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 salicylaldehy de isonicotinoyl hydrazone (SIH) are iron chelators which inhibit in v itro proliferation of Plasmodium falciparum with similar potency (IC50 similar to 20 mu M in 24- to 48-h tests). The in vivo assessment of t hese drugs was performed on Swiss mice infected with Plasmodium vincke i petteri with novel modes of drug administration and release. The dru gs were delivered postpatently either by multiple i.p. injections or b y a single i.p, or s.c. insertion of a drug-containing polymeric devic e which released most of the drug within 7 days at apparently first-or der rates. A regimen of three daily i.p injections of 5 mg DFO for 3 c onsecutive days or a 70-mg dose of the drug given as an i.p. or s.c. p olymer 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 hydr ophilic SIH. In combination, the two drugs apparently potentiated each other. The polymeric devices were particularly useful for treating Pl asmodium berghei k173-infected C57BI mice, a suggested model of cerebr al malaria, in which classical methods of DFO delivery were ineffectiv e. The insertion of a 140-mg DFO-containing device on day 6 postinfect ion (parasitemia similar to 1%) led to a marked reduction in parasite proliferation, appearance of neurological sequelae and mortality of mi ce. 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 sustai ned blood levels. The results obtained with slow-release devices have implications for malaria chemotherapy as well as for iron chelation th erapy in iron overload conditions.