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

作者：Wasan Ellen K^*; Gershkovich Pavel; Zhao Jinying; Zhu Xiaohua; Werbovetz Karl; Tidwell Richard R; Clement John G; Thornton Sheila J; Wasan Kishor M

来源：PLoS Neglected Tropical Diseases, 2010, 4(12): e913.

DOI：10.1371/journal.pntd.0000913

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 degrees 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 degrees 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).

• 出版日期2010-12