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A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model

PURPOSE: To develop an oral formulation of amphotericin B (AmB) that is stable at the temperatures of WHO Climatic Zones 3 and 4 (30–43°C) and to evaluate its efficacy in a murine model of visceral leishmaniasis (VL). METHODS: The stability testing of four novel oral lipid AmB formulations composed...

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Detalles Bibliográficos
Autores principales: Wasan, Ellen K., Gershkovich, Pavel, Zhao, Jinying, Zhu, Xiaohua, Werbovetz, Karl, Tidwell, Richard R., Clement, John G., Thornton, Sheila J., Wasan, Kishor M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998436/
https://www.ncbi.nlm.nih.gov/pubmed/21151883
http://dx.doi.org/10.1371/journal.pntd.0000913
Descripción
Sumario:PURPOSE: To develop an oral formulation of amphotericin B (AmB) that is stable at the temperatures of WHO Climatic Zones 3 and 4 (30–43°C) and to evaluate its efficacy in a murine model of visceral leishmaniasis (VL). METHODS: The stability testing of four novel oral lipid AmB formulations composed of mono- and di-glycerides and pegylated esters (iCo-010 to iCo-013) was performed over 60 d and analyzed by HPLC-UV. In addition, the four formulations were incubated 4 h in fasted-state simulated intestinal fluid. AmB concentration was measured spectrophotometrically and emulsion droplet diameter was assessed by dynamic light scattering. Antileishmanial activity of iCo-010 was evaluated at increasing oral doses (2.5 to 10 mg/kg) in a murine model of VL. RESULTS: AmB stability in the lipid formulation (iCo-010) was >75% over 60 days. After 4 h in fasted-state simulated intestinal fluid, AmB concentration was >95%. iCo-010 demonstrated significant efficacy when orally administered to VL-infected mice bid for five days (inhibition of 99%, 98%, and 83% at 10, 5 and 2.5 mg/kg compared to the vehicle control). In addition, the qd dose of 20 mg/kg provided 96% inhibition compared to the vehicle control. CONCLUSIONS: The oral AmB formulation iCo-010 is stable at the temperatures of WHO Climatic Zones 3 and 4 (30–43°C). iCo-010 showed excellent antileishmanial activity at both 10 mg/kg po bid for 5 days (<99% reduction in parasitic infection) and 20 mg/kg po qd for 5 days (95% inhibition when compared to control).