COVID-19 Herbs: Spanish In Vitro Study Finds That Phytochemicals Extracted From Angelica Archangelica Plant Shows SARS-CoV-2 Inhibitory Properties.

COVID-19 Herbs: A new study by researchers from Spain led by WorldPathol Global United S.A, Universidad de Zaragoza-Spain and various other institutions have found that non-toxic furocoumarin phytochemical extracted from the roots and seeds of the Angelica Archangelica plant was able to inhibit the SARS-CoV-2 coronavirus in vitro studies.


 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.04.410340v1
 
Angelica archangelica, commonly known as garden angelica, wild celery, and Norwegian angelica, is a biennial plant from the family Apiaceae, a subspecies of which is cultivated for its sweetly scented edible stems and roots. Like several other species in Apiaceae, its appearance is similar to several poisonous species (Conium, Heracleum, and others), and should not be consumed unless it has been identified with absolute certainty.
 
From the 10th century on, angelica was cultivated as a vegetable and medicinal plant, and achieved popularity in Scandinavia in the 12th century and is used especially in Sami culture. Angelica is a shamanic medicine among the Saami or Laplanders. It is used to flavor liqueurs or aquavits, (e.g., Chartreuse, Bénédictine, Vermouth, and Dubonnet), omelettes and trout, and as jam. The long bright-green stems are also candied and used as food decoration. Angelica is unique among the Umbelliferae for its pervading aromatic odor, a pleasant perfume entirely different from fennel, parsley, anise, caraway, or chervil. It has been compared to musk and to juniper. 
 
Angelica archangelica roots are among the most common botanicals used in gin distillation, often used in concert with juniper berries and coriander as a chief aromatic characteristic for gin. They are also used in absinthes, aquavits, and bitters, in addition to culinary uses such as jams and omelettes. The hollow stems of Angelica archangelica may be eaten. The stems are picked clean of their leaves, crystallized in sugar syrup and colored green as cake decoration or as candy.
 
The seeds and roots of the plant contains a type of phytochemicals known as  coumarins and furocoumarins. Among these are 2′-angeloyl-3′-isovaleryl vaginate, archangelicin, oxypeucedanin hydrate, bergapten, byakangelicin angelate, imperatorin, isoimperatorin, isopimpinellin, 8-[2-(3-methylbutroxy)-3-hydroxy-3-methylbutoxy]psoralen, osthol, ostruthol, oxypeucedanin, phellopterin, psoralen and xanthotoxin, can be isolated from a chloroform extract of the roots of A. archangelica as well as several heraclenol derivatives. The water root extract of A. archangelica subsp. litoralis contains adenosine, coniferin , the two dihydrofurocoumarin glycosides apterin and 1′-O-β-d-glycopyranosyl-(S)-marmesin (marmesinin), 1′-O-β-d-glucopyranosyl-(2S, 3R)-3-hydroxymarmesin and 2′-β-d-glucopyranosyloxymarmesin.
 
The current COVID-19 is currently wreaking havoc across the world with more than 66 million infected cases globally and more than 1.52 million people have died so far. In America, the worst hit country, more than 14.4 million individuals have been infected and almost 280,000 American have died so far from the COVID-19 disease. To date there is no effective drugs or therapeutics to treat the disease and scientist are now turning to herbs and phytochemicals for possible solutions.
 
The Spanish study team have identified purified furocoumarin-related phytochemical compound called (ICEP4) from the roots and seeds of the Angelica archangelica  plan.
 
ICEP4-related herbal preparations have been extensively used as active herbal ingredient in traditional medicine treatments in several European countries.
 
The phytochemical extracted through a patented process has showed previously strong manufacturing robustness, long-lasting stability, and repeated chemical consistency.
 
In the study the researchers show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARSCoV-2 challenged Vero E6 cellular cultures by using 34.5 and 69 µM doses. No dose related ICEP4 toxicity was seen on Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) and Natural Killer T (NKT) cells. No dose related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNFα release in cell supernatant. No survival rate decrease was observed neither on 24-hour acute nor 21-days chronic in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins.
 
Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA).
 
The characteristic ICEP4 chemical compounding and its safe TTC let us to assume that an antiviral first-observed natural compound has been discovered. Potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe widely extended remedy, which may be ready-to-go for large-scale clinical trials under EMA emergency regulatory pathway.
 
The phytochemical coumarins comprise a large class of compounds found within medicine herbal preparations. https://pubmed.ncbi.nlm.nih.gov/1491033/
 
https://pubmed.ncbi.nlm.nih.gov/12049815/
 
https://pubmed.ncbi.nlm.nih.gov/2078993/
 
These phytochemicals are found at high levels in some essential oils, particularly cinnamon bark oil, cassia leaf oil and lavender oil. Coumarin is also found in fruits (e.g. bilberry, cloudberry), green tea and other foods such as chicory. Most coumarins occur in higher plants, with the richest sources being the Rutaceae and Umbelliferae. Although distributed throughout all parts of the plant, the coumarins occur at the highest levels in the fruits, followed by the roots, stems and leaves. Environmental conditions and seasonal changes can influence the occurrence in diverse parts of the plant.
 
Psoralens are natural products, linear furanocoumarins (most furanocoumarins can be regarded as derivatives of psoralen or angelicin), that are extremely toxic to a wide variety of prokaryotic and eukaryotic organism. Some important psoralen derivatives are xanthotoxin, imperatorin, bergapten and nodekenetin.
 
Demonstrated activities of coumarins are anticoagulant, anticancer, antioxidant, antiviral, anti-diabetics, anti-inflammatory, antibacterial, antifungal and anti-neurodegerative agents as drugs, and, additionally, as fluorescent sensors for biological systems. https://pubmed.ncbi.nlm.nih.gov/29595110/
 
The genus Angelica litoralis is comprised of over 90 species spread throughout most areas of the globe. More than half of these species are used in traditional therapies, while some of them are included in several national and European pharmacopoeias.
 
Bioactive constituents in different Angelica species include coumarins, EOs, polysaccharides, organic acids and acetylenic compounds.
 
In vitro testing confirmed cytotoxic, anti-inflammatory, antibacterial, antifungal, neuroprotective and serotonergic activities for extracts obtained from a range of Angelica species. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052638/
 
https://pubmed.ncbi.nlm.nih.gov/15646793/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833429/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254726/
 
https://pubmed.ncbi.nlm.nih.gov/19113871/
 
https://pubmed.ncbi.nlm.nih.gov/18087802/
 
Past studies have showed that many species of Angelica genus, e.g. A. acutiloba, A. archangelica, A. atropupurea, A. dahurica, A. japonica, A. glauca, A. gigas, A. koreana, A. sinensis, A. sylvestris, etc., have been used for centuries as anti-inflammatory, expectorant and diaphoretic, and remedy for colds, flu, influenza, coughs, chronic bronchitis, pleurisy, headaches, fever, and diverse bacterial and fungal infections, among others. https://pubmed.ncbi.nlm.nih.gov/15180579/
 
Active principles isolated from these plants mainly include various types of coumarins, acetylenic compounds, chalcones, sesquiterpenes and polysaccharides. Frequently, most of the existing conventional antiviral treatments frequently lead to the development of viral resistance combined with the problem of side effects, viral re-emergence, and viral dormancy. https://pubmed.ncbi.nlm.nih.gov/32837854/

Currently the World Health Organization (WHO) also supports and welcomes innovations around the world regarding scientifically proven traditional medicine, to increase clinical alternatives of safe antiviral therapies. https://www.who.int/medicines/publications/traditional/trm_strategy14_23/en/
 
The Angelica archangelica-related phytochemical ICEP4 has shown a significant in vitro cytoprotective effect in SARS-CoV-2-challenged Vero E6 cellular cultures by using 34.5 and 69 µM doses (0.75 and 1.5 µg/dose). Successful ICEP4 doses against SARS-CoV-2 are included within the maximum TTC of furocoumarin as herbal preparation or remedy. https://www.ema.europa.eu/en/risks-associated-furocoumarins-contained-preparations-angelica-archangelica-l
 
Total daily human exposure to coumarins from dietary or cosmetic sourcesis 0.06 mg/Kg/day, with a total daily dose of 0.2% furocoumarins (1.2 µg/Kg/day). https://cms.herbalgram.org/expandedE/Angelicaroot.html?ts=1606421458&signature=48b9cd2ad7fcc5d691784102f498e149&ts=1606558508&signature=2a594d9c3c4a6b38629367878c8d059a&ts=1607172074&signature=2946c8324cf0b667105bf60dbd202c0a
 
No adverse effects of coumarin have been reported in susceptible species in response to doses which are more than 100-fold the maximum human daily intake, such as it happened with successfully-used ICEP4 doses (1.5 µg in 100 µL per well). https://link.springer.com/article/10.1007/BF02975883
 
It is worthy to mention than non-cytotoxic proof-of-concept ICEP4 dose is 4-fold lower than antiproliferative cytotoxicity threshold observed in previous Angelica-related studies. https://pubmed.ncbi.nlm.nih.gov/16158920/
 
https://pubmed.ncbi.nlm.nih.gov/15796173/
 
https://europepmc.org/article/med/15813373
 
The study team said, “These study findings might open the possibility to further studies for druggability of ICEP4. Remarkably, high-virulent SARS-CoV-2 strain has been used during the experiment so, we can postulate ICEP4-related herbal drug as a promising potential treatment for COVID19.”
 
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