title: A novel tropically stable oral amphotericin B formulation (iCo-010) exhibits efficacy against visceral Leishmaniasis in a murine model.
abstract: OBJECTIVE
  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).
authors.affiliation: School of Health Sciences, British Columbia Institute of Technology, Burnaby, Canada. kwasan@interchange.ubc.ca
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Wasan
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
authors.forename: Jinying
authors.initials: J
authors.lastname: Zhao
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.forename: Karl
authors.initials: K
authors.lastname: Werbovetz
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.forename: John G
authors.initials: JG
authors.lastname: Clement
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Thornton
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
mesh_terms: D000284:Administration, Oral; D000666:Amphotericin B / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004355:Drug Stability; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013696:Temperature; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D000666:Amphotericin B