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
Identifieur interne : 004195 ( Main/Exploration ); précédent : 004194; suivant : 004196Quinoline 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
Auteurs : Andrea Savarino [Italie] ; Mothanje B. Lucia [Italie] ; Rob Ter Heine [Pays-Bas] ; Elena Rastrelli [Italie] ; Sergio Rutella [Italie] ; Giancarlo Majori [Italie] ; Alwin Huitema [Pays-Bas] ; Johan R. Boelaert [Belgique] ; Roberto Cauda [Italie]Source :
- Drug Development Research [ 0272-4391 ] ; 2006-10.
English descriptors
- Teeft :
- Achievable, Achievable concentrations, Antimalarial, Antimalarial drugs, Antimalarial prophylaxis, Antiretroviral, Antiretroviral drugs, Antiretroviral effects, Antiretroviral synergism, Antiretrovirals, Assay, Bcrp, Becton dickinson, Boelaert, Breast cancer resistance protein, Calibration standards, Cell pellets, Chloroquine, Chloroquine concentrations, Clinical trials, Data points, Envelope glycoproteins, Functional activity, H9iiib, H9iiib cells, Healthy donors, Independent experiments, Inhibitor, Intracellular, Intracellular concentrations, Intracellular lopinavir concentrations, Istituto superiore, Liquid chromatography, Lopinavir, Mrp1, Multidrug, Nevirapine, Nrti, Pbmc, Pellet, Peripheral blood, Peripheral blood lymphocytes, Present study, Protease, Protease inhibitors, Quality controls, Quinoline, Quinoline antimalarials, Replication, Saquinavir, Savarino, Sperber, Statistical test, Syncytial formation, Synergism, Synergistic, Synergistic effects, Tandem mass spectrometry, Toxicity, Transporter, Uorescence, Uorescent substrates, Viral, Zidovudine.
Abstract
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.
Url:
DOI: 10.1002/ddr.20147
Affiliations:
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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.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Italie</li><li>Pays-Bas</li></country><region><li>Hollande-Septentrionale</li><li>Latium</li></region><settlement><li>Amsterdam</li><li>Rome</li></settlement></list><tree><country name="Italie"><region name="Latium"><name sortKey="Savarino, Andrea" sort="Savarino, Andrea" uniqKey="Savarino A" first="Andrea" last="Savarino">Andrea Savarino</name></region><name sortKey="Cauda, Roberto" sort="Cauda, Roberto" uniqKey="Cauda R" first="Roberto" last="Cauda">Roberto Cauda</name><name sortKey="Lucia, Mothanje B" sort="Lucia, Mothanje B" uniqKey="Lucia M" first="Mothanje B." last="Lucia">Mothanje B. Lucia</name><name sortKey="Majori, Giancarlo" sort="Majori, Giancarlo" uniqKey="Majori G" first="Giancarlo" last="Majori">Giancarlo Majori</name><name sortKey="Rastrelli, Elena" sort="Rastrelli, Elena" uniqKey="Rastrelli E" first="Elena" last="Rastrelli">Elena Rastrelli</name><name sortKey="Rutella, Sergio" sort="Rutella, Sergio" uniqKey="Rutella S" first="Sergio" last="Rutella">Sergio Rutella</name><name sortKey="Savarino, Andrea" sort="Savarino, Andrea" uniqKey="Savarino A" first="Andrea" last="Savarino">Andrea Savarino</name></country><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Ter Heine, Rob" sort="Ter Heine, Rob" uniqKey="Ter Heine R" first="Rob" last="Ter Heine">Rob Ter Heine</name></region><name sortKey="Huitema, Alwin" sort="Huitema, Alwin" uniqKey="Huitema A" first="Alwin" last="Huitema">Alwin Huitema</name></country><country name="Belgique"><noRegion><name sortKey="Boelaert, Johan R" sort="Boelaert, Johan R" uniqKey="Boelaert J" first="Johan R." last="Boelaert">Johan R. Boelaert</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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