Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial
Hasan Önal, Bengü Arslan, Nurcan Üçüncü Ergun, Şeyma Topuz, Seda Yilmaz Semerci, Mehmet Eren Kurnaz, Yulet Miray Molu, Mehmet Abdussamet Bozkurt, Nurettin Süner, Ali Kocataş
TURKISH JOURNAL OF BIOLOGY, doi:10.3906/biy-2104-16
Introduction Scientific research continues on new preventive and therapeutic strategies against severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). So far, there is no proven curative treatment for the novel coronavirus disease 2019 (COVID-19), and while vaccination is continuing worldwide, "wild" protocols based on "ancient" anti-inflammatory and anti-viral drugs are being offered. A valid and alternative therapeutic approach needs to be developed. Affecting the nasopharyngeal cells first, SARS-CoV-2 can target different tissues such as lung, vascular endothelium, kidney and nervous system at various degrees, and it can cause severe illness and death (Russo et al., 2017; Spagnuolo et al., 2018) . With the advantage of the lack of systemic toxicity, flavonoids, including quercetin are proven to potentialize the effects of routine drugs against coronavirus (Ferrer et al., 2008) . Flavonoids owe their antioxidant, anti-inflammatory and anti-viral properties against a wide range of DNA and RNA viruses, to their pleiotropic molecular structure that acts by targeting variable cells on multiple pathways
References
Ackermann, Verleden, Kuehnel, Haverich, Welte, Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19, New England Journal of Medicine,
doi:10.1056/NEJMoa2015432Askari, Ghiasvand, Feizi, Ghanadian, Karimian, The effect of quercetin supplementation on selected markers of inflammation and oxidative stress, Journal of Research in Medical Sciences
Bindoli, Valente, Cavallini, Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activity, Pharmacological Research Communications,
doi:10.1016/0031-6989(85)90041-4Bowles, Platton, Yartey, Lee, Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19, New England Journal of Medicine,
doi:10.1056/NEJMc2013656Bösmüller, Traxler, Bitzer, Häberle, Raiser, The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation, Virchows Archiv,
doi:10.1007/s00428-020-02881-xChen, Li, Luo, Liu, Xu, Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features, Bioorganic & Medicinal Chemistry,
doi:10.1016/j.bmc.2006.09.014Chen, Zhou, Dong, Qu, Gong, Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study, Lancet,
doi:10.1016/S0140-6736(20)30211-7Conti, Ronconi, Caraffa, Gallenga, Ross, Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies, Journal of Biological Regulators and Homeostatic Agents,
doi:10.23812/CONTI-EDavis, Murphy, Carmichael, Effects of the dietary flavonoid quercetin upon performance and health, Current Sports Medicine Reports,
doi:10.1249/JSR.0b013e3181ae8959Evers, Chao, Wang, Zhang, Huong, Human cytomegalovirus-inhibitory flavonoids: studies on antiviral activity and mechanism of action, Antiviral Research,
doi:10.1016/j.antiviral.2005.08.002Fauvel, Weizman, Trimaille, Mika, Pommier, Pulmonary embolism in COVID-19 patients: a French multicentre cohort study, European Heart Journal,
doi:10.1093/eurheartj/ehaa500Ferrer, Austin, Stewart, Noel, Structure and function of enzymes involved in the biosynthesis of phenylpropanoids, Plant Physiology and Biochemistry,
doi:10.1016/j.plaphy.2007.12.009Graefe, Derendorf, Veit, Pharmacokinetics and bioavailability of the flavonol quercetin in humans, Int Journal of Clinical Pharmacology and Therapeutics
Harwood, Danielewska-Nikiel, Borzelleca, Flamm, Williams, A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties, Food and Chemical Toxicology,
doi:10.1016/j.fct.2007.05.015Hottz, Azevedo-Quintanilha, Palhinha, Teixeira, Barreto, Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19, Blood,
doi:10.1182/blood.2020007252Hubbard, Stevens, Cicmil, Sage, Jordan, Quercetin inhibits collagen-stimulated platelet activation through inhibition of multiple components of the glycoprotein VI signaling pathway, Journal of Thrombosis Haemostasis,
doi:10.1046/j.1538-7836.2003.00212.xIshitsuka, Ohsawa, Ohiwa, Umeda, Suhara, Antipicornavirus flavone Ro 09-0179, Antimicrobial Agents and Chemotherapy Journal,
doi:10.1128/AAC.22.4.611Junior, Miggiolaro, Nagashima, De Paula, Baena, Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis, Frontiers in Immunology,
doi:10.3389/fimmu.2020.574862Karhausen, Choi, Maddipati, Mathew, Ma, Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury, Science Advances,
doi:10.1126/sciadv.aay6314Kim, Kim, Bae, Choi, Lim, Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection, Immune Network,
doi:10.4110/in.2013.13.2.70Kumazawa, Kawaguchi, Takimoto, Immunomodulating effects of flavonoids on acute and chronic inflammatory responses caused by tumor necrosis factor alpha, Current Pharmaceutical Design,
doi:10.2174/138161206778743565Kuznetsova, Prange, Glass, De Winther, Transcriptional and epigenetic regulation of macrophages in atherosclerosis, Nature Reviews Cardiology,
doi:10.1038/s41569-019-0265-3Lei, Jiang, Su, Chen, Chen, Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection, EClinicalMedicine,
doi:10.1016/j.eclinm.2020.100331Li, Maeda, Beck, Vitamin C deficiency increases the lung pathology of influenza virus-infected gulo-/-mice, Journal of Nutrition,
doi:10.1093/jn/136.10.2611Loke, Proudfoot, Mckinley, Needs, Kroon, Quercetin and its in vivo metabolites inhibit neutrophil-mediated low-density lipoprotein oxidation, Journal of Agriculture and Food Chemistry,
doi:10.1021/jf8003042Loke, Proudfoot, Stewart, Mckinley, Needs, Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: lack of association between antioxidant and lipoxygenase inhibitory activity, Biochemical Pharmacology,
doi:10.1016/j.bcp.2007.11.002Marchandot, Trimaille, Curtiaud, Matsushita, Jesel, Thromboprophylaxis: balancing evidence and experience during the COVID-19 pandemic, Journal of Thrombosis and Thrombolysis,
doi:10.1007/s11239-020-02231-3Mcfadyen, Stevens, Peter, The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications, Circulation Research,
doi:10.1161/CIRCRESAHA.120.317447Mendes, Gaspar, Conde, Mano, Duarte et al., Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways, Biopharmaceutics & Drug Disposition,
doi:10.1038/s41598-019-51113Nair, Kandaswami, Mahajan, Chadha, Chawda, The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells, Biochimica et Biophysica Acta,
doi:10.1016/s0167-4889(02)00328-2Palma, Vliegen, Clercq, Neyts, Selective inhibitors of picornavirus replication, Medical Research Reviews,
doi:10.1002/med.20125Palmer, Bell, Fox, Brown, Design of second generation phosphodiesterase 5 inhibitors, Current Topics in Medicinal Chemistry,
doi:10.2174/156802607779941288Pavan, Jain, Shraddha, Kumar, Properties and therapeutic application of bromelain: a review, Biotechnology Research International,
doi:10.1155/2012/976203Pearce, Befus, Bienenstock, Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigeninduced histamine secretion from rat intestinal mast cells, Journal of Allergy Clinical Immunology,
doi:10.1016/0091-6749(84)90453-6Pignatelli, Santo, Carnevale, Violi, The polyphenols quercetin and catechin synergize in inhibiting platelet CD40L expression, Thrombosis and Haemostasis,
doi:10.1160/TH05-04-0888Potus, Mai, Lebret, Malenfant, Breton-Gagnon, Novel insights on the pulmonary vascular consequences of COVID-19, American Journal of Physiology Lung Cellular and Molecular Physiology,
doi:10.1152/ajplung.00195.2020Puelles, Lütgehetmann, Lindenmeyer, Sperhake, Wong, Multiorgan and Renal Tropism of SARS-CoV-2, New England Journal of Medicine,
doi:10.1056/NEJMc2011400Ranucci, Ballotta, Dedda, Bayshnikova, Poli, The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome, Journal of Thrombosis and Haemostasis,
doi:10.1111/jth.14854Robaszkiewicz, Balcerczyk, Bartosz, Antioxidative and prooxidative effects of quercetin on A549 cells, Cell Biology International,
doi:10.1016/j.cellbi.2007.04.009Romero, Jiménez, Sánchez, López-Sepúlveda, Zarzuelo, Quercetin inhibits vascular superoxide production induced by endothelin-1: Role of NADPH oxidase, uncoupled eNOS and PKC, Atherosclerosis,
doi:10.1016/j.atherosclerosis.2008.03.007Rota, Oberste, Monroe, Nix, Campagnoli, Characterization of a novel coronavirus associated with severe acute respiratory syndrome, Science,
doi:10.1126/science.1085952Salamanna, Maglio, Landini, Fini, Platelet functions and activities as potential hematologic parameters related to Coronavirus Disease 2019 (Covid-19), Platelets,
doi:10.1080/09537104.2020.1762852Shaik, Castellani, Perrella, Conti, Salini, Role of quercetin (a natural herbal compound) in allergy and inflammation, Journal of Biologic Regulators and Homeostatic Agents
Shukor, Camp, Gonzales, Staljanssens, Struijs, Angiotensin-converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships, Journal of Agricultural and Food Chemistry,
doi:10.1021/jf404641vSmith, Smith, Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface
Spagnuolo, Moccia, Russo, Anti-inflammatory effects of flavonoids in neurodegenerative disorders, European Journal of Medicinal Chemistry,
doi:10.1016/j.ejmech.2017.09.001Uchide, Toyoda, Antioxidant therapy as a potential approach to severe influenza-associated complications, Molecules,
doi:10.3390/molecules16032032Valero, Mosquera, Alcocer, Bonilla, Salazar, Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis, Brain Research,
doi:10.1016/j.brainres.2015.06.034Zandi, Teoh, Sam, Wong, At, Antiviral activity of four types of bioflavonoid against dengue virus type-2, Virology Journal,
doi:10.1186/1743-422X-8-560Zhang, Lin, Sun, Curth, Drosten, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science,
doi:10.1126/science.abb3405Zhang, Xiao, Zhang, Xia, Cao, Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19, New England Journal of Medicine,
doi:10.1056/NEJMc2007575Zwicker, Schlechter, Stopa, Liebman, Aggarwal, Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer, JCI Insight,
doi:10.1172/jci.insight.125851
