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Quinoline antimalarials as investigational drugs for HIV‐1/AIDS: in vitro effects on HIV‐1 replication, HIV‐1 response to antiretroviral drugs, and intracellular antiretroviral drug concentrations
Author(s) -
Savarino Andrea,
Lucia Mothanje B.,
ter Heine Rob,
Rastrelli Elena,
Rutella Sergio,
Majori Giancarlo,
Huitema Alwin,
Boelaert Johan R.,
Cauda Roberto
Publication year - 2006
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.20147
Subject(s) - mefloquine , pharmacology , nevirapine , chloroquine , zidovudine , ritonavir , drug , virology , lopinavir , drug resistance , biology , medicine , immunology , viral load , virus , viral disease , malaria , microbiology and biotechnology , antiretroviral therapy
In this study, the effects of the quinoline antimalarials, chloroquine and mefloquine, were tested on: (1) HIV‐1 replication; (2) virus response to existing antiretrovirals; (3) functional activity of drug efflux pumps; and (4) intracellular accumulation of antiretrovirals. Antiretroviral activity was evaluated using cells acutely infected with drug‐sensitive/resistant HIV‐1 isolates or retroviral vectors, chronically infected cell lines, and syncytium assays. Drug interactions were assessed isobolographically. Activity of efflux pumps was tested using specific fluorochromes. Antitretroviral concentrations were quantitated by HPLC. Results indicated that: (1) the antimalarials (mefloquine > chloroquine) inhibited the replication of drug‐sensitive and drug‐resistant HIV‐1 at therapeutically achievable concentrations and specifically impaired the formation of fusion‐competent viral glycoproteins; (2) anti‐HIV‐1 effects were additive to those of zidovudine and nevirapine, and synergistic to those of lopinavir; (3) the antimalarials (mefloquine > chloroquine) inhibited the P‐glycoprotein, multidrug‐resistance‐associated proteins, and breast‐cancer resistance‐associated protein; (4) Chloroquine, but not mefloquine, increased lopinavir concentrations in peripheral blood mononuclear cells (PBMCs) by approximately 5 (five)‐fold. Thus quinoline antimalarials inhibited HIV‐1 replication by a novel mechanism, resulting in additive or synergistic effects in combination with known antiretrovirals. These drugs may also have an impact on the cellular pharmacokinetics of antiretrovirals. Drug Dev. Res. 67:806–817, 2006. © 2007 Wiley‐Liss, Inc.