Comparative activities of the triterpene saponin maesabalide III and liposomal amphotericin B (AmBisome) against Leishmania donovani in hamsters.
Maesabalide III (MB-III), an oleane triterpene saponin isolated from the Vietnamese plant Maesa balansae, is a new antileishmanial lead compound whose activity against Leishmania donovani (MHOM/ET/67/L82) in groups of five golden hamsters was evaluated after administration of a single subcutaneous dose on either day 1 (prophylactic treatment) or day 28 (curative treatment) after infection. Liposomal amphotericin B (AmBisome), administered intravenously at 5 mg/kg of body weight, was used as the reference drug. Amastigote burdens in liver, spleen, and bone marrow were determined either 7 days (early effects) or 56 days (late effects) after treatment. Prophylactic administration of MB-III at 0.2 mg/kg reduced liver amastigote burdens by 99.8 and 83% within 7 and 56 days after treatment, respectively. In the latter group, however, all animals became ill and some died. Both MB-III at 0.8 mg/kg and liposomal amphotericin B were 100% effective against liver stages, but clearance from the spleen and bone marrow was not achieved. Curative administration of MB-III at 0.2 and 0.4 mg/kg was not protective, as no survivors were left at the termination of the experiment on day 84. Despite the high level of reduction of the liver amastigote burden after treatment with MB-III at 0.8 mg/kg (94.2%) or liposomal amphotericin B (99.4%), clinical protection could not be obtained in either group, with two deaths occurring and the residual liver burdens persisting. It is concluded that administration of a single dose of MB-III at 0.8 mg/kg has efficacy potential comparable to that of a single dose of liposomal amphotericin B at 5 mg/kg and is therefore considered a promising new antileishmanial lead compound. However, multiple-dose pharmacological, toxicological, and pharmacokinetic studies are still needed before it can become a valid drug candidate for development.
Maes
Louis
L
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Antwerp University, Groenenborgerlaan 171-V523, B-2610 Wilrijk, Belgium. louis.maes@ua.ac.be
Germonprez
Nils
N
Quirijnen
Ludo
L
Van Puyvelde
Luc
L
Cos
Paul
P
Vanden Berghe
Dirk
D
D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight / Q000502:physiology; D006224:Cricetinae; D004337:Drug Carriers; D005260:Female; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008081:Liposomes; D008099:Liver / Q000469:parasitology; D008297:Male; D010270:Parasite Egg Count; D012503:Saponins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000981:Antiprotozoal Agents; D004337:Drug Carriers; D008081:Liposomes; D012503:Saponins; C487650:maesabalide III; D000666:Amphotericin B