In Vivo Activity of #Amodiaquine against #Ebola Virus #Infection (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2019 Dec 27;9(1):20199. doi: 10.1038/s41598-019-56481-0.

In Vivo Activity of Amodiaquine against Ebola Virus Infection.

DeWald LE1,2, Johnson JC1,3, Gerhardt DM1, Torzewski LM1,4, Postnikova E1, Honko AN1,5, Janosko K1, Huzella L1, Dowling WE6, Eakin AE6, Osborn BL6, Gahagen J7, Tang L7, Green CE7, Mirsalis JC7, Holbrook MR1, Jahrling PB1,8, Dyall J9, Hensley LE1.

Author information: 1 Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, 21702, USA. 2 Emergent BioSolutions Inc, Gaithersburg, MD, 20879, USA. 3 AbViro LLC, Bethesda, MD, 20814, USA. 4 Bioqual Inc, Rockville, MD, 20850, USA. 5 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. 6 Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA. 7 SRI International, Menlo Park, CA, 94025, USA. 8 Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, 21702, USA. 9 Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, 21702, USA. dyallj@niaid.nih.gov.

 

Abstract

During the Ebola virus disease (EVD) epidemic in Western Africa (2013‒2016), antimalarial treatment was administered to EVD patients due to the high coexisting malaria burden in accordance with World Health Organization guidelines. In an Ebola treatment center in Liberia, EVD patients receiving the combination antimalarial artesunate-amodiaquine had a lower risk of death compared to those treated with artemether-lumefantrine. As artemether and artesunate are derivatives of artemisinin, the beneficial anti-Ebola virus (EBOV) effect observed could possibly be attributed to the change from lumefantrine to amodiaquine. Amodiaquine is a widely used antimalarial in the countries that experience outbreaks of EVD and, therefore, holds promise as an approved drug that could be repurposed for treating EBOV infections. We investigated the potential anti-EBOV effect of amodiaquine in a well-characterized nonhuman primate model of EVD. Using a similar 3-day antimalarial dosing strategy as for human patients, plasma concentrations of amodiaquine in healthy animals were similar to those found in humans. However, the treatment regimen did not result in a survival benefit or decrease of disease signs in EBOV-infected animals. While amodiaquine on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of amodiaquine when used in combination with artesunate or another antiviral.

PMID: 31882748 DOI: 10.1038/s41598-019-56481-0

Keywords: Antivirals; Ebola; Amodiaquine; Animal models.

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Effect of Mass #Artesunate-Amodiaquine #Distribution on #Mortality of #Patients With #Ebola Virus Disease During West #African #Outbreak (Open Forum Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Open Forum Infect Dis. 2019 May 24;6(7):ofz250. doi: 10.1093/ofid/ofz250. eCollection 2019 Jul.

Effect of Mass Artesunate-Amodiaquine Distribution on Mortality of Patients With Ebola Virus Disease During West African Outbreak.

Garbern SC1, Yam D2, Aluisio AR1, Cho DK3, Kennedy SB4, Massaquoi M4, Sahr F5, Perera SM6, Levine AC1, Liu T2.

Author information: 1 Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island. 2 Department of Biostatistics, Center for Statistical Sciences, Brown University School of Public Health, Providence, Rhode Island. 3 Brown University, Providence, Rhode Island. 4 Ministry of Health, Monrovia, Liberia. 5 Sierra Leone Ministry of Defense, Freetown, Sierra Leone. 6 International Medical Corps, Washington, DC.

 

Abstract

BACKGROUND:

Experiments in vitro have shown that the drug amodiaquine may inhibit Ebola virus activity. During the Ebola virus disease (EVD) epidemic in West Africa in 2014-2016, 2 mass drug administrations (MDAs) of artesunate-amodiaquine (ASAQ) were implemented to decrease the burden of malaria. The objective of this study was to assess the effect of the ASAQ MDAs on the mortality of patients with EVD.

METHODS:

A retrospective cohort design was used to analyze mortality data for patients with EVD admitted to 5 Ebola treatment units in Liberia and Sierra Leone. Patients admitted to the ETUs during the time period of ASAQ’s therapeutic effect from areas where the MDA was implemented were matched to controls not exposed to ASAQ, using a range of covariates, including malaria co-infection status, and a logistic regression analysis was performed. The primary outcome was Ebola treatment unit mortality.

RESULTS:

A total of 424 patients with EVD had sufficient data for analysis. Overall, the mortality of EVD patients was 57.5%. A total of 22 EVD patients were exposed to ASAQ during the MDAs and were found to have decreased risk of death compared with those not exposed in a matched analysis, but this did not reach statistical significance (relative risk, 0.63; 95% confidence interval, 0.37-1.07; P = .086).

CONCLUSIONS:

There was a non-statistically significantly decreased risk of mortality in EVD patients exposed to ASAQ during the 2 MDAs as compared with EVD patients not exposed to ASAQ. Further prospective trials are needed to determine the direct effect of ASAQ on EVD mortality.

KEYWORDS: Ebola virus disease; amodiaquine; epidemic; mass drug administration; mortality

PMID: 31281856 PMCID: PMC6602760 DOI: 10.1093/ofid/ofz250

Keywords: Ebola; Malaria; West Africa; Artesunate; Amodiquinine.

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Novel #amodiaquine derivatives potently inhibit #Ebola virus #infection (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2018 Nov 2. pii: S0166-3542(18)30535-7. doi: 10.1016/j.antiviral.2018.10.025. [Epub ahead of print]

Novel amodiaquine derivatives potently inhibit Ebola virus infection.

Sakurai Y1, Sakakibara N2, Toyama M3, Baba M3, Davey RA4.

Author information: 1 Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA; National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki, Japan. 2 Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Japan. 3 Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan. 4 Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA. Electronic address: radavey@bu.edu.

 

Abstract

Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed therapeutic. During the recent epidemic in West Africa, it was demonstrated that administration of antimalarial medication containing amodiaquine significantly lowered mortality rate of patients infected with the virus. Here, in order to improve its antiviral activity, a series of amodiaquine derivatives were synthesized and tested for Ebola virus infection. We found that multiple compounds were more potent than amodiaquine. The structure-activity relationship analysis revealed that the two independent parts, which are the alkyl chains extending from the aminomethyl group and a halogen bonded to the quinoline ring, were keys for enhancing antiviral potency without increasing toxicity. When these modifications were combined, the antiviral efficacy could be further improved with the selectivity indexes being over 10-times higher than amodiaquine. Mechanistic evaluation demonstrated that the potent derivatives blocked host cell entry of Ebola virus, like the parental amodiaquine. Taken together, our work identified novel potent amodiaquine derivatives, which will aid in further development of effective antiviral therapeutics.

PMID: 30395872 DOI: 10.1016/j.antiviral.2018.10.025

Keywords: Ebola; Antivirals; Amodiaquine.

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#Effect of #Artesunate–Amodiaquine on #Mortality Related to #Ebola #Virus #Disease (N Engl J Med., abstract)

[Source: The New England Journal of Medicine, full page: (LINK). Abstract, edited.]

Original Article

Effect of Artesunate–Amodiaquine on Mortality Related to Ebola Virus Disease [      ]

Etienne Gignoux, M.P.H., Andrew S. Azman, Ph.D., Martin de Smet, M.D., Philippe Azuma, M.D., Moses Massaquoi, M.D., Dorian Job, M.D., Amanda Tiffany, M.P.H., Roberta Petrucci, M.D., Esther Sterk, M.D., M.I.H., Julien Potet, M.D., Motoi Suzuki, M.D., Andreas Kurth, Ph.D., Angela Cannas, Ph.D., Anne Bocquin, M.Sc., Thomas Strecker, Ph.D., Christopher Logue, Ph.D., Thomas Pottage, B.Sc., Constanze Yue, Ph.D., Jean-Clement Cabrol, M.D., Micaela Serafini, M.D., M.P.H., and Iza Ciglenecki, M.D.

N Engl J Med 2016; 374:23-32 / January 7, 2016 / DOI: 10.1056/NEJMoa1504605

 

Abstract

Background

Malaria treatment is recommended for patients with suspected Ebola virus disease (EVD) in West Africa, whether systeomatically or based on confirmed malaria diagnosis. At the Ebola treatment center in Foya, Lofa County, Liberia, the supply of artemether–lumefantrine, a first-line antimalarial combination drug, ran out for a 12-day period in August 2014. During this time, patients received the combination drug artesunate–amodiaquine; amodiaquine is a compound with anti–Ebola virus activity in vitro. No other obvious change in the care of patients occurred during this period.

Methods

We fit unadjusted and adjusted regression models to standardized patient-level data to estimate the risk ratio for death among patients with confirmed EVD who were prescribed artesunate–amodiaquine (artesunate–amodiaquine group), as compared with those who were prescribed artemether–lumefantrine (artemether–lumefantrine group) and those who were not prescribed any antimalarial drug (no-antimalarial group).

Results

Between June 5 and October 24, 2014, a total of 382 patients with confirmed EVD were admitted to the Ebola treatment center in Foya. At admission, 194 patients were prescribed artemether–lumefantrine and 71 were prescribed artesunate–amodiaquine. The characteristics of the patients in the artesunate–amodiaquine group were similar to those in the artemether–lumefantrine group and those in the no-antimalarial group. A total of 125 of the 194 patients in the artemether–lumefantrine group (64.4%) died, as compared with 36 of the 71 patients in the artesunate–amodiaquine group (50.7%). In adjusted analyses, the artesunate–amodiaquine group had a 31% lower risk of death than the artemether–lumefantrine group (risk ratio, 0.69; 95% confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria.

Conclusions

Patients who were prescribed artesunate–amodiaquine had a lower risk of death from EVD than did patients who were prescribed artemether–lumefantrine. However, our analyses cannot exclude the possibility that artemether–lumefantrine is associated with an increased risk of death or that the use of artesunate–amodiaquine was associated with unmeasured patient characteristics that directly altered the risk of death.

Keywords: Research; Abstracts; Ebola; Liberia; Artesunate; Amodiaquine.

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