medicine as an adjuvant treatment for severe COVID-19 [1].

Previous experiences with SARS and MERS-CoV viruses highlight the need of the early intervention with available traditional medicine, and that is relevant for SARS-CoV-2 infection. The treatment of the early stages appears beneficial to improving the clinical outcomes, reducing the risk of disease progression, accelerating recovery, and reducing intensive supportive care and long-term hospitalization.

From current experimental treatment protocols, traditional medicine prescriptions aim to alleviate the overall symptoms of the virus induced pneumonia. It has been suggested to prescribe traditional Chinese medicine concoctions such as qingfei paidu (QPD), Yang-Yin-Qing-Fei-Tang (YYQFT) and a number of others [2]. Their use is described in 4000 years old texts such as Treatise on Cold Induced Febrile Disease (Shang Han Lun) circa 280 AD and Imperial Grace Formulary of the Tai Ping Era, written in 1078-85 AD.

The herbal concoctions consist of numerous individual plants mixed to provide a synergy of actions. For example, QPD (qingfei paidu decoction) consists of Ephedrae Herb, Liquorice Root, Prunus Armeniaca, Gypsum Fibrosum (form of mineral calcium sulphate), Cinnamon Twig, Alisma Rhizoma, Polyporus, Rhizoma Atractylodis Macrocephalae, Poria mushroom, Bupleuri Radix, Scutellariae Radix, Pinelliae Rhizoma, Zingiber, Aster Root, Farfarae Flos, Belamcandae Rhizoma, Asarum, Chinese Yam, Citrus Aurantium (or Bitter Orange), Citri Reticulatae peel and Patchouli: 21 ingredients (Fig.1).

Fig. 1. Qingfei pidu decoction dry plants

The "Plant Profilers": collections of data on plant metabolites based on contemporary monographs on various plant species, provide the information on possible specific active compounds derived from medicinal plants. The evidence-based information on each Plant Profiler monograph is gathered by Natural Standard, the authority on integrative medicine. Natural Standard is a group of clinicians and researchers that systematically gathers scientific data on medicinal plants and functional foods, frequently studied for their therapeutic effects[3].

There we can find the information on plants-constituents of qingfei paidu that was proposed for and currently is on clinical trial in COVID-19 studies. For example, Bupleuri Radix, the root of B. chinense, is often used in traditional Chinese medicine. Phytochemical studies demonstrated that this plant contains essential oils, triterpenoids, flavonoids, lignans, fatty acids, and sterols. Crude extracts and pure compounds isolated from Bupleuri Radix exhibit anti-inflammatory, anticancer, antipyretic, antimicrobial, antiviral, hepatoprotective, neuroprotective, and immunomodulatory effects.

Similarly, Asari radix et rhizoma or Manchurian wild ginger, is a medical plant commonly used as an ingredient in traditional Chinese medicine. The plant's medicinal use was first recorded in the Shennong Compendium of Materia Medica: the earliest written work detailing traditional Chinese medicine, written in about 25 AD. Nowadays, this herbal drug is widely used as an antitussive and analgesic agent in the treatment of cough, rheumatoid arthritis and sinusitis. Besides lignins, flavonoids and sterols, Asari radix et rhizoma contains 1-4% essential oil, of which safrole and methyleugenol are considered to be the main components.

Next compound is Citri Reticulatae peel; among 167 of this plant's metabolites there are 50 monoterpenes, 36 sesquiterpenes, 31 esters and acids, 9 aldehydes and ketones, 6 alcohols, 3 ethers, 12 phenyl compounds, and 20 other components. Monoterpenes and sesquiterpenes are the main components of it's volatile oil.

Yang-Yin-Qing-Fei-Tang (YYQFT) is another well-known traditional mixed herbs Chinese medicine used in the treatment of chronic obstructive pulmonary emphysema, bronchitis, pneumonia, but the mechanisms of the medicine are not clear. The YYQFT is currently on multiple clinical trials as supplementary and supporting treatment in SARS-CoV-2 related illnesses.

The Yang-Yin-Qing-Fei-Tang contains Chinese Foxglove Root (Radix Rehmanniae Glutinosae), Radix Scrophulariae Ningpoensis, Tuber Ophiopogonis Japonici, Radix Albus Paeoniae Lactiflorae, Cortex Radicis Moutan, Bulbus Fritillariae Cirrhosae, Herba Menthae Haplocalycis, Radix Glycyrrhizae.

Even before the outbreak of SARS-CoV-2, YYQFT was listed by the National Institute of Cancer as a traditional medicine applied in new anticancer drug development, based on numerous research publications. A plant flavonol quercetin from the flavonoid group of polyphenols was singled out as the proposed active component of the YYQFT mix. It has been previously found to induce apoptosis in non-small cell lung cancer [4].

It has been shown that host-targeted small molecules approved for treatment of other human diseases may modulate the virus-host interactions of SARS-CoV-2. In the controlled clinical studies, the supplementary treatment with traditional Chinese medicine is shown to result in marked improvement of symptoms and shortened the disease course[5]. The individual bioactive metabolites derived from traditional medical plants may become the lead inspirations in design of new drugs. Thus tanshinone, schisandrin and kaempferol compounds from various bioactive plants are being discussed and currently in preparation for clinical trials in the treatment of pulmonary fibrosis caused by SARS-CoV-2 [6].

Identification of bioactive compounds from medical herbs that demonstrate antiviral effects is continually pursued. Due to the common homology of SARS-CoV and SARS-CoV-2, the previous studies may shed light on the particular compounds capacity to inhibit SARS-CoV-2 [7]. Thus the extracts of Chinese Rhubarb, flavonoids fractions of litchi seeds and beta-sitosterol extracted from Isatis indigotica were all reported to improve patients' conditions. Plant derived sinigrin, indigo, aloe-emodin, hesperetin, quercetin, epigallocatechin gallate, gallocatechin gallate, herbacetin, rhoifolin and pectolinarin, were able to inhibit the SARS related viral activity. Similarly flavonoids herbacetin, isobavaschalcone, quercetin 3-β-D-glucoside, and helichrysetin showed the potential to block an enzymatic activity of MERS-CoV 3CL protease.

Same as SARS-CoV, SARS-CoV-2 uses encoded protein receptor ACE2 in human lungs, kidneys and some other organs' cells for cellular entrance. Therefore bioactive compounds with the capacity to target ACE2 hold the promise to prevent the infection by SARS-CoV-2. Emodin from genus Rheum and Polygonum, baicalin from in Scutellaria baicalensis, scutellarin and luteolin from Veronicalina riifolia markedly inhibited the interaction of SARS-CoV S-protein and ACE2. However the anti-SARS-CoV activity of these compounds remains to be properly evaluated [8].

Other remarkable plant metabolites with broad antiviral and anti-inflammation activity listed in ongoing clinical COVID-19 trials [1], are colchicine (NSC 757) and aristolochic acid (NSC 11926). In the clinical trial called COLCORONA the plant metabolite colchicine is being used to reduce the excessive inflammatory reaction caused by coronavirus that may lead to acute respiratory distress syndrome, organ failure and death. COLCORONA will evaluate the phenomenon of major cytokine storm often present in adults suffering from severe complications related to COVID-19. The researchers hypothesize that the treatment by colchicine could reduce the associated complications [9, 10].

Based on the preliminary data, colchicine might alter the process of inflammasome NLP3 (a large multiprotein complex with a key role in innate immunity) and cellular microtubule formation in the pathogenetic cycle of SARS-COV-2. Could colchicine administered in a relatively low dose, potentially have an effect on the clinical course by limiting the myocardial necrosis and pneumonia development caused by COVID-19? If present, this effect could be attributed to its potential to inhibit inflammation and to the process of SARS-CoV-2 endocytosis in myocardial and endothelial respiratory cells.

Colchicine is one of the oldest remedies still in use today. It is derived from the bulb-like corms of the Colchicum autumnale plant, also known as autumn crocus (Fig.2). Its history as a herbal remedy for joint pain goes back to the 1500 BCE Egyptian manuscript, the Ebers Papyrus. The active ingredient: colchicine, was isolated in the early 1800's and remains in use today as a purified natural product.

autumn crocus
Fig. 2. Autumn crocus, source of colchicine

Another group of plant metabolites on clinical trials: aristolochic acids, are found in Aristolochiaceae plants. The plants Aristolochia and Asarum (wild ginger) are commonly used in Chinese herbal medicine (for example as a part of qingfei paidu decoction QPD) in spite of reported possible carcinogenic, mutagenic, and nephrotoxic effects.

Numerous retrospective case studies on traditional medicine intervention for the management of COVID-19 have been reported since the outbreak. A total of 28 traditional medicine guidelines that provide treatment measures for COVID-19 have been proposed. Of the 28 guidelines, there were 26 government-issued Chinese guidelines and 2 Korean professional associations issued guidelines. The Japanese government did not officially issue any traditional medicine guidelines on COVID-19, but they adopted a translated version of the national guideline issued in China [9]. The frequency of the plants used in the herbal formulae recommended for every illness stage and in total were computed. The results showed that these formulae contain 12 herbs with a frequency of use 30 or more times in the treatment formulae. Further research aims to outline particular bioactive moieties; that may eventually result in new pharmaceuticals [11].

Addressing bioactive properties and a quantification of the herb's metabolites involve notoriously elaborated analytical methods and laboratory procedures. Nuclear magnetic resonance (NMR) spectroscopy is routinely used as a technique to provide insight into a mixture of natural compounds belonging to the same or different chemical classes, often without previous separation of the individual components. The sample preparation for NMR is simple and nondestructive. In this context, NMR methods have been used with success in the structural identification of possible bioactive compounds in natural products. The metabolites database at the BMRB contains 1H, 13C, DEPT90, DEPT135, TOCSY, COSY45, HSQC, HMBC and HSQC-TOCSY-ADIA NMR spectral data for numerous compounds related to the ongoing COVID-19 related research, such as tanshinone (BMSE001333), schisandrin (BMSE001334), safrole (BMSE001265), naringenin (BMSE001121), quercetin (BMSE001176), kaempferol (BMSE001167), genistein (BMSE001174), hesperetin (BMSE001127), and of course colchicine (BMSE001341), to name several. Time domain data, spectra pictures as well as the tables of peak transitions and assigned chemical shifts are also available. Besides direct research, the data are of interest in creating the exercise modules for laboratory sessions in biochemistry, physical chemistry and instrumental analysis, and specifically useful for teaching the 1D and 2D 1H-13C data assignments by providing visual context.

6 Am J Chin Med. 2007;35(4):575-81. "The efficacy of Chinese medicine for SARS: a review of Chinese publications after the crisis" by Leung P C.
10 doi:10.1016/j.semarthrit.2015.06.013 Semin Arthritis Rheum. 2015 December; 45(3): 341-350. "Colchicine - update on mechanisms of action and therapeutic uses" by Leung, YY., et al.
11 Integrative Medicine Research, Volume 9, Issue 2, June 2020, 100407; "Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines" by Lin Ang et al.