The treatment of animal models of malaria with iron chelators by use of a novel polymeric device for slow drug release.

The hydrophilic desferrioxamine (DFO) and the lipophilic salicylaldehyde isonicotinoyl hydrazone (SIH) are iron chelators which inhibit in vitro proliferation of Plasmodium falciparum with similar potency (IC50 approximately 20 microM in 24- to 48-h tests). The in vivo assessment of these drugs was performed on Swiss mice infected with Plasmodium vinckei petteri with novel modes of drug administration and release. The drugs were delivered postpatently either by multiple i.p. injections or by a single i.p. or s.c. insertion of a drug-containing polymeric device which released most of the drug within 7 days at apparently first-order rates. A regimen of three daily i.p injections of 5 mg DFO for 3 consecutive days or a 70-mg dose of the drug given as an i.p. or s.c. polymer implant evoked similar delay and reduction in peak parasitemias and reduced mortality with no apparent signs of toxicity. Relatively faster, but otherwise similar results were obtained with the less hydrophilic SIH. In combination, the two drugs apparently potentiated each other. The polymeric devices were particularly useful for treating Plasmodium berghei K173-infected C57Bl mice, a suggested model of cerebral malaria, in which classical methods of DFO delivery were ineffective. The insertion of a 140-mg DFO-containing device on day 6 postinfection (parasitemia approximately 1%) led to a marked reduction in parasite proliferation, appearance of neurological sequelae and mortality of mice. Our studies indicate that polymeric devices for slow drug release might be highly advantageous for both hydrophilic and lipophilic drugs whose antimalarial efficacy might depend on the maintenance of sustained blood levels. The results obtained with slow-release devices have implications for malaria chemotherapy as well as for iron chelation therapy in iron overload conditions.