saquinavir and Malaria

Topics: Animals; Antimalarials; Humans; Life Cycle Stages; Liver; Malaria; Plasmodium; Structure-Activity Relationship

Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.

Topics: Aminoquinolines; Animals; Antimalarials; Biological Transport; Cell Line; Chloroquine; Clotrimazole; Drug Resistance; Female; Half-Life; Hemeproteins; Humans; Malaria; Male; Membrane Transport Proteins; Mice; Models, Molecular; Mutation; Oocytes; Piperazines; Plasmodium berghei; Plasmodium falciparum; Protozoan Proteins; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Ventricular Pressure; Xenopus laevis

The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.

Topics: Adult; Anti-HIV Agents; Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Malaria; Nitriles; Plasma; Proguanil; Pyridazines; Pyrimidines; Saquinavir

Antiretroviral protease inhibitors significantly potentiated the sensitivity of chloroquine-resistant malaria parasites to the antimalarial drug in vitro and in vivo. Ritonavir was found to be potent in potentiating CQ antimalarial activities in both -resistant and -sensitive lines. The mechanism by which the APIs modulate the CQ resistance in malaria parasites was further investigated. CQ-resistant parasites showed increased intracellular glutathione levels in comparison with the CQ-sensitive parasites. Treatment with APIs significantly reduced the levels of GSH and glutathione S-transferase activities in CQ-resistant parasites. Ritonavir also decreased glutathione reductase activities and glutathione peroxidase activities in CQ-resistant parasite line. Taken together, these results demonstrate that parasite GSH and GST may play an important role in CQ resistance and APIs are able to enhance the sensitivity of CQ-resistant malaria parasite to the drug by influencing the levels of GSH and the activities of the related enzymes.

Topics: Animals; Anti-Retroviral Agents; Antimalarials; Chloroquine; Drug Resistance; Drug Synergism; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; HIV Protease Inhibitors; Inhibitory Concentration 50; Malaria; Mice; Nelfinavir; Plasmodium chabaudi; Plasmodium falciparum; Ritonavir; Saquinavir

The synergy of the activities between chloroquine and various human immunodeficiency virus protease inhibitors was investigated in chloroquine-resistant and -sensitive malaria parasites. In both in vitro and in vivo assay systems, ritonavir was found to be the most potent in potentiating the antimalarial action of chloroquine.

Topics: Animals; Antimalarials; Atazanavir Sulfate; Chloroquine; Drug Resistance; Drug Synergism; Female; HIV Protease Inhibitors; Humans; In Vitro Techniques; Lopinavir; Malaria; Mice; Nelfinavir; Oligopeptides; Plasmodium chabaudi; Plasmodium falciparum; Pyridines; Pyrimidinones; Ritonavir; Saquinavir