CHAPTER


DOI :10.26650/BB/CH22.2020.008.27   IUP :10.26650/BB/CH22.2020.008.27    Full Text (PDF)

Plant-Based Natural Compounds in Clinical Trials of COVID-19 (SARS-Cov-2) Treatment

Emine Akalın UruşakMiraç EkiciZinar AlanAyşenur Yaman BucakAli Yağız Üresin

Numerous drug and active natural substances for the treatment and prophylaxis during the COVID-19 pandemic are being tested all over the world. However, although treatment protocols are being developed in each country, in order to reduce the lethal effects of the disease, no drugs or natural compounds have been defined for the prevention and treatment of COVID-19. In this review, the selected active compounds are plant-derived substances and are not synthesised. While the country where natural compounds are being tested most frequently is China, they are also being tried in many countries, especially European countries. Ten natural compounds have been included in the study; colchicine, curcumin, artemisinin, resveratrol, silymarin, thymoquinone, aescin, hesperidin, diosmin and quercetin. These products are being used either alone or in combination. Colchicine is being tested most frequently. The general mechanisms of action of the selected natural compounds on COVID-19 are being identified with antiviral effects and anti-inflammatory activity by inhibiting the synthesis of inflammatory cytokines. There are in vitro studies investigating some plant-based active substances that can interfere with viral entry into cells via ACE2 receptors. This is one of the most frequently investigated antiviral mechanisms of action. In the treatment of COVID-19 infection, all clinical trials must be completed in order to understand and evaluate the results of the effectiveness of natural compounds. The main disadvantage in plant-based compounds is that less clinical trials are conducted compared to synthetic compounds.


DOI :10.26650/BB/CH22.2020.008.27   IUP :10.26650/BB/CH22.2020.008.27    Full Text (PDF)

COVID-19 (SARS-CoV-2) Tedavisinde Klinik Çalışmalarda Yer Alan Bitkisel Kökenli Doğal Bileşikler

Emine Akalın UruşakMiraç EkiciZinar AlanAyşenur Yaman BucakAli Yağız Üresin

COVID-19 küresel salgınında, hastalığın tedavisi ve profilaksisi için, dünyada çok sayıda ilaç ve doğal kaynaklı etken madde denenmektedir. Her ne kadar, her ülkede hastalığın ölümcül etkisini azaltmak için tedavi protokolleri geliştirilse de önleme ve tedavi için herhangi bir ilaç veya doğal bileşik bulunmamıştır. Derlemede seçilen etken maddeler, sentetik olmayan bitkilerden elde edilen etken maddelerdir. Doğal bileşiklerin en çok test edildiği ülke Çin iken, birçok Avrupa ülkesinde de çalışmalar yapılmaktadır. Çalışmaya, kolşisin, kurkumin, artemisinin, resveratrol, silimarin, timokinon, essin, hesperidin, diosmin ve kersetinden oluşan on adet doğal kaynaklı bileşik dâhil edilmiştir. Bu maddeler tek başlarına veya kombine halde kullanılmaktadır. Kolşisin en çok çalışılan maddedir. Seçilen doğal bileşiklerin COVID-19 üzerine etki mekanizmaları genel olarak antiviral etki ve enflamatuvar sitokinlerin sentezini baskılayarak ortaya çıkan antienflamatuvar aktivite ile tanımlanmaktadır. Antiviral etki mekanizmalarından biri olarak en sık araştırılan ACE2 reseptörleri aracılığıyla hücrelere viral girişi etkileyecek bitkisel kökenli etkin maddelerin araştırıldığı in vitro çalışmalar mevcuttur. COVID-19 enfeksiyonu tedavisinde, doğal bileşiklerin etkinliği ile ilgili sonuçların görülmesi ve değerlendirilmesi için tüm çalışmaların tamamlanmış olması gerekmektedir. Bitki kökenli bileşiklerin en başta gelen dezavantajı ise, haklarında sentetik bileşiklere göre çok daha az klinik çalışma yapılmış olmasıdır.



References

  • 1. World health organization (WHO). Coronavirus disease (COVID-19) pandemic. (cited 2020, July 22) Available from: URL:https://www.who.int/emergencies/diseases/novel-coronavirus-2019?gclid=CjwKCAjwx9_4BRAH EiwApAt0zuD7J-ugpk4jawYQsY9hACh6jPPGUoBTfsxEWK4LVA2u5ru-4ptcZxoCDecQAvD_BwE google scholar
  • 2. Akalın E, Ekici M, Alan Z, Özbir Elevli E, Yaman Bucak A, Aobuliaikemu N, et al. Traditional Chinese medicine practices used in COVID-19 (Sars-CoV-2/Coronavirus-19) treatment in clinic and their effects on the cardiovascular system. Archives of the Turkish Society of Cardiology. 2020; 48(4): 410-24. google scholar
  • 3. Natural medicines, Professional monograph, Colchicum autumnale. (serial online) (cited 2020 July 20) Available from: URL: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/ professional.aspx?productid=282 google scholar
  • 4. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins W, editors. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. New York: Thieme; 2003. google scholar
  • 5. Gruenwald J, Brendler T, Jaenicke C, editors. PDR for Herbal Medicines. 2nd ed. Montvale: NJ: Thomson Medical Economics; 2000. 282 COVID-19 (SARS-CoV-2) Tedavisinde Klinik Çalışmalarda Yer Alan Bitkisel Kökenli Doğal Bileşikler google scholar
  • 6. Li TSC. Chinese and Related North American Herbs Phytopharmacology and Therapeutic Values. Second edition. New York: CRC Press Taylor & Francis Group; 2009. google scholar
  • 7. Committee on Herbal Medicinal Products (HMPC). European Medicines Agency (EMA). Assessment report on Vitis vinifera L., folium: 2017 May. Report No: EMA/HMPC/464682/2016 google scholar
  • 8. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins W, et al. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. 1st ed. Austin TX: American Botanical Council, Lippincott Williams & Wilkins; 1998. google scholar
  • 9. Abdel-Zaher AO, Abdel-Rahman MS, Elwasei FM. Protective effect of Nigella sativa oil against tramadol-induced tolerance and dependence in mice: role of nitric oxide and oxidative stress. Neurotoxicology. 2011; 32(6): 725-33. google scholar
  • 10. Assayed ME. Radioprotective effects of black seed (Nigella sativa) oil against hemopoietic damage and immunosuppression in gamma-irradiated rats. Immunopharmacol Immunotoxicol. 2010; 32(2): 284-96. google scholar
  • 11. Boskabady MH, Mohsenpoor N, Takaloo L. Antiasthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomedicine. 2010; 17(10): 707-13. google scholar
  • 12. Goreja WG. Black seed: nature’s miracle remedy. New York, NY: Amazing Herbs Press; 2003. google scholar
  • 13. Khaled AAS. Gastroprotective effects of Nigella Sativa oil on the formation of stress gastritis in hypothyroidal rats. Int J Physiol Pathophysiol Pharmacol. 2009; 1: 143-9. google scholar
  • 14. Sirtori CR. Aescin: pharmacology, pharmacokinetics and therapeutic profile. Pharmacol Res. 2001; 44: 183-93. google scholar
  • 15. Mollace V, Scicchitano M, Paone S, Casale F, Calandruccio C, Gliozzi M, et al. Hypoglycemic and Hypolipemic Effects of a New Lecithin Formulation of Bergamot Polyphenolic Fraction: A Double Blind, Randomized, Placebo- Controlled Study. Endocr Metab Immune Disord Drug Targets. 2019; 19(2): 136-43. google scholar
  • 16. Tejada S, Pinya S, Martorell M, Capó X, Tur JA, Pons A, et al. Potential Anti-inflammatory Effects of Hesperidin from the Genus Citrus. Curr Med Chem. 2018; 25(37): 4929-45. google scholar
  • 17. Jawien A, Bouskela E, Allaert FA, Nicolaïdes AN. The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of chronic venous disease. Int Angiol. 2017; 36(1): 31-41. google scholar
  • 18. Professional monograph, Fagopyrum esculentum. (serial online) (cited 2020, July 20) Available from: URL: https:// naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=15 google scholar
  • 19. Professional monograph, Allium cepa. (serial online) (cited 2020, July 20) Available from: URL: https:// naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional. aspx?productid=643 google scholar
  • 20. Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Netw Open. 2020; 3(6): e2013136. doi: 10.1001/jamanetworkopen.2020.13136 google scholar
  • 21. Alkadi H, Khubeiz MJ, Jbeily R. Colchicine: A Review About Chemical Structure and Clinical Using. Infect Disord Drug Targets. 2018; 18(2): 105-21. google scholar
  • 22. Martínez GJ, Robertson S, Barraclough J, Xia Q, Mallat Z, Bursill C et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc. 2015; 4(8): e002128. doi: 10.1161/JAHA.115.002128 23. Özçelik B, Kartal M, Orhan I. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm Biol. 2011; 49(4): 396-402. google scholar
  • 24. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep. 2008; 10(3): 218-27. google scholar
  • 25. Ferro F, Elefante E, Baldini C, Bartoloni E, Puxeddu I, Talarico R, et al. COVID-19: the new challenge for rheumatologists. Clin Exp Rheumatol. 2020; 38(2): 175-80. google scholar
  • 26. Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutrition Journal. 2014; 13: 11. doi:10.1186/1475-2891-13-11 google scholar
  • 27. Fatemeh Z, Hosseini SA, Majeed M, Jamialahmadi T, Banach M, Sahebkar A et al. Potential effects of curcumin in the treatment of COVID-19 infection. Phytother Res. 2020:10.1002/ptr.6738. doi: 10.1002/ptr.6738 google scholar
  • 28. Aggarwal BB, Chitra Sundaram C, Nikita Malani N, Ichikawa H.Curcimin:The Indian Solid Gold. In: Aggarwal BB, Surh YJ, Shishodia S, editors. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Diseases (Advance in Experimental Medicine and Biology. Vol 595). Newyork: Springer Science & Business Media LLC; 2007. p. 1-75. Akalın, Ekici, Alan, Yaman Bucak, Üresin 283 google scholar
  • 29. Kocaadam B, Şanlier N. Curcumin, an active component of turmeric(Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr. 2017; 57(13): 2889-95. google scholar
  • 30. Utomo RY., Ikawati M, Meiyanto E. Revealing the potency of citrus and galangal constituents to Halt SARS‐ CoV‐2 infection. Preprints. 2020 March 12. doi: 10.20944/preprints202003.0214.v1 google scholar
  • 31. Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S. Potential inhibitor of COVID‐19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints. 2020. doi: https://doi.org/10.20944/preprints202003.0226.v1 google scholar
  • 32. Akalın E, Alpınar K. Tekirdağ’ın tıbbi ve yenen yabani bitkileri hakkında bir araştırma. Ege Üniv Ecz Fak Der. 1994; 2: 1-11. google scholar
  • 33. Zhang T, Zhang Y, Jiang N, Zhao X, Sang X, Yanget Na, et al. Dihydroartemisinin regulates the immune system by promotion of CD8(+) T lymphocytes and suppression of B cell responses. Life Sci China Life Sci. 2019; 63(5): 737-49. google scholar
  • 34. Faurant C. From bark to weed: The history of artemisinin. Parasite. 2011; 18(3): 215-8. google scholar
  • 35. Cheonga DHJ, Tan DWS, Wong FWS, Tran T. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacol Res. 2020; 158(1): 104901. doi: 10.1016/j.phrs.2020.104901 google scholar
  • 36. Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti‐malarial. Pharmacol Ther. 2014; 142: 126‐39. google scholar
  • 37. Pervaiz S. Resveratrol: from grapevines to mammalian biology. FASEB J. 2003; 17(14): 1975-85. 38. Saiko P, Szakmary A, Jaeger W, Szekeres T. Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res. 2008; 658(1-2): 68-94. google scholar
  • 39. Schmatz R, Perreira LB, Stefanello N, Mazzanti C, Spanevello R, Gutierres J, et al. Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats. Biochimie. 2012; 94(2): 374-83. google scholar
  • 40. Palamara AT, Nencioni L, Aquilano K, Chiara GD, Hernandez L, Cozzolino F, et al. Inhibition of influenza A virus replication by resveratrol. Journal of Infectious Diseases. 2005; 191(10): 1719-29. google scholar
  • 41. Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis. 2017; 17(1): 144. google scholar
  • 42. Chen X, Qiao H, Liu T, Yang Z, Xu L, Xu Y, et al. Inhibition of herpes simplex virus infection by oligomeric stilbenoids through ROS generation. Antiviral Research. 2012; 95(1): 30-6. google scholar
  • 43. Khanduja KL, Bhardwaj A, Kaushik G. Resveratrol inhibits N-nitrosodiethylamine-induced ornithine decarboxylase and cyclooxygenase in mice. J Nutr Sci Vitaminol. 2004; 50(1): 61-5. google scholar
  • 44. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res. 2014; 34(10): 837-43. google scholar
  • 45. Morales-González JA, Gayosso-Islas E, Sánchez-Moreno C, Valadez-Vega C, Morales-González A, EsquivelSoto J, et al. Protective effect of silymarin on liver damage by xenobiotics. In: Oxidative stress and chronic degenerative diseases-a role for antioxidants. Rijeka: Croatia InTech 2013. google scholar
  • 46. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005; 12: 559-67. google scholar
  • 47. Morishima C, Shuhart MC, Wang CC, Paschal DM, Apodaca MC, Liu Y, et al. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology. 2010; 138: 671-81. google scholar
  • 48. Mitra R, Mitra JK. Silymarin, A Promising Nature’s Remedy for Liver Diseases. J Complement Med Alt Healthcare. 2018; 7(1): 555704. doi: 10.19080/JCMAH.2018.07.555704 google scholar
  • 49. Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddique NA. A review on therapeutic potential of Nigella sativa: a miracle herb. Asian Pac J Trop Biomed. 2013; 3(5): 337-52. google scholar
  • 50. El-Dakhakhany M. Studies on the chemical constitution of Egyptian N. sativa L. seeds. Planta Med. 1963; 11(1): 465-70. google scholar
  • 51. Abukhader MM. Thymoquinone in the clinical treatment of cancer: fact fiction? Pharmacogn Rev. 2013; 7(14): 117-20. google scholar
  • 52. Kadil Y, Mouhcine M, Filali H. In Silico Investigation of the SARS CoV2 Protease with Thymoquinone Major Constituent of Nigella Sativa. Curr Drug Discov Techno. 2020. doi: 10.2174/1570163817666200712164406 google scholar
  • 53. Ahmad A, Rehman MU, Ahmad P, Alkharfy KM. Covid‐19 and thymoquinone: Connecting the dots. Phytother Res. 2020. doi: 10.1002/ptr.6793 284 COVID-19 (SARS-CoV-2) Tedavisinde Klinik Çalışmalarda Yer Alan Bitkisel Kökenli Doğal Bileşikler google scholar
  • 54. Vaillancourt F, Silva P, Shi Q, Fahmi H, Fernandes JC, Benderdour M. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. J Cell Biochem. 2010; 112(1): 107-17. google scholar
  • 55. Bombardelli E, Morazzoni P, Griffini A. Aesculus hippocastanum L. Fitoterapia. 1996; 67(6): 483-511. google scholar
  • 56. Gallelli L, Zhang L, Wang T, Fu F. Severe Acute Lung Injury Related to COVID-19 Infection: A Review and the Possible Role for Escin. J Clin Pharmacol. 2020; 60(7): 815-25. google scholar
  • 57. Salinas FM, Vazquez L, Gentilini MV, O´Donohoe A, Regueira E, Jodar MSN, et al. Aesculus hippocastanum L. seed extract shows virucidal and antiviral activities against respiratory syncytial virus (RSV) and reduces lung inflammation in vivo. Antiviral Res. 2019; 164: 1‐11. google scholar
  • 58. Zanwar AA, Badole SL, Shende PS, Hegde MV, Bodhankar SL. Cardiovascular effects of hesperidin: a flavanone glycoside. Polyphenols in Human Health and Disease. San Diego: Academic Press; 2014. p. 989-92. google scholar
  • 59. Dong W, Wei X, Zhang F, Hao J, Huang F, Zhang C, et al. A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways. Sci Rep. 4, 7237 (2014). https://doi.org/10.1038/srep07237 google scholar
  • 60. Garg A, Garg S, Zaneveld LJD, Singla AK. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phyther Res. 2001; 15(1): 655-69. google scholar
  • 61. Bae EA, Han MJ, Lee M, Kim DH. In vitro inhibitory effect of some flavonoids on rotavirus infectivity. Biol Pharm Bull. 2000; 23(9): 1122-4. google scholar
  • 62. Xiao S, Liu W, Bi J, Liu S, Zhao H, Gong N, et al. Anti-inflammatory effect of hesperidin enhances chondrogenesis of human mesenchymal stem cells for cartilage tissue repair. J Inflamm. 2018; 15: 14. doi: 10.1186/s12950-018-0190-y google scholar
  • 63. Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial. Phytotherapy Res. 2018; 32: 1073-9. google scholar
  • 64. Haggag YA, El-Ashmawy NE, Okasha KM. Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection? Medical Hypotheses. 2020; 144: 109957. 10.1016/j.mehy.2020.109957 google scholar
  • 65. Bertozzi MM, Rossaneis AC, Fattori V, Longhi-Balbinot DT, Freitas A, Cunha FQ, et al. Diosmin reduces chronic constriction injury-induced neuropathic pain in mice. Chemico-Biological Interactions. 2017; 273; 180-9. google scholar
  • 66. Ramelet AA. Pharmacologic aspects of a phlebotropic drug in CVI-associated edema. Angiology. 2000; 51: 19-23. google scholar
  • 67. Manthey JA. Biological properties of flavonoids pertaining to inflammation. Microcirculation. 2000; 7: S29-S34. google scholar
  • 68. Park JY, Yuk HJ, Ryu HW, Lim SH, Kim KS, Park KH, et al. Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors. J Enzyme Inhib Med Chem. 2017; 32(1): 504-15. google scholar
  • 69. Kim JK, Park SU. Quercetin and its role in biological functions: an updated review. EXCLI Journal. 2018; 17(1): 856-63. google scholar
  • 70. Ohnishi E, Bannai H. Quercetin potentiates TNF-induced antiviral activity. Antiviral Res. 1993; 22: 327-31. google scholar
  • 71. Cure MC, Kucuk A, Cure E. Colchicine may not be effective in COVID-19 infection; it may even be harmful? Clin Rheumatol. 2020; 39(7): 2101-2. google scholar
  • 72. Fazal Y, Fatima SN, Shahid SM, Mahboob T. Effects of curcumin on angiotensin-converting enzyme gene expression, oxidative stress and anti-oxidant status in thioacetamide-induced hepatotoxicity. J Renin Angiotensin Aldosterone Syst. 2015; 16(4): 1046-51. google scholar
  • 73. Pang XF, Zhang LH, Bai F, Wang NP, Garner RE, McKallip RJ, et al. Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats. Drug Des Devel Ther. 2015; 9: 6043-54. google scholar
  • 74. Kim HL, Kim WK, Ha AW. Effects of Phytochemicals on Blood Pressure and Neuroprotection Mediated Via Brain Renin-Angiotensin System. Nutrients. 2019; 11(11): 2761. doi: 10.3390/nu11112761 google scholar
  • 75. Akinyemi AJ, Thome GR, Morsch VM, Stefanello N, Goularte JF, Belló-Klein A, et al. Effect of dietary supplementation of ginger and turmeric rhizomes on angiotensin-1 converting enzyme (ACE) and arginase activities in L-NAME induced hypertensive rats. J Funct Foods. 2015; 17: 792-801. google scholar
  • 76. Rachmawati H, Soraya IS, Kurniati NF, Rahma A. In vitro study on antihypertensive and antihypercholesterolemic effects of a curcumin nanoemulsion. Sci Pharm. 2016: 84(1): 131-40. google scholar
  • 77. Sordillo PP, Helson L.Curcumin Suppression of Cytokine Release and Cytokine Storm. A Potential Therapy for Patients with Ebola and Other Severe Viral Infections. İn vivo. 2015; 29: 1-4. google scholar
  • 78. Maxmen A. More than 80 clinical trials launch to test coronavirus treatments. Nature. 2020; 578: 347-8. google scholar


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