Comparative efficacy, toxicity and biodistribution of the liposomal amphotericin B formulations Fungisome® and AmBisome® in murine cutaneous leishmaniasis

TY - JOUR

T1 - Comparative efficacy, toxicity and biodistribution of the liposomal amphotericin B formulations Fungisome® and AmBisome® in murine cutaneous leishmaniasis

AU - Wijnant, Gert-Jan

AU - Van Bocxlaer, Katrien

AU - Yardley, Vanessa

AU - Harris, Andy

AU - Alavijeh, Mo

AU - Silva-Pedrosa, Rita

AU - Antunes, Sandra

AU - Mauricio, Isabel

AU - Murdan, Sudaxshina

AU - Croft, Simon L

N1 - Copyright © 2018. Published by Elsevier Ltd.

PY - 2018/8

Y1 - 2018/8

N2 - Fungisome® (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a disfiguring form of the disease affecting the skin, is currently unknown. Here, we report the evaluation of the efficacy of F in the Leishmania major BALB/c murine model of CL, including a head-to-head comparison with the standard liposomal AmB formulation AmBisome® (A). Upon intravenous administration at dose levels of 5, 10 and 15 mg/kg of body weight (on days 0, 2, 4, 6 and 8), F showed clear signs of toxicity (at 15 mg/kg), while A did not. After complete treatment (day 10), the tolerated doses of 5 and 10 mg/kg F had significant antileishmanial activity (ED50 = 4.0 and 12.8 mg/kg for qPCR-based parasite load and lesion size, respectively), although less than that of A at identical doses (ED50 = 3.0 and 8.8 mg/kg). The efficacy of F was inferior compared to A because lower levels of the active agent AmB accumulated within the infected lesion. In conclusion, despite possibly being less safe and efficacious than A at equivalent doses, the moderate in vivo activity of F could indicate a role in the systemic pharmacotherapy of CL.

AB - Fungisome® (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a disfiguring form of the disease affecting the skin, is currently unknown. Here, we report the evaluation of the efficacy of F in the Leishmania major BALB/c murine model of CL, including a head-to-head comparison with the standard liposomal AmB formulation AmBisome® (A). Upon intravenous administration at dose levels of 5, 10 and 15 mg/kg of body weight (on days 0, 2, 4, 6 and 8), F showed clear signs of toxicity (at 15 mg/kg), while A did not. After complete treatment (day 10), the tolerated doses of 5 and 10 mg/kg F had significant antileishmanial activity (ED50 = 4.0 and 12.8 mg/kg for qPCR-based parasite load and lesion size, respectively), although less than that of A at identical doses (ED50 = 3.0 and 8.8 mg/kg). The efficacy of F was inferior compared to A because lower levels of the active agent AmB accumulated within the infected lesion. In conclusion, despite possibly being less safe and efficacious than A at equivalent doses, the moderate in vivo activity of F could indicate a role in the systemic pharmacotherapy of CL.

KW - Amphotericin B/blood

KW - Animals

KW - Antiprotozoal Agents/administration & dosage

KW - India/epidemiology

KW - Infusions, Intravenous

KW - Leishmania major/drug effects

KW - Leishmaniasis, Cutaneous/drug therapy

KW - Leishmaniasis, Visceral/drug therapy

KW - Mice

KW - Mice, Inbred BALB C

KW - Parasite Load

KW - Tissue Distribution

U2 - 10.1016/j.ijpddr.2018.04.001

DO - 10.1016/j.ijpddr.2018.04.001

M3 - Article

C2 - 29673889

SN - 2211-3207

VL - 8

SP - 223

EP - 228

JO - International journal for parasitology. Drugs and drug resistance

JF - International journal for parasitology. Drugs and drug resistance

IS - 2

ER -