Evaluation of toxicity and effectiveness of the anti-malaria preparation mefloquine with respect to SARS-CoV-2 in experiments on animals

Cover Page

Cite item

Full Text

Abstract

The aim of the study was to clarify the toxicity of mefloquine and to evaluate the effectiveness of its use for Syrian hamsters infected with sARS-Cov-2.

Material and methods. The experiments were performed on 96 Syrian hamsters. The toxicity of mefloquine was determined with a single administration, as well as with a course of administration at doses comparable to therapeutic for humans. To study the effectiveness of the drug against SARS-CoV-2 infection, a comprehensive indicator of the state of lung tissue and a comparison of the dynamics of viral load in the lungs were used.

Results. The LD50 of mefloquine with a single oral administration is 817 mg/kg, the maximum tolerated dose is 600 mg/kg. When administered for 7 days at a cumulative dose of 900 mg/kg, no death was observed. Administration of mefloquine to animals infected with SARS-CoV-2 was accompanied by a decrease in the severity of lung damage and a faster decrease of viral load in the lung tissue.

About the authors

K. N. Filin

Federal State Unitary Enterprise Research & Production Center “Pharmaceutical Protection” of the Federal Medical Biological Agency

Email: info@atompharm.ru

Konstantin N. Filin.

141402, Khimki, Moscow region.

Russian Federation

V. N. Bykov

Federal State Unitary Enterprise Research & Production Center “Pharmaceutical Protection” of the Federal Medical Biological Agency

Author for correspondence.
Email: bykov_imm@mail.ru
ORCID iD: 0000-0001-5755-4045

Vladimir N. Bykov - Doctor of Medical Science, Professor, Deputy Director for Research and Development of the Federal State Unitary Enterprise Research & Production Center “Pharmaceutical Protection” of the Federal Medical Biological Agency.

141402, Khimki, Moscow region.

SPIN-код: 6021-1970

Author ID: 250265; ID: 7003916780

Researcher ID: R-8689-2016

Russian Federation

V. D. Gladkikh

Federal State Unitary Enterprise Research & Production Center “Pharmaceutical Protection” of the Federal Medical Biological Agency

Email: Gladkich2007@rambler.ru

Vadim D. Gladkikh.

141402, Khimki, Moscow region.

SPIN-код: 9272-6130

Author ID: 601432

Russian Federation

I. A. Lugovik

RMC “Home of pharmacy” JSC

Email: info@doclinika.ru

Il'ya A. Lugovik.

188663, Kuzmolovsky, Leningrad region.

Russian Federation

A. N. Grebenyuk

Pavlov First Saint Petersburg State Medical University; Saint Petersburg State Chemical Pharmaceutical University

Email: grebenyuk_an@mail.ru
ORCID iD: 0000-0002-9381-194X

Aleksandr N. Grebenyuk.

197022, Saint Petersburg; 197376, Saint Petersburg.

Scopus Author ID: 7003916780

ResearcherID: R-8689-2016

Russian Federation

References

  1. Temporary guidelines. Prevention, diagnosis and treatment of the new coronavirus infection «COVID-19». Version 4. 27.03.2020. Moscow: Ministry of Health of the Russian Federation [ Vremenny'e metodicheskie rekomendacii. Profilaktika, diagnostika i lechenie novoj koronavirusnoy infekcii «COVID-19». Versiya 4. 27.03.2020. Moscow: Ministerstvo zdravooxraneniya Rossijskoj Federacii, 2020. 2020. (in Russian)
  2. Sarma P., Kaur H., Kumar H., Mahendru D., Avti P., Bhattacharyya A., et al. Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: A systematic review and meta-analysis. J Med Virol. 2020; 92(7): 776-85.
  3. Tang W., Cao Z., Han M., Wang Z., Chen J., Sun W. [et al.]. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020; 369: m1849.
  4. WHO Solidarity Trial Consortium, Pan H., Peto R., Henao-Restrepo A.M., Preziosi M.P., Sathiyamoorthy V., Abdool Karim Q., et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021; 384(6): 497-511.
  5. Biot C., Daher W., Chavain N., Fandeur T., Khalife J., Dive D., De Clercq E. Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J Med Chem. 2006; 49(9): 2845-9.
  6. Liu J., Cao R., Xu M., Wang X., Zhang H., Hu H. [et al.]. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020; 6: 16.
  7. Yao X., Ye F., Zhang M., Cui C., Huang B., Niu P. [et al.]. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2. Clin Infect Dis. 2020; 71(15): 732-9.
  8. Axfors C., Schmitt A.M., Janiaud P., Van't Hooft J., Abd-Elsalam S., Abdo E.F., et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun. 2021;12(1): 2349.
  9. Li R., Yin K., Zhang K., Wang Y.Y., Wu Q.P., Tang S.B., Cheng J.D. Application Prospects of Virtual Autopsy in Forensic Pathological Investigations on COVID-19. Fa Yi Xue Za Zhi. 2020; 36(2): 149-56.
  10. Temporary guidelines. Prevention, diagnosis and treatment of new coronavirus infection «COVID-19» Version 5. 08.04.2020. Moscow: Ministry of Health of the Russian Federation [ Vremenny'e metodicheskie rekomendacii. Profilaktika, diagnostika i lechenie novoj koronavirusnoj infekcii «COVID-19» Versiya 5. 08.04.2020. Moscow: Ministerstvo Ministry of Health of the Russian Federation, 2020. (in Russian)
  11. Sun W., He S., Martfriez-Romero C., Kouznetsova J., Tawa G., Xu M., et al. Synergistic drug combination effectively blocks Ebola virus infection. Antiviral Res. 2017; 137: 165-72.
  12. Balasubramanian A., Teramoto T., Kulkarni A.A., Bhattacharjee A.K., Padmanabhan R. Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus. Antiviral Res. 2017; 137: 141-50.
  13. Fan H.H., Wang L.Q., Liu W.L., An X.P., Liu Z.D., He X.Q., et al. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model. Chin Med J (Engl). 2020; 133(9): 1051-6.
  14. Filin K.N., Berzin I.A., Bykov V.N., Gladkikh V.D., Loginova S.Ya., Savenko S.V., Shchukina V.N. Experimental evaluation of the activity of the drug mefloquine against the SARS-Cov-2 coronavirus. Medicina ekstremal'nyh situaciy (Medicine of extreme situations). 2020; 3: 13-18. (in Russian)
  15. Sweeney T.R. The present status of malaria chemotherapy: Mefloquine, a novel antimalarial. Medicinal Research Reviews. 1981; 1(3): 281-301.
  16. Sweeney T.R. Drugs with Quinine-like Action. In: Peters W., Richards W.H.G. ed. Anti-malarial Drug II: Current Antimalarial and New Drug Developments: Springer-Verlag Berlin Heidelberg; 1984. Chapter 9; p. 267-324.
  17. Korte D.W. Jr., Heiffer M.H., Hacker M.P., Kintner L.D., Hong C.B., Lee C.C. Subchronic toxicity of the antimalarial drug, mefloquine hydrochloride (WR-142,490), in monkeys and dogs. Fed Proc Fed Am Soc Exp Bioi. 1979; 38: 680.
  18. Karbwang J., Na-Bangchang K. Clinical application of mefloquine pharmacokinetics in the treatment of P falciparum malaria. Fundam Clin Pharmacol. 1994; 8(6): 491-502.
  19. Guidelines for conducting preclinical studies of medicines. Moscow: FSBI "NCESMP" of the Ministry of Health and Social Development of Russia; 2012.
  20. Desjardins R.E., Pamplin C.L. 3rd, von Bredow J., Barry K.G., Canfield C.J. Kinetics of a new antimalarial, mefloquine. Clin Pharmacol Ther. 1979; 26(3): 372-9.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2021 Filin K.N., Bykov V.N., Gladkikh V.D., Lugovik I.A., Grebenyuk A.N.


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 81728 от 11 декабря 2013.