PLASMODIUM VINCKEI - OPTIMIZATION OF DESFERRIOXAMINE-B DELIVERY IN THE TREATMENT OF MURINE MALARIA

Optimization of desferrioxamine B (DFO) delivery for the treatment of malaria was studied in Plasmodium vinckei infected mice. DFO was admin istered by three different treatment regimens: (1) multiple subcutaneo us injections of free DFO, (2) intraperitoneal infusion of free DFO, o r (3) multiple subcutaneous injections of liposomal DFO. In a first se ries of experiments, DFO treatment was started prior to infection. Mul tiple subcutaneous injections of free DFO before and during infection suppressed parasitemia, whereas injections only prior to infection did not. Suppression of parasitemia and long-term survival (> 1 month aft er infection) of mice were obtained by intraperitoneal infusion starti ng 1 day before infection (14 days, 130 mg DFO/kg/day) or by subcutane ous injections of liposomal DFO prior to infection (days - 1 and 0, 40 0 or 800 mg DFO/kg/day). The efficacy of the antimalarial activity of liposomal DFO was influenced by the drug-to-lipid ratio but was hardly affected by bilayer rigidity. In a second series of experiments, DFO treatment was started at days 6 and 7 after infection. Parasitemia was reduced by all three treatment regimens; however, long-term survival was obtained only by treatment with liposomal DFO (days 7 and 8, 400 m g/kg/day). The present results indicate that continuous exposure of th e parasite to low doses of DFO suffice to clear parasitemia, whereas h igh doses of free DFO administered intermittently do not. A right bala nce between dose of DFO, time of exposure to DFO, and parasitemia supp resses parasitemia even in the treatment of late-stage malaria. It was shown that liposomes are suitable carrier systems for DFO in experime ntal malaria therapy when given prior to infection and, moreover, in t he treatment of advanced stages of malaria. (C) 1998 Academic Press.