Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters - Volume 21, Number 6—June 2015 - Emerging Infectious Disease journal - CDC

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Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters - Volume 21, Number 6—June 2015 - Emerging Infectious Disease journal - CDC

Volume 21, Number 6—June 2015

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Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters

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• The Study
• Conclusions
• Suggested Citation

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• Figure 2

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Darryl Falzarano1, David Safronetz, Joseph Prescott, Andrea Marzi, Friederike Feldmann, and Heinz Feldmann 

Author affiliations: National Institute of Allergy and Infectious Diseases, Hamilton, Montana, USA

Suggested citation for this article

Abstract

The antimalarial drug chloroquine has been suggested as a treatment for Ebola virus infection. Chloroquine inhibited virus replication in vitro, but only at cytotoxic concentrations. In mouse and hamster models, treatment did not improve survival. Chloroquine is not a promising treatment for Ebola. Efforts should be directed toward other drug classes.

Chloroquine was first used as an antimalarial drug until widespread resistance in Plasmodium falciparum strains emerged. However, for >30 years this drug also has been recognized as having broad-spectrum antiviral properties (1), including activity against HIV-1 (2); the human coronaviruses, severe acute respiratory syndrome coronavirus (3) and OC43 (4); dengue virus (5); chikungunya virus (6); and influenza virus (7) in cell culture. Despite these data, chloroquine is not approved for use against any viral infections.

Previous in vitro data state a half maximal effective concentration (EC50) and EC90 of 16 and 25 mol/L for chloroquine against Ebola virus (EBOV), respectively (8). Twice daily dosing at 90 mg/kg intraperitoneally rapidly achieved a steady-state concentration of 2.5 μg/mL in the blood of mice. This dosing regimen resulted in survival of 85% of mice after infection with mouse-adapted (MA) EBOV (8). These data have led to the suggestion that chloroquine and its derivatives be used in persons with EBOV infection because this drug is approved for use in humans, has an extensive safety profile, and is inexpensive (1,9). To determine whether protection would extend to the EBOV hamster model, during 2013–2014 we investigated chloroquine treatment in this model and attempted to repeat previous in vitro findings and findings in the mouse model.

Dr. Falzarano, a research scientist at the University of Saskatchewan, performed this work while a visiting fellow at Rocky Mountain Laboratories. His research interests include determining posttranslational modifications on EBOV glycoproteins and antiviral strategies for severe virus infections.

Acknowledgments

We thank the animal care technicians for maintaining the animals used in this study.

This study was performed in accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, the Office of Animal Welfare, and the US Department of Agriculture. The Institutional Animal Care and Use Committee at Rocky Mountain Laboratories (RML) approved animal work. RML is an American Association for Accreditation of Laboratory Animal Care–approved facility. Trained personnel carried out all procedures with the animals under isoflurane anesthesia. The Institutional Biosafety Committee at RML approved all work with infectious EBOV under biosafety level 4 conditions.

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

References

1. De Clercq E. Ebola virus (EBOV) infection: therapeutic strategies. Biochem Pharmacol. 2015;93:1–10 . DOIPubMed
2. Savarino A, Gennero L, Sperber K, Boelaert JR. The anti-HIV-1 activity of chloroquine. J Clin Virol. 2001;20:131–5 . DOIPubMed
3. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004;323:264–8. DOIPubMed
4. Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother. 2009;53:3416–21. DOIPubMed
5. Farias KJ, Machado PR, de Almeida Junior RF, de Aquino AA, da Fonseca BA. Chloroquine interferes with dengue-2 virus replication in U937 cells.Microbiol Immunol. 2014;58:318–26. DOIPubMed
6. Delogu I, de Lamballerie X. Chikungunya disease and chloroquine treatment. J Med Virol. 2011;83:1058–9. DOIPubMed
7. Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial.[Erratum in: Lancet Infect Dis. 2011;11:655.]. Lancet Infect Dis. 2011;11:677–83. DOIPubMed
8. Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC, A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS ONE. 2013;8:e60579. DOIPubMed
9. Bishop BM. Potential and emerging treatment options for Ebola virus disease. Ann Pharmacother. 2015;49:196–206. DOIPubMed
10. Marzi A, Ebihara H, Callison J, Groseth A, Williams KJ, Geisbert TW, Vesicular stomatitis virus–based Ebola vaccines with improved cross-protective efficacy. J Infect Dis. 2011;204(Suppl 3):S1066–74. DOIPubMed
11. Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J Infect Dis. 1998;178:651–61. DOIPubMed
12. Ebihara H, Zivcec M, Gardner D, Falzarano D, LaCasse R, Rosenke R, A Syrian golden hamster model recapitulating Ebola hemorrhagic fever. J Infect Dis. 2013;207:306–18. DOIPubMed
13. Ebola haemorrhagic fever in Zaire, 1976. Bull World Health Organ. 1978;56:271–93 .PubMed
14. Ebola haemorrhagic fever in Sudan, 1976. Report of a WHO/International Study Team. Bull World Health Organ. 1978;56:247–70 .PubMed
15. Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.PLoS Negl Trop Dis. 2010;4:e785. DOIPubMed

Figures

• Figure 1. Viral loads from supernatants derived from Vero cells infected with Ebola virus expressing enhanced green fluorescent protein and treated with chloroquine at the indicated concentrations (0, 5, 25, 50,...
• Figure 2. Survival of MA EBOV-inoculated mice (A) and hamsters (B) treated with CQ (90 mg/kg). C) Survival of MA EBOV–infected hamsters treated with a combination of CQ (50 mg/kg), doxycycline...

Suggested citation for this article: Falzarano D, Safronetz D, Prescott J, Marzi A, Feldmann F, Feldmann H. Lack of protection against Ebola virus from chloroquine in mice and hamsters. Emerg Infect Dis. 2015 Jun [date cited]. http://dx.doi.org/10.3201/eid2106.150176

DOI: 10.3201/eid2106.150176

1Current affiliation: University of Saskatchewan, Saskatoon, Saskatchewan, Canada.