title: Synergy of the antiretroviral protease inhibitor indinavir and chloroquine against malaria parasites in vitro and in vivo.
abstract: Many malaria-endemic areas are also associated with high rates of human immunodeficiency virus (HIV) infection. An understanding of the chemotherapeutic interactions that occur during malaria and HIV co-infections is important. Our previous studies have demonstrated that some antiretroviral protease inhibitors are effective in inhibiting Plasmodium falciparum growth in vitro. Currently, studies examining the interactions between antiretroviral protease inhibitors and antimalarial drugs are being conducted, but the data are limited. In this study, we examined the synergistic interactions between the antiretroviral protease inhibitor indinavir and chloroquine (CQ) in chloroquine-resistant and chloroquine-sensitive malaria parasites in vitro and in vivo. In vitro, by using modified fixed-ratio isobologram method, fractional inhibitory concentrations index (FICI) was calculated to indicate the interaction between the two drugs. The results demonstrated that indinavir interacted synergistically with chloroquine against both chloroquine-sensitive P. falciparum clone 3D7 (mean FICI 0.784) and multidrug-resistant P. falciparum clone Dd2 (mean FICI 0.599). In vivo drug interactions were measured using a 4-day suppressive test in a rodent malaria model infected with Plasmodium chabaudi. We observed that indinavir enhanced the antimalarial activity of chloroquine against both the chloroquine-sensitive line P. chabaudi ASS and the chloroquine-resistant line P. chabaudi ASCQ. More importantly, chloroquine had a 100% clearance of asexual parasites when used in combination with indinavir at an appropriate dose ratio (10 mg/kg CQ + 1.8 g/kg indinavir) where there was no obvious toxicity. We conclude from this study that the combination of indinavir and chloroquine may become a novel antimalarial drug regimen.
authors.affiliation: Laboratory of Pathogen Biology, State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Zhengxiang
authors.initials: Z
authors.lastname: He
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Yayong
authors.initials: Y
authors.lastname: Li
authors.forename: Qinyan
authors.initials: Q
authors.lastname: Li
authors.forename: Siting
authors.initials: S
authors.lastname: Zhao
authors.forename: Zhu
authors.initials: Z
authors.lastname: Tao
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D060085:Coinfection; D004357:Drug Synergism; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D019469:Indinavir / Q000494:pharmacology*; D008288:Malaria / Q000150:complications / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D016788:Plasmodium chabaudi / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D017320:HIV Protease Inhibitors; D019469:Indinavir; D002738:Chloroquine