EVALUATION OF ACUTE TOXICITY AND EFFICACY IN EXPERIMENTAL INVASIVE ASPERGILLOSIS OF A NEW CARBAZOLE DERIVATIVE PLX01107
Carbazole derivative PLX01107 has previously demonstrated antifungal potential in vitro against Aspergillus fumigatus. In the present research the acute toxicity and in vivo antifungal activity of PLX01107 was evaluated. The average lethal doses LD50 of PLX01107 evaluated in white outbred mice were 64,9 mg/kg in female and 56,6 mg/kg in male after single intravenous administration, and 85,7 mg/kg in female and 94,4 mg/kg in male after oral administration. LD50 evaluated in white outbred rats were 30,6 mg/kg in female and 30,1 mg/kg in male after single intravenous administration, and 80,3 mg/kg in female and 79,0 mg/kg in male after oral administration. Murine invasive pulmonary aspergillosis model was used in the experiment to estimate the antifungal activity. The effect was evaluated by comparing the percentage of surviving animals with negative inoculation from lungs. Voriconazole (Vifend®, Pfizer), 25 mg/kg, was used as a comparator. PLX01107 at doses of 1, 3 and 9 mg/kg administered intravenously 5 days daily to intranasally infected with A. fumigatus mice did not cause any significant effect on the registered parameter. Thus, carbazole derivative PLX01107 relates to the 3rd class of toxicity and does not demonstrate antifungal activity at doses of 1, 3 and 9 mg/kg on murine invasive pulmonary aspergillosis model in contrast to voriconazole.