Combined liposomal immuno- and chemotherapy of visceral leishmaniasis.
Visceral leishmaniasis is a tropical disease caused by Leishmania donovani, an obligate intracellular parasite. Host cells of these parasites are macrophages. The conventional therapy of visceral leishmaniasis uses pentavalent antimony (Pentostam). To minimize the undesired side effects of antimony and to possibly reduce the therapeutical dose of antimony it was combined with interferon gamma (IFN gamma) and encapsulated both in multilamellar vesicles for treatment of murine visceral leishmaniasis. Using liposomes composed of one synthetic phospholipid and applying the freeze-thawing technique an encapsulation rate of about 30-70% of the offered antimony concentration was obtained. In the case of IFN gamma an entrapment of 20-30% was reached. Thus these liposomes were used to perform experiments in order to achieve pharmacological data about organ distribution of the encapsulated vs. free drug. For this purpose defined amounts of antimony were injected i.v. in B 10D2/n mice. At several time-points mice were sacrificed and lung, spleen, liver, kidneys and blood samples were assessed for antimony concentration. The results presented evidence that liposomal drugs were enriched in spleen and liver, organs mainly affected by visceral leishmaniasis. It has been shown previously that liposomes are phagocytozed by macrophages, the host cells of the parasites. Therefore treatment of L. donovani infected mice with liposomal antimony and IFN-gamma resulted in a nearly complete parasite reduction, while treatment with the free drug slightly reduced the parasite burden only in the liver. The aim of these studies was to minimize the undesired side effects of antimony and to possibly reduce the necessary dosage by 1 encapsulating it into multilamellar vesicles and 2, by combining the liposomal antimony with liposomal encapsulated IFN gamma, which is known to be a potent macrophage activating agent.
Everlien
H
H
Fraunhofer Institute for Toxicology and Environmental Medicine Hamburg.
Hockertz
S
S
D000818:Animals; D000965:Antimony / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D004337:Drug Carriers; D004338:Drug Combinations; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology / Q000628:therapy*; D008081:Liposomes; D008099:Liver / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins; D013154:Spleen / Q000469:parasitology; D014018:Tissue Distribution
D000981:Antiprotozoal Agents; D004337:Drug Carriers; D004338:Drug Combinations; D008081:Liposomes; D011994:Recombinant Proteins; D007371:Interferon-gamma; D000965:Antimony