Возможности комбинированной терапии на раннем этапе течения новой коронавирусной инфекции (COVID-19). Разбор клинических случаев и дизайн исследования: Бромгексин И Спиронолактон для лечения КоронаВирусной Инфекции, Требующей госпитализации (БИСКВИТ)

Статья посвящена вопросу эффективного лечения новой коронавирусной инфекции (COVID-19) на ранних стадиях болезни. Обосновывается необходимость противовирусной терапии и снижения вирусной нагрузки с целью не допустить прогрессирования инфекции. Констатируется отсутствие специфической противовирусной терапии именно в отношении вируса SARS-CoV-2. Разбираются результаты первых рандомизированных исследований по применению лопинавира / ритонавира, ремдесивира и фавипиравира при COVID-19, и их потенциал в лечении новой коронавирусной инфекции. Среди препаратов, блокирующих вход вируса в клетки, наибольшее внимание было уделено противомалярийным препаратам хлорохину и гидроксихлорохину. В статье подробно анализируются неэффективность, а также потенциальная опасность гидроксихлорохина, не показавшего снижения сроков клинического восстановления и улучшения прогноза больных с COVID-19. Главной темой является обоснование возможности применения муколитического и противокашлевого препарата бромгексина, блокирующего трансмембранную сериновую протеазу 2, необходимую для проникновения вируса SARS-CoV-2 в клетки. Аналогичным свойством может обладать и спиронолактон, который за счет антиандрогенных эффектов блокирует связанные с Х-хромосомой синтез рецепторов АПФ-2 и активизацию трансмембранной сериновой протеазы 2. Кроме замедления входа в клетки, спиронолактон уменьшает выраженность фиброза различных органов, в том числе легких. Основная часть статьи посвящена клиническим примерам ведения пациентов в Университетской клинике МНОЦ МГУ имени М. В. Ломоносова, в том числе с успешным использованием схемы лечения пациентов с COVID 19, включающей в себя бромгексин и спиронолактон. В заключении приводится дизайн рандомизированного проспективного исследования БИСКВИТ, проводившегося в Университетской клинике МГУ. Его целью явилось изучение эффективности предложенной схемы.

COVID-19, бромгексин, спиронолактон, вирусная нагрузка

1. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine. 2020;46(5):846–8. DOI: 10.1007/s00134-020-05991-x

2. Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A et al. High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) Requiring Invasive Mechanical Ventilation. Obesity. 2020;28(7):1195–9. DOI: 10.1002/oby.22831

3. The OpenSAFELY Collaborative, Williamson E, Walker AJ, Bhaskaran KJ, Bacon S, Bates C et al. OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. Epidemiology. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.05.06.20092999.] DOI: 10.1101/2020.05.06.20092999.

4. 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;323(13):1239. DOI: 10.1001/jama.2020.2648

5. Instituto Superiore Di Sanita. Characteristics of COVID-19 patients dying in ItalyReport based on available data on March 20th, 2020. [Av. at: https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_20_marzo_eng.pdf].

6. Wang S, Ma P, Zhang S, Song S, Wang Z, Ma Y et al. Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study. Diabetologia. 2020; [Epub ahead of print]. DOI: 10.1007/s00125-020-05209-1

7. Gao C, Cai Y, Zhang K, Zhou L, Zhang Y, Zhang X et al. Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study. European Heart Journal. 2020;41(22):2058–66. DOI: 10.1093/eurheartj/ehaa433

8. Guo Y-R, Cao Q-D, Hong Z-S, Tan Y-Y, Chen S-D, Jin H-J et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Military Medical Research. 2020;7(1):11. DOI: 10.1186/s40779-020-00240-0

9. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020; [Epub ahead of print]. DOI: 10.1001/jama.2020.6019

10. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine. 2020;382(19):1787–99. DOI: 10.1056/NEJMoa2001282

11. Министерство здравоохранения РФ. Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)». Версия 7 (03.06.2020). Москва. Доступно на: https://static-0.rosminzdrav.ru/system/attachments/attaches/000/050/584/original/03062020_%D0%9CR_COVID-19_v7.pdf

12. University of Oxford. Randomised Evaluation of COVID-19 Therapy. No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY. 2020. [Av. at: https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery].

13. World Health Organization. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. 2020. [Интернет] Available at: https://www.who.int/news-room/detail/04- 07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19

14. Hung IF-N, Lung K-C, Tso EY-K, Liu R, Chung TW-H, Chu M-Y 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. The Lancet. 2020;395(10238):1695–704. DOI: 10.1016/S0140-6736(20)31042-4

15. Ko W-C, Rolain J-M, Lee N-Y, Chen P-L, Huang C-T, Lee P-I et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. International Journal of Antimicrobial Agents. 2020;55(4):105933. DOI: 10.1016/j.ijantimicag.2020.105933

16. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. New England Journal of Medicine. 2020;382(24):2327–36. DOI: 10.1056/NEJMoa2007016

17. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial. The Lancet. 2020;395(10236):1569–78. DOI: 10.1016/S0140-6736(20)31022-9

18. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC et al. Remdesivir for the Treatment of Covid-19 – Preliminary Report. New England Journal of Medicine. 2020;NEJMoa2007764. [Epub ahead of print]. DOI: 10.1056/NEJMoa2007764

19. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. New England Journal of Medicine. 2020;NEJMoa2015301. [Epub ahead of print]. DOI: 10.1056/NEJMoa2015301

20. FDA. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. 2020. [Интернет] Available at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment

21. Day M. Covid-19: Experts criticise claim that remdesivir cuts death rates. BMJ. 2020;370:m2839. DOI: 10.1136/bmj.m2839

22. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. 2020. [Av. at: https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v4].

23. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering. 2020; [Epub ahead of print]. DOI: 10.1016/j.eng.2020.03.007

24. Российский Фонд Прямых Инвестиций. Минздрав одобрил переход к финальной стадии испытаний препарата «Фавипиравир». Пресс-релиз от 22.05.2020. [Internet] Available at: https://www.finanz.ru/novosti/aktsii/minzdrav-odobril-perekhod-k-finalnoy-stadii-ispytaniy-preparata-favipiravir-rfpi-1029226026

25. Fujita Health University Favipiravir Trial Evidences no Statistically Conclusive Benefit to COVID-19 Patients: A Question Mark for Favipiravir? 2020. [Интернет] Available at: https://www.trialsitenews.com/ fujita-health-university-favipiravir-trial-evidences-no-statistically-conclusive-benefit-to-covid-19-patients-a-question-mark-for-favipiravir/

26. The Dhaka Trial: Clear-Cut Evidence Favipiravir Effective against COVID-19 with Compelling Results. 2020. [Интернет] Available at: https://www.trialsitenews.com/the-dhaka-trial-clear-cut-evidencefavipiravir-effective-against-covid-19-with-compelling-results/

27. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases. The Lancet Infectious Diseases. 2003;3(11):722–7. DOI: 10.1016/S1473-3099(03)00806-5

28. Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. The Journal of Rheumatology. 1993;20(5):803–8. PMID: 8336306

29. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal. 2005;2(1):69. DOI: 10.1186/1743-422X-2-69

30. Petersen E, Koopmans M, Go U, Hamer DH, Petrosillo N, Castelli F et al. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. The Lancet Infectious Diseases. 2020;S1473309920304849. [Epub ahead of print]. DOI: 10.1016/S1473-3099(20)30484-9

31. Fani M, Teimoori A, Ghafari S. Comparison of the COVID-2019 (SARSCoV-2) pathogenesis with SARS-CoV and MERS-CoV infections. Future Virology. 2020;15(5):317–23. DOI: 10.2217/fvl-2020-0050

32. Sinha N, Balayla G. Hydroxychloroquine and covid-19. Postgraduate Medical Journal. 2020;1–6. [Av. at: https://pmj.bmj.com/content/postgradmedj/early/2020/05/28/postgradmedj-2020-137785.full.pdf]. DOI: 10.1136/postgradmedj-2020-137785

33. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020;56(1):105949. DOI: 10.1016/j.ijantimicag.2020.105949

34. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.03.22.20040758].

35. Mahevas M, Tran V-T, Roumier M, Chabrol A, Paule R, Guillaud C et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.04.1 0.20060699]. 2020 г.

36. Мареев В.Ю., Орлова Я.А., Павликова Е.П., Мацкеплишвили С.Т., Краснова Т.Н., Малахов П.С. и др. Пульс-терапия стероидными гормонами больных с коронавирусной пневмонией (COVID-19), системным воспалением и риском венозных тромбозов и тромбоэмболий (исследование ПУТНИК). Кардиология. 2020;60(6):15-29. DOI: 10.18087/cardio.2020.6.n1226

37. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine. 2020;382(25):2411–8. DOI: 10.1056/NEJMoa2012410

38. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J 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: 10.1001/jama.2020.8630

39. Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS et al. Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19. Med. 2020; [Epub ahead of print]. DOI: 10.1016/j.medj.2020.06.001

40. Hernandez AV, Roman YM, Pasupuleti V, Barboza JJ, White CM. Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review. Annals of Internal Medicine. 2020;173(4):287–96. DOI: 10.7326/M20-2496

41. Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiology. 2020;e201834. [Epub ahead of print]. DOI: 10.1001/jamacardio.2020.1834

42. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. New England Journal of Medicine. 2020;383(6):517–25. DOI: 10.1056/NEJMoa2016638

43. Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Annals of Internal Medicine. 2020;M20-4207. [Epub ahead of print]. DOI: 10.7326/M20-4207

44. University of Oxford. Randomised Evaluation of COVID-19 Therapy. Hydroxychloroquine results. 2020. [Av. at: https://www.recoverytrial. net/results/hydroxychloroquine-results].

45. Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.07.15.20151852].

46. Rabi FA, Al Zoubi MS, Kasasbeh GA, Salameh DM, Al-Nasser AD. SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far. Pathogens. 2020;9(3):231. DOI: 10.3390/pathogens9030231

47. Мареев Ю.В., Мареев В.Ю. Роль возраста, сопутствующих заболеваний и активности ренин-ангиотензин-альдостероновой системы в проявлениях COVID-19. Эффекты ингибиторов АПФ и блокаторов ангиотензиновых рецепторов. Кардиология. 2020;60(4):4-9. DOI: 10.18087/cardio.2020.4.n1122

48. Zanasi A, Mazzolini M, Kantar A. A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidisciplinary Respiratory Medicine. 2017;12(1):7. DOI: 10.1186/s40248-017-0088-1

49. Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD et al. The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discovery. 2014;4(11):1310–25. DOI: 10.1158/2159-8290.CD-13-1010

50. Sonawane K, Barale SS, Dhanavade MJ, Waghmare SR, Nadaf NH, Kamble SA et al. Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2. 2020. [Av. at: https://chemrxiv.org/articles/Homology_Modeling_and_Docking_Studies_of_TMPRSS2_with_Experimentally_Known_Inhibitors_Camostat_Mesylate_Nafamostat_and_Bromhexine_Hydrochloride_to_Control_SARS-Coronavirus-2/12162360/1].

51. Habtemariam S, Nabavi SF, Ghavami S, Cismaru CA, Berindan-Neagoe I, Nabavi SM. 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. Pharmacological Research. 2020;157:104853. DOI: 10.1016/j.phrs.2020.104853

52. Ferrario CM, Schiffrin EL. Role of Mineralocorticoid Receptor Antagonists in Cardiovascular Disease. Circulation Research. 2015;116(1):206–13. DOI: 10.1161/CIRCRESAHA.116.302706

53. Lechowicz K, Drożdżal S, Machaj F, Rosik J, Szostak B, ZeganBarańska M et al. COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with SARS-CoV-2 Infection. Journal of Clinical Medicine. 2020;9(6):1917. DOI: 10.3390/jcm9061917

54. 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. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.03.30.20047878].

55. Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. Journal of the American Academy of Dermatology. 2020;83(1):308–9. DOI: 10.1016/j.jaad.2020.04.032

56. 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(1):318. DOI: 10.1186/ s13054-020-03055-6

57. Stubnova V, Os I, Grundtvig M, Atar D, Waldum-Grevbo B. Spironolactone Treatment and Effect on Survival in Chronic Heart Failure Patients with Reduced Renal Function: A Propensity-Matched Study. Cardiorenal Medicine. 2017;7(2):128–36. DOI: 10.1159/000454933

58. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A et al. Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study. New England Journal of Medicine. 2004;351(6):543–51. DOI: 10.1056/NEJMoa040135

59. Alfano G, Ferrari A, Fontana F, Perrone R, Mori G, Ascione E et al. Hypokalemia in Patients with COVID-19. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.06.14.20131169].

60. Lomonosov Moscow State University Medical Research and Educational Center. Open Label Randomized Clinical Trial BromhexIne And Spironolactone For CoronаVirUs Infection Requiring HospiTalization. ClinicalTrials.gov Identifier: NCT04424134. 2020. [Av. at: https://clinicaltrials.gov/ct2/show/NCT04424134].

61. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. 2020. [Av. at: http://medrxiv.org/lookup/doi/10.1101/2020.06.22.20137273].