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Pereira MR, Henrich PP, Sidhu AB, et al. In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine. Antimicrob Agents Chemother. 2011;55(7):3115-24doi: 10.1128/AAC.01566-10.
Pereira, M. R., Henrich, P. P., Sidhu, A. B., Johnson, D., Hardink, J., Van Deusen, J., Lin, J., Gore, K., O'Brien, C., Wele, M., Djimde, A., Chandra, R., & Fidock, D. A. (2011). In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine. Antimicrobial agents and chemotherapy, 55(7), 3115-24. https://doi.org/10.1128/AAC.01566-10
Pereira, Marcus R, et al. "In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine." Antimicrobial agents and chemotherapy vol. 55,7 (2011): 3115-24. doi: https://doi.org/10.1128/AAC.01566-10
Pereira MR, Henrich PP, Sidhu AB, Johnson D, Hardink J, Van Deusen J, Lin J, Gore K, O'Brien C, Wele M, Djimde A, Chandra R, Fidock DA. In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine. Antimicrob Agents Chemother. 2011 Jul;55(7):3115-24. doi: 10.1128/AAC.01566-10. Epub 2011 Apr 04. PMID: 21464242; PMCID: PMC3122405.
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Antimicrob Agents Chemother. 2011 Jul;55(7):3115-24. doi: 10.1128/AAC.01566-10. Epub 2011 Apr 04.

In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine.

Antimicrobial agents and chemotherapy

Marcus R Pereira, Philipp P Henrich, Amar Bir Singh Sidhu, David Johnson, Joel Hardink, Jeffrey Van Deusen, Jian Lin, Katrina Gore, Connor O'Brien, Mamadou Wele, Abdoulaye Djimde, Richa Chandra, David A Fidock

Affiliations

  1. Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.

PMID: 21464242 PMCID: PMC3122405 DOI: 10.1128/AAC.01566-10

Abstract

Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.

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