Conceptual approaches to finding effective treatment for a new coronavirus infection at different stages


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Abstract

The article attempts to analyze the change in philosophy in approaches to the treatment of COVID-19 that have occurred in recent months, based on published research and their own experience in the treatment of a new coronavirus infection at the medical research and education center of Moscow state University.  Emphasis is placed on the rationale for the phased use of different types of therapy. The reasons for using spironolactone in patients with COVID-19 as a drug for etiotropic and pathogenetic therapy are discussed in detail. The authors conclude that the use of antiviral drugs in combination with drugs that prevent the entry of the SARS-CoV-2 virus into cells from the first days of the disease should be supplemented with pre-emptive anti-inflammatory therapy that interrupts the progression of the disease. The parallel use of anticoagulants that reduce the risk of thrombotic and thromboembolic complications.

About the authors

Armais A. Kamalov

Medical Research and Educational Center of Lomonosov Moscow State University

Email: priemnaya@mc.msu.ru
ORCID iD: 0000-0003-4251-7545
SPIN-code: 6609-5468

MD, PhD, Professor, Academician of the RAS

Russian Federation, Moscow

Viacheslav Y. Mareev

Medical Research and Educational Center of Lomonosov Moscow State University

Email: prof_mareev@ossn.ru
ORCID iD: 0000-0002-7285-2048
SPIN-code: 9465-8979
Scopus Author ID: 55410873900

MD, PhD, Professor

Russian Federation, Moscow

Iana A. Orlova

Medical Research and Educational Center of Lomonosov Moscow State University

Author for correspondence.
Email: 5163002@bk.ru
ORCID iD: 0000-0002-8160-5612
SPIN-code: 3153-8373
Scopus Author ID: 24503460300
https://istina.msu.ru/profile/YAOrlova@mc.msu.ru/

MD, PhD, Associate Professor

Russian Federation, 27/10 Lomonosovskiy prosp., 119192, Moscow

References

  1. Официальный сайт Правительства РФ — стопкоронавирус.рф. Available from: https://xn--80aesfpebagmfblc0a.xn--p1ai/ (accessed: 13.07.2020).
  2. Официальный сайт ВОЗ. Available from: https://covid19.who.int/ (accessed:13.07.2020).
  3. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Eng J Med. 2020;382(18):1708–1720. doi: https://doi.org/10.1056/NEJMoa2002032
  4. Randomised evaluation of COVID-19 therapy (RECOVERY trail). 29.06.2020. Available from: https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery
  5. Chen C, Huang J, Cheng Z, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv. 2020. doi: https://doi.org/10.1101/2020.03.17.20037432
  6. Cai Q, Yang M, Liu D, et al. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering (Beijing). 2020;6(10):1192-1198. doi: https://doi.org/10.1016/j.eng.2020.03.007
  7. 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):722–727. doi: https://doi.org/10.1016/S1473-3099(03)00806-5
  8. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. doi: https://doi.org/10.1186/1743-422X-2-69
  9. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open- label non-randomized clinical trial. Int J Antimicrob Agents. 2020; 56(1):105949. doi: https://doi.org/10.1016/j.ijantimicag.2020.105949
  10. Chen Z, Hu J, Zhang Z, Jiang S, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv. 2020. doi: https://doi.org/10.1101/2020.03.22.20040758
  11. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Eng J Med. 2020;382(25):2411–2418. doi: https://doi.org/10.1056/NEJMoa2012410
  12. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):2493. doi: https://doi.org/10.1001/jama.2020.8630
  13. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Eng J Med. 2020;383(6):517-525. doi: https://doi.org/10.1056/NEJMoa2016638
  14. Shen LW, Mao HJ, Wu YL, et al. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie. 2017;142:1–10. doi: https://doi.org/10.1016/j.biochi.2017.07.016
  15. Sonawane K, Barale SS, Dhanavade MJ, et al. Homology modeling and docking studies of TMPRSS2 with experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-Coronavirus-2. ChemRxiv. Preprint. 2020. doi: https://doi.org/10.26434/chemrxiv.12162360.v1
  16. Rabi FA, Al Zoubi MS, Kasasbeh GA, et al. SARS-CoV-2 and coronavirus disease 2019: what we know so far. Pathogens. 2020;9(3):231. doi: https://doi.org/10.3390/pathogens9030231
  17. Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S. Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? Intern Emerg Med. 2020;15:801-812. doi: https://doi.org/10.1007/s11739-020-02383-3
  18. Habtemariam S, Nabavi SF, Ghavami S, et al. Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2. Pharmacol Res. 2020;157:104853. doi: https://doi.org/10.1016/j.phrs.2020.104853
  19. Zhao H, Gu DW, Li HT, et al. Inhibitory effects of spironolactone on myocardial fibrosis in spontaneously hypertensive rats. Genet Mol Res. 2015;14(3):10315–10321. doi: https://doi.org/10.4238/2015.August.28.17
  20. Funder JW. Spironolactone in cardiovascular disease: an expanding universe? F1000Res. 2017;6:1738. doi: https://doi.org/10.12688/f1000research.11887.1
  21. Yavas G, Yavas C, Celik E, et al. The impact of spironolactone on the lung injury induced by concomitant trastuzumab and thoracic radiotherapy. Int J Rad Res. 2019;17(1):87–95. doi: https://doi.org/10.18869/acadpub.ijrr.17.1.87
  22. Ji WJ, Ma YQ, Zhou X, et al. Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments. PLoS One. 2013;8(11):e81090. doi: 10.1371/journal.pone.0081090' target='_blank'>https://doi: 10.1371/journal.pone.0081090
  23. Lechowicz K, Drożdżal S, Machaj F, et al. COVID-19: the potential treatment of pulmonary fibrosis associated with SARS-CoV-2 infection. J Clin Med. 2020;9(6):1917. doi: https://doi.org/10.3390/jcm9061917
  24. Atalay C, Dogan N, Aykan S, et al. The efficacy of spironolactone in the treatment of acute respiratory distress syndrome-induced rats. Singapore Med J. 2010;51(6):501–505.
  25. Asselta R, Paraboschi EM, Mantovani A, Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. doi: https://doi.org/10.1101/2020.03.30.20047878
  26. The human protein atlas. Available from: https://www.proteinatlas.org/ENSG00000151694-ADAM17/tissue (accessed: 13.07.2020).
  27. Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of ACE2 in men and women with heart failure and effects of renin-angiotensin-aldosterone-inhibitors. Eur Heart J. 2020;41(19):1810–1817. doi: https://doi.org/10.1093/eurheartj/ehaa373
  28. Dalpiaz PL, Lamas AZ, Caliman IF, et al. Sex hormones promote opposite effects on ACE and ACE2 activity, hypertrophy and cardiac contractility in spontaneously hypertensive rats. PLoS One. 2015;10(5):e0127515. doi: https://doi.org/10.1371/journal.pone.0127515
  29. Lin B, Ferguson C, White JT, et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 1999;59(17):4180–4184.
  30. Wambier CG, Goren A, Ossimetha A, et al. Theory Androgen-driven COVID-19 pandemic theory. ResearchGate. 2020. doi: https://doi.org/10.13140/RG.2.2.21254.11848
  31. Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. J Am Acad Dermatol. 2020;83:308–309. doi: https://doi.org/10.1016/j.jaad.2020.04.032
  32. Goren A, Vaño‐Galván S, Wambier CG, et al. A preliminary observation: Male pattern hair loss among hospitalized COVID‐19 patients in Spain — A potential clue to the role of androgens in COVID‐19 severity. J Cosmet Dermatol. 2020;19(7):1545-1547. doi: https://doi.org/10.1111/jocd.13443
  33. Montopoli M, Zumerle S, Vettor R, et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 2020;31(8):1040–1045. doi: https://doi.org/10.1016/j.annonc.2020.04.479
  34. Loriaux DL, Menard R, Taylor A, et al. Spironolactone and endocrine dysfunction. Ann Int Med. 1976;85(5):630–636. doi: https://doi.org/10.7326/0003-4819-85-5-630
  35. McMullen GR, Van Herle AJ. Hirsutism and the effectiveness of spironolactone in its management. J Endocrinol Invest. 1993;16(11):925–932. doi: https://doi.org/10.1007/BF03348960
  36. Cadegiani F, Goren A, Wambier CG. Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS). Med Hypotheses. 2020;143:110112. doi: https://doi.org/10.1016/j.mehy.2020.110112
  37. Liaudet L, Szabo C. Blocking mineralocorticoid receptor with spironolactone may have a wide range of therapeutic actions in severe COVID-19 disease. Critical Care. 2020;24:318. doi: https://doi.org/10.1186/s13054-020-03055-6
  38. U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04424134 (accessed: 30.05.2020).
  39. Мареев В.Ю., Орлова Я.А., Павликова Е.П., и др. Пульс-терапия стероидными гормонами больных с коронавирусной пневмонией (COVID-19), системным воспалением и риском венозных тромбозов и тромбоэмболий (исследование ПУТНИК) // Кардиология. — 2020. — Т. 60. — № 6. — С. 15–29. [Mareev VYu, Orlova YA, Pavlikova EP, et al. Steroid pulse-herapy in patients with coronavirus pneumonia (COVID-19), systemic in flammation and risk of venous thrombosis and thromboembolism (WAYFARER Study). Kardiologiia. 2020;60(6):15–29. (In Russ.)] doi: https://doi.org/10.18087/cardio.2020.6.n1226
  40. Dagenais M, Skeldon A, Saleh M. The inflammasome: in memory of Dr. Jurg Tschopp. Cell Death Differ. 2012;19(1):5–12. doi: https://doi.org/10.1038/cdd.2011.159
  41. Misawa T, Takahama M, Kozaki T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14:454–460. doi: https://doi.org/10.1038/ni.2550
  42. Naghavi MH, Walsh D. Microtubule regulation and function during virus infection. J Virology. 2017;91(16):e00538-17. doi: https://doi.org/10.1128/JVI.00538-17
  43. Lu Y, Chen J, Xiao M, et al. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm Res. 2012;29(11):2943–2971. doi: https://doi.org/10.1007/s11095-012-0828-z
  44. McLoughlin EC, O’Boyle NM. Colchicine-binding site inhibitors from chemistry to clinic: a review. Pharmaceuticals. 2020;13(1):8. doi: https://doi.org/10.3390/ph13010008
  45. Deftereos SG, Giannopoulos G, Vrachatis DA, 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: https://doi.org/10.1001/jamanetworkopen.2020.13136
  46. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497–2505. doi: https://doi.org/10.1056/NEJMoa1912388
  47. U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04403243
  48. Deftereos S, Giannopoulos G, Vrachatis DA, et al. Colchicine as a potent anti-inflammatory treatment in COVID-19: can we teach an old dog new tricks? Eur Heart J Cardiovasc Pharmacother. 2020:6:255. doi: https://doi.org/10.1093/ehjcvp/pvaa033
  49. Cattaneo M, Bertinato EM, Birocchi S, et al. Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified? Thromb Haemost. 2020;120(8):1230–1232. doi: https://doi.org/10.1016/j.thromres.2020.04.013
  50. Leonard-Lorant I, Delabranche X, Severac F, et al. Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. Radiology. 2020;296:E189–E191. doi: https://doi.org/10.1148/radiol.2020201561
  51. Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb and Haemost. 2020. Apr 9. doi: https://doi.org/10.1111/JTH.14830
  52. Poissy J, Goutay J, Caplan M. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation. 2020;142(2):184–186. doi: https://doi.org/10.1161/CIRCULATIONAHA.120.047430
  53. Zhang L, Yan X, Fan Q, et al. D‐dimer levels on admission to predict in‐hospital mortality in patients with COVID‐19. J Thromb Haemost. 2020;18(6):1324–1329. doi: https://doi.org/10.1111/jth.14859
  54. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost. 2020;120(6):998–1000. doi: https://doi.org/10.1055/s-0040-1710018
  55. McGonagle D, O’Donnell JS, Sharif K, et al. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2020;2(7):e437–e445. doi: https://doi.org/10.1016/S2665-9913(20)30121-1
  56. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Eng J Med. 2020;338(2):120–128. doi: https://doi.org/10.1056/NEJMoa2015432
  57. Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020;20(7):389–391. doi: https://doi.org/10.1038/s41577-020-0343-0
  58. 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):1094–1099. doi: https://doi.org/10.1111/JTH.14817
  59. Wichmann D, Sperhake J, Lutgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020:M20-2003 doi: https://doi.org/10.7326/M20-2003
  60. Leonard-Lorant I, Delabranche X, Severac F, et al. Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. Radiology. 2020;296(3):E189–E191. doi: https://doi.org/10.1148/radiol.2020201561
  61. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76(1):122–124. doi: https://doi.org/10.1016/j.jacc.2020.05.001
  62. 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):1094–1099. doi: https://doi.org/10.1111/JTH.14817
  63. Шляхто Е.В., Арутюнов Г.П., Беленков Ю.Н., и др. Применение статинов, антикоагулянтов, антиагрегантов и антиаритмических препаратов у пациентов с COVID-19 // Кардиология. — 2020. — Т. 60. — № 6. — С. 4–11. [Shlyakhto YV, Arutyunov GP, Belenkov YuN, et al. Use of statins, anticoagulants, antiaggregants and antiarrhythmic drugs in patients with COVID-19. Kardiologiia. 2020;60(6):4–14. (In Russ.)] doi: https://doi.org/10.18087/cardio.2020.6.n1180.

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2. Fig. 1. Stages of the course of a new coronavirus infection: the role of viremia, immune inflammation and coagulopathy in the progression of the disease

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3. Fig. 2. Blockade of transmembrane transserine protease 2 and the possibility of disrupting the penetration of the SARS-CoV-2 virus into the cell. The effect of bromhexine and spironolactone

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