Activity of Pentamidine-Containing Human Red Cell Ghosts against Visceral Leishmaniasis in the Hamster

摘要

A recent approach to the chemotherapy of visceral leishmaniasis has been the encapsulation of clinical agents within macrophage directed carriers such as liposomes. Because in mammals Leishmania are obligate intramacrophage micro-organisms, injection of an encapsulated drug should deliver large quantities of drug to the organisms, thus decreasing both the number of drug administrations needed for the cure and drug toxicity. Drug contained within red cell ghosts have been used clinically to treat other macrophage disorders. We encapsulated the clinical antileishmanial agent pentamidine within human red cell ghosts and administered it to hamsters infected with Leishmania donovani against liver parasites, the ED50 and ED90 of single injections of this preparation were 231-240 times lower than that of the positive control drug, sodium stibo-gluconate (Pentostam), and essentially all parasites could be eliminated by 2.5 mg encapsulated drugs/kg. Against splenic parasites, the ED50 was 195 times lower than that of antimony, although only 80% of parasites were eliminated by the highest doses of encapsulated drug (2.5-6.4 mg/kg). The difference in liver vs. splenic parasite killing is probably related to the greater uptake of encapsulated drug by the liver (11-14 ug/g tissue) vs. the spleen (2-3 ug/g). If activity in this model is comparable to activity in humans, these results suggest that a single injection of a preparation consisting of ghosts of a patient's own red cells and the amount of pentamidine in one standard dosage (4 mg/kg) would eliminate 80%-100% of L. donovani from the spleen and liver.