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 administered by three different treatment regimens: (1) multiple subcutaneous injections of free DFO, (2) intraperitoneal infusion of free DFO, or (3) multiple subcutaneous injections of liposomal DFO. In a first series of experiments, DFO treatment was started prior to infection. Multiple 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 after infection) of mice were obtained by intraperitoneal infusion starting 1 day before infection (14 days, 130 mg DFO/kg/day) or by subcutaneous injections of liposomal DFO prior to infection (days -1 and 0, 400 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 mg/kg/day). The present results indicate that continuous exposure of the parasite to low doses of DFO suffice to clear parasitemia, whereas high doses of free DFO administered intermittently do not. A right balance between dose of DFO, time of exposure to DFO, and parasitemia suppresses parasitemia even in the treatment of late-stage malaria. It was shown that liposomes are suitable carrier systems for DFO in experimental malaria therapy when given prior to infection and, moreover, in the treatment of advanced stages of malaria.
Department of Pharmaceutics, Utrecht University, The Netherlands.
N S
NS
Postma
C C
CC
Hermsen
J
J
Zuidema
W M
WM
Eling
D000818:Animals; D003676:Deferoxamine / Q000008:administration & dosage* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D007263:Infusions, Parenteral; D007279:Injections, Subcutaneous; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008081:Liposomes; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000188:drug therapy*; D013047:Specific Pathogen-Free Organisms; D017741:Survivors
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007502:Iron Chelating Agents; D008081:Liposomes; D003676:Deferoxamine