HEAT-INDUCED SUPERAGGREGATION OF AMPHOTERICIN-B REDUCES ITS IN-VITRO TOXICITY - A NEW WAY TO IMPROVE ITS THERAPEUTIC INDEX

Superaggregation of amphotericin B (AmB) was previously shown to occur upon heating of solutions at 70 degrees C. In the present study, we d emonstrate that heat pretreatment of Fungizone (deoxycholate salt of A mB [AmB-DOC]) solutions induces a drastic decrease in the in vitro tox icity of this antibiotic. Heated AmB-DOC colloidal solutions, which ma inly contained superaggregated and monomeric forms of the antibiotic, were strongly less hemolytic than unheated solutions (aggregates and m onomers). Thermal pretreatment of AmB-DOC solutions also reduced the t oxicity to the cell line HT29, as deduced from two simultaneous cell v iability assays -4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro mide and lactate dehydrogenase release). These heated colloidal soluti ons were only slightly less efficient than the unheated ones at inhibi ting the growth of Candida albicans cells in vitro. Such results sugge st that mild heat treatment of AmB-DOC solutions could provide a new a nd simple solution for improving the therapeutic index of this antifun gal agent by reducing its toxicity to mammalian cells.