A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection

Yıl: 2020 Cilt: 3 Sayı: 4 Sayfa Aralığı: 293 - 311 Metin Dili: İngilizce DOI: 10.30714/j-ebr.2020463629 İndeks Tarihi: 14-05-2021

A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection

Öz:
The year 2020 is began with the declaration of a pandemic of novel coronavirus, which first occurred by the end of 2019 in Wuhan region of China. The novel virus infection is so called as Covid-19 or SARS Cov-2. The infection rapidly spread all over the world and changed the lives of millions. In this extended review, we aimed to discuss current and possible treatment strategies against SARS Cov-2 infection. Treatment options mentioned here include but not limited to chloroquine/hydroxychloroquine, favipiravir, remdesivir, lopinavir/ritonavir, umifenovir, steroids, cepharanthine, convalescent plasma, anticoagulants and monoclonal antibodies. In conclusion, mainstay of the SARS Cov-2 treatment is general measures such as patient isolation and supportive care. However, encouraging developments are being achieved in terms of discovery of an effective treatment and production of a potent vaccine.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
  • [1] Cortegiani A, Ingoglia G, Ippolito M et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID- 19. J Crit Care. 2020;57:279-83.
  • [2] Hoffmann M, Kleine-Weber H, Schroeder S et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-80.
  • [3] Zhao Y, Zhao Z, Wang Y et al. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. BioRxiv. 2020: doi: 10.1101/2020.01.26.919985.
  • [4] Tikellis C, Thomas MC. Angiotensin- Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012;2012:256294.
  • [5] Zhang H, Penninger JM, Li Y et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586-90.
  • [6] Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020: doi: 10.1001/jama.2020.2648.
  • [7] Lavezzo E, Franchin E, Ciavarella C et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo'. Nature. 2020;584(7821):425-29.
  • [8] Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395 (10223):507-13.
  • [9] Yang X, Yu Y, Xu J et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81.
  • [10] Pascarella G, Strumia A, Piliego C et al. COVID-19 diagnosis and management: a comprehensive review. J Intern Med. 2020;288(2):192-206.
  • [11] Jiang F, Deng L, Zhang L et al. Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19). J Gen Intern Med. 2020;35(5):1545-49.
  • [12] World Health Organisation. Coronavirus Disease (COVID-19) Dashboard. In: WHO; 2020. https://covid19.who.int/?gclid=EAIaIQobC hMI3YCC-- u26wIVWuztCh1JzAh8EAAYASABEgLIh vD_BwE.
  • [13] Bilgin S, Kurtkulagi O, Kahveci GB et al. Millennium pandemic: a review of coronavirus disease (COVID-19). Exp Biomed Res. 2020;3(2):117-25.
  • [14] Li T. Diagnosis and clinical management of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0). Emerg Microbes Infect. 2020;9(1):582-85.
  • [15] Fan E, Del Sorbo L, Goligher EC et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017;195(9):1253-63.
  • [16] Munshi L, Del Sorbo L, Adhikari NKJ et al. Prone Position for Acute Respiratory Distress Syndrome. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2017;14 (Supplement_4):S280-s88.
  • [17] Savarino A, Boelaert JR, Cassone A et al. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-27.
  • [18] Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV- 2. Int J Antimicrob Agents. 2020;55(3):105923.
  • [19] Singh AK, Singh A, Shaikh A et al. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr. 2020;14(3):241-46.
  • [20] Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73.
  • [21] Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949.
  • [22] Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019- nCoV) in vitro. Cell Res. 2020;30(3):269- 71.
  • [23] Lu H. Drug treatment options for the 2019- new coronavirus (2019-nCoV). Biosci Trends. 2020;14(1):69-71.
  • [24] Zhou N, Pan T, Zhang J et al. Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERSCoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). J Biol Chem. 2016;291(17):9218-32.
  • [25] Biot C, Daher W, Chavain N et al. Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J Med Chem. 2006;49(9):2845-9.
  • [26] Liu J, Cao R, Xu M et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.
  • [27] Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020; 71(15):732-39.
  • [28] Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):185-88.
  • [29] Interim clinical guidelines for patients suspected of/confirmed with COVID-19 infection. In; 2020. https://lci.rivm.nl/covid- 19/bijlage/behandeladvies. Accessed on 20th March 2020.
  • [30] Italian Society of Infectious and Tropical Diseases (Lombardy Section. In; 2020, http://www.simit.org/medias/1555-covid19- linee-guida-trattamento-01mar.pdf. Last accessed on 20th March 2020.
  • [31] Korea biomedical review website. In; 2020. http://www.koreabiomed.com/news/article View.html?idxno¼7428.
  • [32] Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020;177:104762.
  • [33] Colson P, Rolain JM, Lagier JC et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020;55(4):105932.
  • [34] Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449- 63.
  • [35] Wang Y, Fan G, Salam A et al. Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection. J Infect Dis. 2020;221(10):1688-98.
  • [36] XinhuaNet. Favipiravir shows good clinical efficacy in treating COVID-19: official. . In; 2020. In; 2020. From. http://www.xinhuanet.com/english/ 2020- 03/17/c_138888226.htm.
  • [37] Shiraki K, Daikoku T. Favipiravir, an antiinfluenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020;209:107512.
  • [38] Cai Q, Yang M, Liu D et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020: doi: 10.1016/j.eng.2020.03.007.
  • [39] Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect. 2020;53(3):436-43.
  • [40] Turkish Republic Ministery of Health. Management of adult patients with SARS Cov-2 infection. . In; 2020. https://covid19bilgi.saglik.gov.tr/depo/rehb erler/covid-19-rehberi/COVID- 19_rehberi_eriskin_hasta_tedavisi.pdf. (Accessed on 2nd of August, 2020).
  • [41] Sissoko D, Laouenan C, Folkesson E et al. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proofof- Concept Trial in Guinea. PLoS Med. 2016;13(3):e1001967.
  • [42] Scavone C, Brusco S, Bertini M et al. Current pharmacological treatments for COVID-19: What's next? Br J Pharmacol. 2020. DOI: 10.1111/bph.15072.
  • [43] Sheahan TP, Sims AC, Graham RL et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396):eaal3653.
  • [44] Martinez MA. Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus. Antimicrob Agents Chemother. 2020;64(5):e00399-20.
  • [45] Sheahan TP, Sims AC, Leist SR et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERSCoV. Nat Commun. 2020;11(1):222.
  • [46] Agostini ML, Andres EL, Sims AC et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;9(2):e00221- 18.
  • [47] Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. 2020;34:101615.
  • [48] Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382(10):929-36.
  • [49] Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020. DOI: 10.1056/NEJMoa2007764.
  • [50] Grein J, Ohmagari N, Shin D et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020;382(24):2327-36.
  • [51] Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial. Lancet. 2020;395(10236):1569-78.
  • [52] Zumla A, Chan JF, Azhar EI et al. Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327-47.
  • [53] Chu CM, Cheng VC, Hung IF et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-56.
  • [54] Lim J, Jeon S, Shin HY et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci. 2020;35(6):e79
  • [55] Yao TT, Qian JD, Zhu WY et al. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus- A possible reference for coronavirus disease-19 treatment option. J Med Virol. 2020;92(6):556-63.
  • [56] Cao B, Wang Y, Wen D et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-99.
  • [57] Baden LR, Rubin EJ. Covid-19 - The Search for Effective Therapy. N Engl J Med. 2020;382(19):1851-52.
  • [58] Blaising J, Polyak SJ, Pécheur EI. Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014;107:84-94.
  • [59] Xu X, Ong YK, Wang Y. Role of adjunctive treatment strategies in COVID-19 and a review of international and national clinical guidelines. Mil Med Res. 2020;7(1):22.
  • [60] Wang Z, Yang B, Li Q et al. Clinical Features of 69 Cases With Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71(15):769-77.
  • [61] Deng L, Li C, Zeng Q et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J Infect. 2020;81(1):e1-e5.
  • [62] Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343
  • [63] Arabi YM, Mandourah Y, Al-Hameed F et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67.
  • [64] Lee N, Leo YS, Cao B et al. Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients. Eur Respir J. 2015;45(6):1642-52.
  • [65] Zhou W, Liu Y, Tian D et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal Transduct Target Ther. 2020;5(1):18.
  • [66] Lu S, Zhou Q, Huang L et al. Effectiveness and safety of glucocorticoids to treat COVID-19: a rapid review and metaanalysis. Ann Transl Med. 2020;8(10):627.
  • [67] Liu K, Fang YY, Deng Y et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J. 2020;133(9):1025-31.
  • [68] Lee KY, Rhim JW, Kang JH. Early preemptive immunomodulators (corticosteroids) for severe pneumonia patients infected with SARS-CoV-2. Clin Exp Pediatr. 2020;63(4):117-18.
  • [69] Selvaraj V, Dapaah-Afriyie K, Finn A et al. Short-Term Dexamethasone in Sars-CoV-2 Patients. R I Med J. 2020;103(6):39-43.
  • [70] Rogosnitzky M, Danks R. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. Pharmacol Rep. 2011;63(2):337- 47.
  • [71] Nomoto S, Imada H, Ohguri T et al. [Effect of Cepharanthin in preventing radiation induced normal tissue damage in prostate cancer]. Gan To Kagaku Ryoho. 2004;31(7):1063-66.
  • [72] Bailly C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019;62:152956.
  • [73] Nakayama S, Matsushita A, Ichiba S et al. [Clinical evaluation of cepharanthin for chronic idiopathic thrombocytopenic purpura]. Rinsho Ketsueki. 1992;33(3):408- 9.
  • [74] Kim DE, Min JS, Jang MS et al. Natural Bis- Benzylisoquinoline Alkaloids-Tetrandrine, Fangchinoline, and Cepharanthine, Inhibit Human Coronavirus OC43 Infection of MRC-5 Human Lung Cells. Biomolecules. 2019; 9 (11):696.
  • [75] Sakaguchi S, Furusawa S, Wu J et al. Preventive effects of a biscoclaurine alkaloid, cepharanthine, on endotoxin or tumor necrosis factor-alpha-induced septic shock symptoms: involvement of from cell death in L929 cells and nitric oxide production in raw 264.7 cells. Int Immunopharmacol. 2007;7(2):191-97.
  • [76] Paudel KR, Karki R, Kim DW. Cepharanthine inhibits in vitro VSMC proliferation and migration and vascular inflammatory responses mediated by RAW264.7. Toxicol In Vitro. 2016;34:16- 25.
  • [77] Ershun Z, Yunhe F, Zhengkai W et al. Cepharanthine attenuates lipopolysaccharide-induced mice mastitis by suppressing the NF-κB signaling pathway. Inflammation. 2014;37(2):331-37.
  • [78] Okamoto M, Ono M, Baba M. Potent inhibition of HIV type 1 replication by an antiinflammatory alkaloid, cepharanthine, in chronically infected monocytic cells. AIDS Res Hum Retroviruses. 1998;14(14):1239- 45.
  • [79] 79. Zhang CH, Wang YF, Liu XJ et al. Antiviral activity of cepharanthine against severe acute respiratory syndrome coronavirus in vitro. Chin Med J. 2005;118(6):493-96.
  • [80] Fan HH, Wang LQ, Liu WL et al. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model. Chin Med J. 2020;133(9):1051-56.
  • [81] Yin W, Mao C, Luan X et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science 2020;368(6498):1499- 504.
  • [82] Lan J, Ge J, Yu J et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215-20.
  • [83] Ohashi H, Watashi K, Saso W et al. Multidrug treatment with nelfinavir and cepharanthine against COVID-19. bioRxiv. 2020: doi: 10.1101/2020.04.14.03992 5.
  • [84] Jeon S, Ko M, Lee J et al. Identification of Antiviral Drug Candidates against SARSCoV- 2 from FDA-Approved Drugs. Antimicrob Agents Chemother. 2020;64(7):e00819-20.
  • [85] Chen L, Xiong J, Bao L et al. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020;20(4):398-400.
  • [86] Shen C, Wang Z, Zhao F et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020;323(16):1582-9.
  • [87] Mair-Jenkins J, Saavedra-Campos M, Baillie JK et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory metaanalysis. J Infect Dis. 2015;211(1):80-90.
  • [88] FDA. Investigational COVID-19 Convalescent Plasma - Emergency INDs. . In https://www.fda.gov/media/136470/downlo ad. Accessed April 16, 2020.
  • [89] Ahn JY, Sohn Y, Lee SH et al. Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea. J Korean Med Sci. 2020;35(14):e149.
  • [90] Duan K, Liu B, Li C et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-96.
  • [91] COVID-19 Treatment Guidance Writing Group. JHMI clinical guidance for available pharmacologic therapies 2020 [updated 25 March 2020]. Available from: https://www.hopkinsguides.com/hopkins/vi ew/Johns_Hopkins_ABX_Guide/540747/al l/Coronavirus_COVID_19__SARS_CoV_2 .
  • [92] Lai CC, Wang CY, Hsueh PR. Co-infections among patients with COVID-19: The need for combination therapy with non-anti- SARS-CoV-2 agents? J Microbiol Immunol Infect. 2020;53(4):505-12.
  • [93] Chou CC, Shen CF, Chen SJ et al. Recommendations and guidelines for the treatment of pneumonia in Taiwan. J Microbiol Immunol Infect. 2019;52(1):172- 99.
  • [94] Jean SS, Chang YC, Lin WC et al. Epidemiology, Treatment, and Prevention of Nosocomial Bacterial Pneumonia. J Clin Med. 2020;9(1):275.
  • [95] Bacharier LB, Guilbert TW, Mauger DT et al. Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. JAMA. 2015;314(19):2034- 44.
  • [96] Madrid PB, Panchal RG, Warren TK et al. Evaluation of Ebola Virus Inhibitors for Drug Repurposing. ACS Infect Dis. 2015;1(7):317-26.
  • [97] Baron SA, Devaux C, Colson P et al. Teicoplanin: an alternative drug for the treatment of COVID-19? Int J Antimicrob Agents. 2020;55(4):105944.
  • [98] Wang Y, Cui R, Li G et al. Teicoplanin inhibits Ebola pseudovirus infection in cell culture. Antiviral Res. 2016;125:1-7.
  • [99] Beigel JH, Nam HH, Adams PL et al. Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res. 2019;167:45-67.
  • [100] Zhou Y, Vedantham P, Lu K et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015;116:76-84.
  • [101] Luo P, Liu Y, Qiu L et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 2020;92(7):814- 18.
  • [102] Zhang C, Wu Z, Li JW et al. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954.
  • [103] Lin L, Lu L, Cao W et al. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727-32.
  • [104] Magro C, Mulvey JJ, Berlin D et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020;220:1-13.
  • [105] Cui S, Chen S, Li X et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421-24.
  • [106] Deng Y, Liu W, Liu K et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study. Chin Med J. 2020;133(11):1261-67.
  • [107] Tang N, Bai H, Chen X et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-99.
  • [108] Shi C, Wang C, Wang H et al. Clinical observations of low molecular weight heparin in relieving inflammation in COVID-19 patients: A retrospective cohort study. medRxiv. 2020. doi: 10.1101/2020.03.28.20046144.
  • [109] World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 is suspected. In; 2020. Available from https://www.who.int/publicationsdetail/ clinicalmanagement-of-severe-acuterespiratory- infection-when-novelcoronavirus-( ncov)-infection-is-suspected.
  • [110] Thachil J, Tang N, Gando S et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-26.
  • [111] Chan JF, Yao Y, Yeung ML et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015;212(12):1904- 13.
  • [112] Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 2020;248:117477.
  • [113] Khalili JS, Zhu H, Mak NSA et al. Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19. J Med Virol. 2020;92(7):740- 46.
  • [114] Hung IF, Lung KC, Tso EY et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395(10238):1695-704.
  • [115] Zhang R, Wang X, Ni L et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020;250:117583.
  • [116] Nordlund JJ, Lerner AB. The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. 1977;45(4):768-74.
  • [117] Bazyar H, Gholinezhad H, Moradi L et al. The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebocontrolled trial. Inflammopharmacology. 2019;27(1):67-76.
  • [118] Wösten-van Asperen RM, Bos AP, Bem RA et al. Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome. Pediatr Crit Care Med. 2013;14(9):e438-41.
  • [119] Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med. 2016;4(21):421.
  • [120] Fedson DS, Opal SM, Rordam OM. Hiding in Plain Sight: an Approach to Treating Patients with Severe COVID-19 Infection. mBio. 2020; 11 (2):e00398-20.
  • [121] P.J. R. Antiprotozoal drugs. In: B.G K ed, Basic & Clinical Pharmacology. 17 ed. New York: McGraw-Hill Education; 2017.
  • [122] Haffizulla J, Hartman A, Hoppers M et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014;14(7):609-18.
  • [123] Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016;9(3):227-30.
  • [124] Kelleni MT. Nitazoxanide/azithromycin combination for COVID-19: A suggested new protocol for early management. Pharmacol Res. 2020;157:104874.
  • [125] Calderón JM, Zerón HM, Padmanabhan S. Treatment with Hydroxychloroquine vs Hydroxychloroquine + Nitazoxanide in COVID-19 patients with risk factors for poor prognosis: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):504.
  • [126] Şimşek Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turk J Med Sci. 2020;50(Si- 1):611-19.
  • [127] Caly L, Druce JD, Catton MG et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.
  • [128] Ketkar H, Yang L, Wormser GP et al. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis. 2019;95(1):38-40.
  • [129] Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot. 2020;73(9):593-602.
  • [130] Horie S, Gonzalez HE, Laffey JG et al. Cell therapy in acute respiratory distress syndrome. J Thorac Dis. 2018;10(9):5607- 20.
  • [131] Dimitrov DS. The secret life of ACE2 as a receptor for the SARS virus. Cell. 2003;115(6):652-3.
  • [132] Simmons G, Reeves JD, Rennekamp AJ et al. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc Natl Acad Sci U S A. 2004;101(12):4240-45.
  • [133] Zumla A, Hui DS, Azhar EI et al. Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet. 2020;395(10224):e35-e36.
  • [134] Chakraborty A, Tannenbaum S, Rordorf C et al. Pharmacokinetic and pharmacodynamic properties of canakinumab, a human antiinterleukin- 1β monoclonal antibody. Clin Pharmacokinet. 2012;51(6):e1-18.
  • [135] Wedzicha JA, Calverley PM, Rabe KF. Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:81-90.
  • [136] Yang L, Tian D, Liu W. [Strategies for vaccine development of COVID-19]. Sheng Wu Gong Cheng Xue Bao. 2020;36(4):593- 604.
  • [137] Thanh Le T, Andreadakis Z, Kumar A et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5):305-06.
  • [138] World Health Organisation. Landscape of vaccine candidates against SARS Cov-2. In; 2020. https://www.who.int/publications/m/item/dr aft-landscape-of-covid-19-candidatevaccines.
  • [139] Lurie N, Saville M, Hatchett R et al. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 2020;382(21):1969- 73.
  • [140] Graham BS. Rapid COVID-19 vaccine development. Science. 2020;368(6494):945- 46.
  • [141] website: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/covid-19- vaccines.
  • [142] website: https://www.ft.com/content/588ce bbc-cbae-45ba-8b9a-e8ad2760c0ed.
  • [143] HYPERLINK "https://www.fda.gov/newsevents/ press-announcements/covid-19- update-fda-broadens-emergency-useauthorization- veklury-remdesivir-includeallhospitalized.% 20accessed%2029.08.2020" https://www.fda.gov/news-events/pressannouncements/ covid-19-update-fdabroadens- emergency-use-authorizationveklury- remdesivir-include-all-hospitalized. accessed 29.08.2020
  • [144] https://www.who.int/news-room/detail/04- 07-2020-who-discontinueshydroxychloroquine- and-lopinavirritonavir- treatment-arms-for-covid-19
  • [145] https://www.nih.gov/news-events/newsreleases/ phase-3-clinical-testing-usastrazeneca- covid-19-vaccine-candidatebegins.
  • [146] Horby P, Lim WS, Emberson J, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv 2020.
APA Aktas G (2020). A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. , 293 - 311. 10.30714/j-ebr.2020463629
Chicago Aktas Gulali A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. (2020): 293 - 311. 10.30714/j-ebr.2020463629
MLA Aktas Gulali A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. , 2020, ss.293 - 311. 10.30714/j-ebr.2020463629
AMA Aktas G A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. . 2020; 293 - 311. 10.30714/j-ebr.2020463629
Vancouver Aktas G A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. . 2020; 293 - 311. 10.30714/j-ebr.2020463629
IEEE Aktas G "A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection." , ss.293 - 311, 2020. 10.30714/j-ebr.2020463629
ISNAD Aktas, Gulali. "A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection". (2020), 293-311. https://doi.org/10.30714/j-ebr.2020463629
APA Aktas G (2020). A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. Experimental Biomedical Research, 3(4), 293 - 311. 10.30714/j-ebr.2020463629
Chicago Aktas Gulali A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. Experimental Biomedical Research 3, no.4 (2020): 293 - 311. 10.30714/j-ebr.2020463629
MLA Aktas Gulali A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. Experimental Biomedical Research, vol.3, no.4, 2020, ss.293 - 311. 10.30714/j-ebr.2020463629
AMA Aktas G A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. Experimental Biomedical Research. 2020; 3(4): 293 - 311. 10.30714/j-ebr.2020463629
Vancouver Aktas G A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. Experimental Biomedical Research. 2020; 3(4): 293 - 311. 10.30714/j-ebr.2020463629
IEEE Aktas G "A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection." Experimental Biomedical Research, 3, ss.293 - 311, 2020. 10.30714/j-ebr.2020463629
ISNAD Aktas, Gulali. "A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection". Experimental Biomedical Research 3/4 (2020), 293-311. https://doi.org/10.30714/j-ebr.2020463629