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- Title
A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model.
- Authors
Wasan, Ellen K.; Gershkovich, Pavel; Zhao, Jinying; Zhu, Xiaohua; Werbovetz, Karl; Tidwell, Richard R.; Clement, John G.; Thornton, Sheila J.; Wasan, Kishor M.
- Abstract
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 VLinfected 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).
- Subjects
AMPHOTERICIN B; ORAL drug administration; VISCERAL leishmaniasis; DRUG efficacy; VITAMIN E; LABORATORY mice; MONOGLYCERIDES; MISCIBILITY; CLIMATIC zones; WORLD Health Organization; PHYSIOLOGY; THERAPEUTICS
- Publication
PLoS Neglected Tropical Diseases, 2010, Vol 4, Issue 12, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0000913