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Activity of pentamidine-containing human red cell ghosts against visceral leishmaniasis in the hamster
Abstract:
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 microorganisms, injection of an encapsulated drug should deliver large quantities of drug to the organisms, thus decreasing both the number of drug administrations needed for cure and drug toxicity. Drugs 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. The ED50 and ED90 of single injections of this preparation were 231-240 times lower than that of the positive control drug, sodium stibogluconate (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 micrograms/g tissue) vs. the spleen (2-3 micrograms/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.
Insights
Encapsulating pentamidine in red blood cell ghosts dramatically improved efficacy against visceral leishmaniasis in hamsters. This novel drug delivery system offers a promising, less toxic treatment for leishmaniasis.
Area of Science:
- Parasitology
- Drug Delivery Systems
- Biochemistry
Background:
- Visceral leishmaniasis is treated with chemotherapy, but current drugs have toxicity and require multiple doses.
- Leishmania parasites reside within macrophages, making targeted drug delivery crucial for effective treatment.
- Red blood cell ghosts have been utilized as drug carriers for macrophage-associated disorders.
Purpose of the Study:
- To evaluate the efficacy of pentamidine encapsulated within human red blood cell ghosts against Leishmania donovani in a hamster model.
- To compare the therapeutic potential of this novel drug delivery system with the standard treatment, sodium stibogluconate.
Main Methods:
- Pentamidine was encapsulated within human red blood cell ghosts.
- The encapsulated drug was administered via single injection to hamsters infected with Leishmania donovani.
- Efficacy was assessed by determining the ED50 and ED90 values and comparing parasite load in liver and spleen.
Main Results:
- Single injections of encapsulated pentamidine were 231-240 times more potent than sodium stibogluconate (Pentostam).
- Essentially all parasites were eliminated at doses of 2.5 mg encapsulated drugs/kg in the liver.
- 80% parasite elimination was achieved in the spleen at doses of 2.5-6.4 mg/kg, with higher drug uptake observed in the liver compared to the spleen.
Conclusions:
- Encapsulation of pentamidine in red blood cell ghosts significantly enhances its antileishmanial activity and reduces required dosage.
- This approach holds potential for a single-injection treatment for visceral leishmaniasis, minimizing drug toxicity.
- Further investigation is warranted to confirm efficacy in human patients.