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We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-course treatments. Oral administration of the TE3 prodrug completely cures Plasmodium cynomolgi infection in rhesus monkeys. The drugs specifically accumulate inside infected erythrocytes, block phosphatidylcholine biosynthesis, and interact with hemozoin. To our knowledge, this class of compounds represents one of the most potent antimalarials tested to date. These unique properties signal a promising future for this class of antimalarial.M alaria is a public health problem affecting Ͼ40% of the world's population. It causes up to 2 million deaths, mostly young children, in Africa, and Ͼ300 million clinical cases each year (1), with major consequent impact on economic productivity and livelihood (2). Currently, there are no licensed vaccines and the spread of drug-resistant parasites and insecticideresistant mosquitoes is an increasing problem. New antimalarial compounds, particularly those based on compounds structurally unrelated to existing antimalarial drugs with new mechanisms of action, are urgently needed (3-5).We have developed classes of antimalarial drugs targeting membrane biogenesis during intraerythrocytic Plasmodium falciparum development. We have focused on mono-and bisquaternary ammonium compounds for their potent antimalarial activity in vitro and in vivo (6, 7). These compounds mimic choline structure; they potently inhibit the low-affinity choline carrier related to phospholipid biosynthesis in eukaryotic cells and the high-affinity carrier involved in biosynthesis of the neurotransmitter acetylcholine in the CNS (8, 9). These compounds have exceptional in vitro and in vivo antimalarial properties devoid of mutagenic activity (10 -12).G25 [1,16-hexadecamethylenebis(N-methylpyrrolidinium) dibromide] and other drugs in this class possess a permanently charged cationic group (7, 13) that is essential for activity but detrimental to oral absorption. This action prejudiced development for the clinic. Oral administration is essential for treatment in dispensaries in endemic countries and for prophylactic or curative treatment for travelers. A targeting carrier system is unsuitable because, in the absence of carrier-mediated specific processes, quaternary ammonium compounds are intrinsically incapable of crossing bilayered cellular membranes. Designing drugs that mask the ionizable groups was therefore the most attractive solution. This was the rationale behind development of a chemically modified form of drug that is converted into an active ionized form by enzymes present in plasma. Here, we repo...

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

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