Toxic Effects of Antileishmanial Reverse-Phase Evaporation Liposomes ContainingDicetyl Phosphate in Monkeys

摘要

Liposomes containing or lacking encapsulated pentavalent antimony (Sb), a widelyused antileshmanial agent were administered to cynomolgous monkeys to investigate possible toxicity. The liposomes consisted of either reverse-phase evaporation vesicles (REV) composed of dipalmitoyl phosphatidylcholine, cholesterol (CHOL), and dicetyl phosphate (DCP) or multilamellar vesicles (MLV) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol, with or without CHOL. Toxicity was observed in monkeys receiving REV containing or lacking Sb as evidenced by thrombocytopenia, splenomegaly, and hemorrhage. The severity of the symptoms was potentiated by two factors, the presence of Sb in REV and the frequency of REV administration. In contrast, no significant adverse reactions were observed in animals treated with MLV containing or lacking Sb. Since the main difference between REV and MLV was the presence of DCP in REV, this observations suggested that toxicity was due, at least partly, to DCP. An alternative theoretical mechanism for the toxic reaction was also investigated, namely thrombocytopenia caused by complement activation induced by naturally occurring autoantibodies to liposomal components.