In-vivo therapeutic efficacy in experimental murine mycoses of a new formulation of deoxycholate-amphotericin B obtained by mild heating

Heat-induced 'superaggregation' of deoxycholate-amphotericin B (AmB-DOC, Fu ngizone) was shown previously to reduce the in-vitro toxicity of this antif ungal agent. We compared AmB-DOC with the formulation obtained by heating t he commercial form (Fungizone, Bristol Myers Squibb, Paris, France) for 20 min at 70 degrees C, in the treatment of murine infections. An improvement of antifungal activity was obtained with heated AmB-DOC formulations due to a lower toxicity which allowed the administration of higher drug doses tha n those achievable with the commercial preparation. Single Intravenous inje ctions of heated AmB-DOC solutions were demonstrated to be two-fold less to xic than unheated ones to healthy mice. For mice infected with Candida albi cans, the maximum tolerated dose was higher with heated than with unheated AmB-DOC solutions. In the model of murine candidiasis, following a single d ose of heated AmB-DOC 0.5 mg/kg, 85% of mice survived for 3 weeks, whereas at this dose the immediate toxicity of the standard formulation in infected mice restricted the therapeutic efficacy to 25% survival. Both formulation s were equally effective in increasing the survival time for murine cryptoc occal pneumonia and meningoencephalitis. Injection of heated AmB-DOC soluti ons at a dose two-fold higher than the maximal tolerated dose observed with the unheated preparation (1.2 mg/kg) increased the survival time by a fact or of 1.4 in cryptococcal meningoencephalitis. These results indicate that mild heat treatment of AmB-DOC solutions could provide a simple and economi cal method to improve the therapeutic index of this antifungal agent by red ucing its toxicity on mammalian cells.