title: In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine.
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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Pereira
authors.forename: Philipp P
authors.initials: PP
authors.lastname: Henrich
authors.forename: Amar Bir Singh
authors.initials: AB
authors.lastname: Sidhu
authors.forename: David
authors.initials: D
authors.lastname: Johnson
authors.forename: Joel
authors.initials: J
authors.lastname: Hardink
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Van Deusen
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Katrina
authors.initials: K
authors.lastname: Gore
authors.forename: Connor
authors.initials: C
authors.lastname: O'Brien
authors.forename: Mamadou
authors.initials: M
authors.lastname: Wele
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimde
authors.forename: Richa
authors.initials: R
authors.lastname: Chandra
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D017311:Amlodipine; D017963:Azithromycin; D002738:Chloroquine