Ивермектин: оценка эффективности и безопасности при COVID-19

Поиск эффективной и безопасной терапии COVID-19 проводится в том числе путем изучения эффективности препаратов, уже используемых для лечения различных заболеваний и обладающих потенциальной противовирусной активностью в отношении SARS-CoV-2. Актуальность представленного исследования определяется неоднозначными данными о не регламентированном инструкцией применении противопаразитарного препарата ивермектин для лечения пациентов с COVID-19. Цель работы — анализ эффективности и безопасности применения ивермектина при лечении COVID-19 по данным научной литературы. Ивермектин — противопаразитарный препарат из группы макроциклических лактонов, продуцируемых Streptomyces avermitilis, усиливает выработку тормозного нейромедиатора гамма-аминомасляной кислоты, что приводит к нарушению передачи нервных импульсов, параличу и гибели паразитов. Результаты доклинических исследований свидетельствуют об ингибирующей активности ивермектина в отношении ряда РНК- и ДНК-вирусов, включая SARS-CoV-2. Результаты клинических исследований неоднозначны: в ряде исследований показано положительное влияние ивермектина на состояние пациентов с COVID-19, тем не менее убедительные доказательства обоснованности и эффективности применения ивермектина для профилактики и лечения пациентов с COVID-19 в настоящее время отсутствуют. Профиль безопасности ивермектина относительно благоприятный. Необходимы крупные рандомизированные контролируемые исследования, результаты которых позволят в полной мере оценить целесообразность применения ивермектина при COVID-19.

1. Novac N. Challenges and opportunities of drug repositioning. Trends Pharmacol Sci. 2013;34(5):267–72. https://doi.org/10.1016/j.tips.2013.03.004

2. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):185–8. https://doi.org/10.3760/cma.j.issn.1001-0939.2020.03.009

3. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020;177:104762. https://doi.org/10.1016/j.antiviral.2020.104762

4. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020;57:279–83. https://doi.org/10.1016/j.jcrc.2020.03.005

5. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans – a mini-review. AAPS J. 2008;10(1):42–6. https://doi.org/10.1208/s12248-007-9000-9

6. Götz V, Magar L, Dornfeld D, Giese S, Pohlmann A, Höper D, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138. https://doi.org/10.1038/srep23138

7. Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100(3):662–72. https://doi.org/10.1016/j.antiviral.2013.10.004

8. Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99(3):301–6. https://doi.org/10.1016/j.antiviral.2013.06.002

9. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851–6. https://doi.org/10.1042/bj20120150

10. Mega ER. Latin America’s embrace of an unproven COVID treatment is hindering drug trials. Nature. 2020;586(7830):481–2. https://doi.org/10.1038/d41586-020-02958-2

11. Temple C, Hoang R, Hendrickson RG. Toxic effects from Ivermectin use associated with prevention and treatment of Covid-19. N Engl J Med. 2021;385(23):2197–8. https://doi.org/10.1056/nejmc2114907

12. Omura S, Crump A. The life and times of ivermectin – a success story. Nat Rev Microbiol. 2004;2(12):984–9. https://doi.org/10.1038/nrmicro1048

13. Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8(2):317–31. PMID: 29511601

14. Crump A, Ōmura S. Ivermectin, “wonder drug” from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(2):13–28. https://doi.org/10.2183/pjab.87.13

15. Ōmura S. Chapter 13 – Mode of action of Avermectin. In: Ōmura S, ed. Macrolide Antibiotics. 2nd ed. San Diego: Academic Press; 2003. P. 571–6.

16. Shiomi K. Antiparasitic antibiotics from Japan. Parasitol Int. 2021;82:102298. https://doi.org/10.1016/j.parint.2021.102298

17. Martin RJ, Robertson AP, Choudhary S. Ivermectin: an anthelmintic, an insecticide, and much more. Trends Parasitol. 2021;37(1):48–64. https://doi.org/10.1016/j.pt.2020.10.005

18. Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, Jans DA. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 2020;177:104760. https://doi.org/10.1016/j.antiviral.2020.104760

19. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. https://doi.org/10.1016/j.antiviral.2020.104787

20. Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo). 2020;73(9):593–602. https://doi.org/10.1038/s41429-020-0336-z

21. Choudhury A, Das NC, Patra R, Bhattacharya M, Ghosh P, Patra BC, Mukherjee S. Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach. Future Virol. 2021. https://doi.org/10.2217/fvl-2020-0342

22. Eweas AF, Alhossary AA, Abdel-Moneim AS. Molecular docking reveals Ivermectin and Remdesivir as potential repurposed drugs against SARS-CoV-2. Front Microbiol. 2021;11:592908. https://doi.org/10.3389/fmicb.2020.592908

23. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In Vivo. 2020;34(5):3023–6. https://doi.org/10.21873/invivo.12134

24. Yan S, Ci X, Chen N, Li X, Chu X, Li J, Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res. 2011;60(6):589–596. https://doi.org/10.1007/s00011-011-0307-8

25. Zhang X, Song Y, Ci X, An N, Ju Y, Li X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57(11):524–9. https://doi.org/10.1007/s00011-008-8007-8

26. de Melo G, Lazarini F, Larrous F, Feige L, Kornobis E, Levallois S, et al. Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin. EMBO Mol Med. 2021;13:e14122. https://doi.org/10.15252/emmm.202114122

27. Xydakis MS, Dehgani-Mobaraki P, Holbrook EH, Geisthoff UW, Bauer C, Hautefort C, et al. Smell and taste dysfunction in patients with COVID-19. Lancet Infect Dis. 2020;20(9):1015–6. https://doi.org/10.1016/s1473-3099(20)30293-0

28. Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol. 2009;23(4):449–55. https://doi.org/10.1111/j.1472-8206.2009.00684.x

29. Stokes L, Layhadi JA, Bibic L, Dhuna K, Fountain SJ. P2X4 receptor function in the nervous system and current breakthroughs in pharmacology. Front Pharmacol. 2017;8:291. https://doi.org/10.3389/fphar.2017.00291

30. Layhadi JA, Turner J, Crossman D, Fountain SJ. ATP evokes Ca2+ responses and CXCL5 secretion via P2X4 receptor activation in human monocyte-derived macrophages. J Immunol. 2018;200(3):1159–68. https://doi.org/10.4049/jimmunol.1700965

31. Rizzo E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(7):1153–6. https://doi.org/10.1007/s00210-020-01902-5

32. Sandler ZJ, Firpo MR, Omoba OS, Vu MN, Menachery VD, Mounce BC. Novel ionophores active against La Crosse virus identified through rapid antiviral screening. Antimicrob Agents Chemother. 2020;64(6):e00086–20. https://doi.org/10.1128/aac.00086-20

33. Freedman JC. Chapter 4 – Ionophores in planar lipid bilayers. In: Sperelakis N, ed. Cell Physiology Source Book. 4th ed. San Diego; Academic Press: 2012. P. 61–6.

34. Chaccour C, Hammann F, Ramón-García S, Rabinovich NR. Ivermectin and COVID-19: keeping rigor in times of urgency. Am J Trop Med Hyg. 2020;102(6):1156–7. https://doi.org/10.4269/ajtmh.20-0271

35. Hossen MS, Barek MA, Jahan N, Safiqul Islam M. A review on current repurposing drugs for the treatment of COVID-19: reality and challenges. SN Compr Clin Med. 2020;2(10):1777–89. https://doi.org/10.1007/s42399-020-00485-9

36. Gritti G, Raimondi F, Ripamonti D, Riva I, Landi F, Alborghetti L, et al. IL-6 signalling pathway inactivation with siltuximab in patients with COVID-19 respiratory failure: an observational cohort study. medRxiv. https://doi.org/10.1101/2020.04.01.20048561

37. Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, et al. Histopathologic changes and SARS-CoV-2 imunostaining in the lung of a patient with COVID-19. Ann Intern Med. 2020:M20–0533. https://doi.org/10.7326/M20-0533

38. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with Coronavirus disease 2019: the ivermectin in COVID nineteen study. Chest. 2021;159(1):85–92. https://doi.org/10.1016/j.chest.2020.10.009

39. Elgazzar A, Basma H, Abo Youssef S, Hafez M, Moussa H, Eltaweel A, et al. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Preprint (Version 2), 2020. https://doi.org/10.21203/rs.3.rs-100956/v2

40. Mahmud R, Rahman MM, Alam I, Ahmed K, Kabir A, Sayeed S, et al. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. J Int Med Res. 2021;49(5):3000605211013550. https://doi.org/10.1177/03000605211013550

41. López-Medina E, López P, Hurtado IC, Davalos DM, Ramirez O, Martinez E, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426–35. https://doi.org/10.1001/jama.2021.3071

42. Rahman MA, Iqbal SA, Islam MA, Niaz MK, Hussain T, Siddiquee TH. Comparison of viral clearance between ivermectin with doxycycline and hydroxychloroquine with azithromycin in COVID-19 patients. J Bangladesh Coll Physicians Surg. 2020;38:5–9. https://doi.org/10.3329/jbcps.v38i0.47514

43. Mohiuddin Chowdhury ATM, Shahbaz M, Karim R, Islam J. A comparative study on ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID-19 patients. Preprint, 2020. https://doi.org/10.13140/RG.2.2.22193.81767/3

44. Hariyanto TI, Halim, DA, Rosalind J, Gunawan C, Kurniawan A. Ivermectin and outcomes from Covid-19 pneumonia: a systematic review and meta-analysis of randomized clinical trial studies. Rev Med Virol. e2265. https://doi.org/10.1002/rmv.2265

45. Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther. 2021;28(4):e434-e460. https://doi.org/10.1097/mjt.0000000000001402

46. Deng J, Zhou F, Ali S, Heybati K, Hou W, Huang E, Wong CY. Efficacy and safety of ivermectin for the treatment of COVID-19: a systematic review and meta-analysis. QJM. 2021;114(10):721–32. https://doi.org/10.1093/qjmed/hcab247

47. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin. Int J Antimicrob Agents. 2021;57(1):106248. https://doi.org/10.1016/j.ijantimicag.2020.106248

48. Ackerman SJ, Kephart GM, Francis H, Awadzi K, Gleich GJ, Ottesen EA. Eosinophil degranulation. An immunologic determinant in the pathogenesis of the Mazzotti reaction in human onchocerciasis. J Immunol. 1990;144(10):3961–9. PMID: 2332637

49. Boussinesq M, Gardon J, Gardon-Wendel N, Chippaux JP. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria J. 2003;2(Suppl 1):S4. https://doi.org/10.1186/1475-2883-2-s1-s4

50. Gardon J, Gardon-Wendel N, Demanga-Ngangue, Kamgno J, Chippaux JP, Boussinesq M. Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet. 1997;350(9070):18–22. https://doi.org/10.1016/s0140-6736(96)11094-1

51. Chandler RE. Serious neurological adverse events after ivermectin – do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg. 2018;98(2):382–8. https://doi.org/10.4269/ajtmh.17-0042

52. Campillo JT, Boussinesq M, Bertout S, Faillie JL, Chesnais CB. Serious adverse reactions associated with ivermectin: a systematic pharmacovigilance study in sub-Saharan Africa and in the rest of the world. PLoS Negl Trop Dis. 2021;15(4):e0009354. https://doi.org/10.1371/journal.pntd.0009354

53. Garrigues A, Nugier J, Orlowski S, Ezan E. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal Biochem. 2002;305(1):106–14. https://doi.org/10.1006/abio.2002.5650

54. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA. 1989;86(2):695–8. https://doi.org/10.1073/pnas.86.2.695

55. Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA. 1997;94(8):4028–33. https://doi.org/10.1073/pnas.94.8.4028

56. Baudou E, Lespine A, Durrieu G, André F, Gandia P, Durand C, Cunat S. Serious ivermectin toxicity and human ABCB1 nonsense mutations. N Engl J Med. 2020;383(8):787–9. https://doi.org/10.1056/nejmc1917344

57. Navarro M, Camprubí D, Requena-Méndez A, Buonfrate D, Giorli G, Kamgno J, et al. Safety of high-dose ivermectin: a systematic review and meta-analysis. J Antimicrob Chemother. 2020;75(4):827–34. https://doi.org/10.1093/jac/dkz524

58. Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong’o BO, Chen T, et al. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(6):615–26. https://doi.org/10.1016/s1473-3099(18)30163-4

59. Kamgno J, Gardon J, Gardon-Wendel N, Demanga-Ngangue, Duke BO, Boussinesq M. Adverse systemic reactions to treatment of onchocerciasis with ivermectin at normal and high doses given annually or three-monthly. Trans R Soc Trop Med Hyg. 2004;98(8):496–504. https://doi.org/10.1016/j.trstmh.2003.10.018

60. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122–33. https://doi.org/10.1177/009127002401382731

61. Awadzi K, Opoku NO, Addy ET, Quartey BT. The chemotherapy of onchocerciasis. XIX: The clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. 1995;46(2):131–7. PMID: 8525285

62. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol. 1999;57(10):1147–52

63. Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J. 2003;2(Suppl 1):S8. https://doi.org/10.1186/1475-2883-2-S1-S8