key: cord-1004291-fntaybil authors: Oesch, Franz; Oesch-Bartlomowicz, Barbara; Efferth, Thomas title: Toxicity as prime selection criterion among SARS-active herbal medications date: 2021-01-28 journal: Phytomedicine DOI: 10.1016/j.phymed.2021.153476 sha: d9b91989d7bb221ded43f68293e430c4c6f9a4db doc_id: 1004291 cord_uid: fntaybil We present here a new selection criterion for prioritizing research on efficacious drugs for the fight against COVID-19: the relative toxicity versus safety of herbal medications, which were effective against SARS in the 2002/2003 epidemic. We rank these medicines according to their toxicity versus safety as basis for preferential rapid research on their potential in the treatment of COVID-19. The data demonstrate that from toxicological information nothing speaks against immediate investigation on, followed by rapid implementation of Lonicera japonica, Morus alba, Forsythia suspensa, and Codonopsis spec. for treatment of COVID-19 patients. Glycyrrhiza spec. and Panax ginseng are ranked in second priority and ephedrine-free Herba Ephedrae extract in third priority (followed by several drugs in lower preferences). Rapid research on their efficacy in the therapy - as well as safety under the specific circumstances of COVID-19 - followed by equally rapid implementation will provide substantial advantages to Public Health including immediate availability, enlargement of medicinal possibilities, in cases where other means are not successful (non-responders), not tolerated (sensitive individuals) or just not available (as is presently the case) and thus minimize sufferings and save lives. Moreover, their moderate costs and convenient oral application are especially advantageous for underprivileged populations in developing countries. Further drawbacks are technical inconveniences (such as the necessity of intravenous 66 treatment of remdesivir) or quite massive adverse side effects, especially true for chloroquine. 67 One treasury of rapidly available medications with acceptable side effects has been largely 73 Codonopsis spec., Glycyrrhiza spec., Panax ginseng which were useful for SARS therapy 74 may also be useful to fight COVID-19. 75 Undesirable effects of any drug obviously are essential limiting factors. Thus, the degree of despair, believing in their safety "as natural products" without knowledge of their respective 84 safety or toxicity. 85 In China more than 85% of SARS-CoV-2-infected patients received therapies from traditional 86 Chinese medicine . It is of outstanding importance, therefore, to 87 disseminate the knowledge on the safety versus toxicity of these drugs. Many of them may in 88 fact have therapeutic or preventive potential for COVID-19. The relative safety or toxicity of 89 them may represent a rational basis for prioritizing urgently needed, convincing research on 90 potentially useful herbal drugs with a much longer experience than with relatively newly 91 developed drugs. It is not impossible that some of the latter may lead to adverse effects, which 92 do not become visible in controlled clinical trials, but only after a latency of several decades 93 (as we painfully had to learn with many carcinogens). At present, we do not yet have The intention of this review article is to specifically provide an overview on published results 111 on preclinical toxicity studies. Chinese medicine with its millennia-long experience follows 112 holistic principles, i.e. the complexity of the human body is seen in its entirety. Hence, 113 fighting diseases starts already with prevention and disease treatment attempts to restore the 114 disease-causing imbalances in the whole body. This is achieved by influencing the meridians internal practices are used (e.g. complex herbal mixtures, meditation and others). By contrast, 119 western academic medicine follows reductionistic approaches to reduce the complex diseases 120 to its single disease causes and fight diseases by attacking single disease mechanisms. Drug development and marketing underlies strict rules and regulations to ensure safety and 122 efficacy of new drugs. Like Western academic medicine, Chinese medicine also aims to apply 123 6 efficient and safe medications. This is reached by bringing the right plant constituents 124 together in herbal mixtures. In this context, the "emperor-minister-servant" principle is of 125 interest. The "emperor" plant exerts the main pharmacological effect, the "minister plants" 126 support the activity of the "emperor" plant, and the "servant" can reduce possible side effects 127 and toxicities. During the past decades, Chinese medicine gained enormous interest in the 128 Western world as a complement to academic Western medicine. If Chinese medicine should 129 find its way to the European pharma-market, applicable laws for drug approval have to be In the present review, our intention is to give an over view on the toxicology of Chinese 139 plants that may help to treat COVID-19. While specific reviews on the toxic effects are rare or Based on their already existing safety profile, the data presented here may provide a rational 149 basis for ranking individual herbal medications for investigations on efficacy against COVID-150 19 (or, where the safety profile shows no concern, possibly even carefully controlled, 151 immediate compassionate use). Potential advantages for patients' welfare and Public Health The aqueous extract of the fruit of Forsythia is widely used in traditional medicines against 223 many frequently occurring disorders including inflammation, pain, fever, nausea, vomiting 224 and abscess, leading to a rich treasure of information on its use . Ephedrae was associated with liver damage at low incidence (Woo et al., 2015) . More 369 frequently the use of Herba Ephedrae led to myocardial infarction, stroke and sudden death. These cardiovascular adverse effects did not depend on preexisting vascular or heart disease 371 and did not only occur at massive doses, rather they were reported to have occurred within the 372 manufacturer's dosing guidelines (Samenuk et al., 2002) . This practically excludes Herba Acute and subchronic (28 days) oral toxicity studies of Codonopsis 616 lanceolata extract in Sprague-Dawley rats Moracin M inhibits airway inflammation by 618 interrupting the JNK/c-Jun and NF-κB pathways in vitro and in vivo Protective effects of luteolin against 621 lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt 622 pathways in neutrophils Structure of a new 624 echinocystic acid bisdesmoside isolated from Codonopsis lanceolata roots and the cytotoxic 625 activity of prosapogenins The history of Ephedra (ma-huang) Safety and tolerability of Panax 628 ginseng root extract: a randomized, placebo-controlled, clinical trial in healthy Korean 629 volunteers Acute and repeated dose 26-631 week oral toxicity study of 20(S)-ginsenoside Repeated-dose 26-week oral toxicity study of 634 ginsenoside compound K in Beagle dogs Quality assessment of Radix Codonopsis by 636 quantitative nuclear magnetic resonance Pharmacokinetic mechanisms underlying the 638 detoxification effect of Glycyrhizae Radix et Rhizoma (Gancao): Drug metabolizing 639 enzymes, transporters and beyond Pharmacokinetic mechanisms underlying the 641 detoxification effect of Glycyrrhizae Radix et Rhizoma (Gancao): Drug metabolizing enzymes, 642 transporters, and beyond Honeysuckle-encoded microRNA2911 inhibits 644 enterovirus 71 replication via targeting VP1 gene Lonicerae japonicae flos and Lonicerae flos: a 646 systematic review of ethnopharmacology, phytochemistry and pharmacology Chinese herbal medicine for treating novel coronavirus (COVID-19) pneumonia: protocol for 650 a systematic review and meta-analysis Safety evaluation of mulberry leaf extract Acute, subacute toxicity and genotoxicity studies ginsenoside Rb1 using a whole mouse embryo culture model Chinese herbs combined with Western medicine for 657 severe acute respiratory syndrome (SARS) Chinese herbs combined with Western 659 medicine for severe acute respiratory syndrome (SARS). Cochrane Database Syst Rev Chronic toxicity of ginsenoside Re on Sprague-Dawley 662 rats Safety assessment of the fermented Phylloporia ribis 664 (Lonicera japonica Thunb.) mycelia by oral acute toxicity study in mice and 90-day feeding 665 study in rats Metabolic changes after licorice consumption: A 667 systematic review with meta-analysis and trial sequential analysis of clinical trials Evaluation of 670 antibody-dependent enhancement of SARS-CoV infection in rhesus macaques immunized 671 with an inactivated SARS-CoV vaccine Can Chinese medicine be used for prevention 673 of corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence 674 and current prevention programs Pharmacological perspective: Glycyrrhizin may be an 676 efficacious therapeutic agent for COVID-19 Focus on receptors for coronaviruses with special 678 reference to angiotensin-converting enzyme 2 as a potential drug target -A perspective Ephedrae herba, an oriental traditional medicine, on the growth of influenza A/PR/8 virus in 682 MDCK cells Caution urged on SARS vaccines A 28-day repeated dose toxicological study 685 of an aqueous extract of Morus alba L Ephedra-containing dietary supplements in 687 the US versus Ephedra as a Chinese medicine Antithrombotic effect of glycyrrhizin, a plant-derived thrombin inhibitor Glycyrrhizin exerts antioxidative effects in 692 H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory 693 gene expression Phosphorylated Codonopsis pilosula polysaccharide 695 could inhibit the virulence of duck hepatitis A virus compared with Codonopsis pilosula 696 polysaccharide Effects of soya 698 bean flakes and liquorice root extract on enzyme induction and toxicity in B6C3F1 mice Quality, safety and efficacy 701 profiling of ginseng adventitious roots produced in vitro Genotoxicity studies on licorice flavonoid 704 (LFO) Licorice Toxicology and carcinogenesis studies 708 of ginseng (CAS No. 50647-08-0) in F344/N rats and B6C3F1 mice (gavage studies) Toxicological effects of Glycyrrhiza 711 glabra (Licorice): A review Glycyrrhizin attenuates mucus production by inhibition of MUC5AC mRNA expression in 714 vivo and in vitro Mechanisms of toxication and detoxication which 716 challenge drug candidates and drugs in: Comprehensive Medicinal Chemistry (Taylor 717 &Triggle cAMP-dependent 719 phosphorylation of CYP2B1 as a functional switch for cyclophosphamide activation and its 720 hormonal control in vitro and in vivo Liquorice and its health implications Licorice abuse: time to send a 724 warning message Review of current and "omics" methods 727 for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines 728 and mushrooms Review of cases of patient risk associated with ginseng abuse and 730 misuse Toxicological study on MUNOPHIL, water 732 extract of Panax ginseng and Hericium erinaceum in rats Licorice extract increases cyclophosphamide 735 teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA Subchronic oral toxicity study of Korean red 738 ginseng extract in Sprague-Dawley rats with a 4-week recovery period Subacute oral toxicity study of Korean red 741 ginseng extract in Sprague-Dawley rats Liquorice 743 (Glycyrrhiza glabra): A phytochemical and pharmacological review Liquorice may tackle SARS Characterization, crystal structure and cytotoxic 747 activity of a rare iridoid glycoside from Lonicera saccata De novo transcriptome assembly and 750 characterization of nine tissues of Lonicera japonica to identify potential candidate genes 751 involved in chlorogenic acid, luteolosides, and secoiridoid biosynthesis pathways Identifying potential treatments of COVID-19 754 from traditional Chinese medicine (TCM) by using a data-driven approach Adverse cardiovascular events 757 temporally associated with ma huang, an herbal source of ephedrine Pharmacologic 760 treatments for coronavirus disease 2019 (COVID-19): A review Safety and efficacy of Panax 762 ginseng during pregnancy and lactation Subacute oral toxicity and 764 bacterial mutagenicity study of a mixture of Korean red ginseng (Panax ginseng C Codonopsis lanceolata attenuates allergic lung 767 inflammation by inhibiting Th2 cell activation and augmenting mitochondrial ROS dismutase 768 (SOD2) expression Lonicera japonica Thunb.: 770 ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese 771 medicine Quality and risk of bias in Panax 773 ginseng randomized controlled trials: a review Licorice extract does not impair the male 775 reproductive function of rats Aqueous 777 extract of Forsythia viridissima fruits: Acute oral toxicity and genotoxicity studies 13-week subchronic toxicity study of 780 a novel ginsenoside composition from ginseng leaves in rats Evaluation of the genotoxicity of 782 ginseng leaf extract UG0712 Lancemaside A from Codonopsis lanceolata 784 prevents hypertension by inhibiting NADPH oxidase 2-mediated MAPK signalling and 785 improving NO bioavailability in rats Structural 787 characterization of three polysaccharides from the roots of Codonopsis pilosula and their 788 immunomodulatory effects on RAW264.7 macrophages Research progress of glycyrrhizic 790 acid on antiviral activity Abnormal coagulation parameters are associated 792 with poor prognosis in patients with novel coronavirus pneumonia Advances on antiviral activity of Morus spp. 795 plant extracts: Human coronavirus and virus-related respiratory tract infections in the 796 spotlight Acute and 798 subacute toxicity study of the ethanol extract from Lonicera japonica Glycyrrhizic-acid-based carbon dots with high 801 antiviral activity by multisite inhibition mechanisms Immunization with SARS 803 coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS 804 virus Glycyrrhizin, an active 806 component of licorice roots, reduces morbidity and mortality of mice infected with lethal 807 doses of influenza virus A comprehensive review for phytochemical, 809 pharmacological, and biosynthesis studies on Glycyrrhiza spp Traditional Chinese medicine 811 for the treatment of influenza: A systematic review and meta-analysis of randomized 812 controlled trials International expansion 814 of a novel SARS-CoV-2 mutant Contribution of traditional Chinese medicine 816 to the treatment of COVID-19 Liquorice, a unique "guide 818 drug" of traditional Chinese medicine: A review of its role in drug interactions Antiviral activity of fermented ginseng extracts 821 against a broad range of influenza viruses Phytochemistry, pharmacology, quality control and 823 future research of Forsythia suspensa (Thunb.) Vahl: A review A double-blind placebo-controlled randomized trial evaluating the effect of polyphenol-827 rich herbal congee on bone turnover markers of the perimenopausal and menopausal women Screening of antiviral components of ma huang tang 830 and investigation on the Ephedra alkaloids efficacy on influenza virus type A Suppression of inflammatory mediators and matrix metalloproteinase (MMP)-13 by Morus 834 alba stem extract and oxyresveratrol in RAW 264.7 cells and C28/I2 human chondrocytes Drug-induced liver injury: A 2-year 837 retrospective study of 1169 hospitalzed patients in a single medical center The severity of toxic reactions 840 to Ephedra: comparisons to other botanical products and national trends from Genotoxicity and 28-day oral 843 toxicity studies of a functional food mixture containing maltodextrin, white kidney bean 844 extract, mulberry leaf extract, and niacin-bound chromium complex Shufeng Jiedu, a promising herbal therapy for moderate 848 COVID-19:Antiviral and anti-inflammatory properties, pathways of bioactive compounds, 849 and a clinical real-world pragmatic study Labdane 851 diterpenoids from Forsythia suspensa with anti-inflammatory and anti-viral activities Trifunctional inhibition of COX-2 by extracts 854 of Lonicera japonica: direct inhibition, transcriptional and post-transcriptional down 855 regulation Traditional Chinese Medicine in the 857 Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and 858 Perspective Traditional Chinese medicine in the 860 treatment of patients infected with 2019-new voronavirus (SARS-CoV-2): A review and 861 perspective Morus alba 863 stem extract suppresses matrix metalloproteinases (MMP)-1, MMP-9, and tissue inhibitors of 864 metalloproteinase (TIMP)-1 expression via inhibition of IκBα degradation Porphyromonas gingivalis LPS signal in THP-1 cells Repeated dose 28-day oral toxicity study of a 867 botanical composition composed of Morus alba L. and Acacia catechu in rats Traditional Chinese medicines (TCMs) for 870 molecular targeted therapies of tumours Shuangkangsu: a novel natural cyclic peroxide from Lonicera japonica (Thunb.) Computational screening of antagonists 875 against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking Therapeutic options 878 of TCM for organ injuries associated with COVID-19 and the underlying mechanism A natural AKT inhibitor swertiamarin targets AKT-881 PH domain, inhibits downstream signaling, and alleviates inflammation Systems pharmacological study illustrates the 885 immune regulation, anti-infection, anti-inflammation, and multi-organ protection mechanism 886 of Qing-Fei-Pai-Du decoction in the treatment of COVID-19 Anti-inflammatory 888 and anti-viral labdane diterpenoids from the fruits of Forsythia suspensa Prevention and 891 treatment of COVID-19 using Traditional Chinese Medicine: A review Network 894 pharmacology analysis of the therapeutic mechanisms of the traditional Chinese herbal 895 formula Lian Hua Qing Wen in Corona virus disease 2019 (COVID-19), gives fundamental 896 support to the clinical use of LHQW Effect of forsythiaside A on the RLRs signaling 898 pathway in the lungs of mice infected with the influenza A virus FM1 strain