Effect of elimination of phagocytic cells by liposomal dichloromethylene diphosphonate on aspergillosis virulence and toxicity of liposomal amphotericin B in mice.
The role of macrophages in the toxicity and efficacy of liposomal amphotericin B (L-Amp B) was studied in a murine aspergillosis model infection. Macrophages and polymorphonuclear phagocytes (PMN cells) were depleted in the liver and spleen of mice by the administration of liposome encapsulated dichloromethylene diphosphonate. Macrophage depletion had no effect on the lethality of Fungizone, a commercial deoxycholate preparation of Amp B, but significantly increased the lethality of L-Amp B (P < 0.01). Macrophage depletion led to an increase in the fungal loads in the lung, liver and kidney (P < 0.05) and to an increase in the virulence of aspergillosis (P < 0.05). Tissue distribution analysis of L-Amp B revealed that in macrophage/PMN-depleted mice there was a decrease in the concentration of Amp B in the liver, with concomitant increases in the circulation, spleen and lung, both in the uninfected and in the infected conditions. The results clearly demonstrate that depletion of macrophage/PMN cells increases the virulence of aspergillosis, as well as the toxicity of L-Amp B. Moreover, L-Amp B treatment does not improve the survival rate of macrophage/PMN-depleted mice subjected to aspergillosis challenge.
Department of Biochemistry, Liposome Research Centre, University of Delhi, India.
M
M
Moonis
I
I
Ahmad
B K
BK
Bachhawat
D000666:Amphotericin B / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy*; D004002:Clodronic Acid / Q000494:pharmacology*; D007928:Lethal Dose 50; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010586:Phagocytes / Q000502:physiology* / Q000648:ultrastructure; D014774:Virulence
D008081:Liposomes; D004002:Clodronic Acid; D000666:Amphotericin B