title: Engineering Oral and Parenteral Amorphous Amphotericin B Formulations against Experimental Trypanosoma cruzi Infections.
abstract: Chagas disease (CD) is a parasitic zoonosis endemic in most mainland countries of Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective if received at the early stages of the disease. Only two drugs (benznidazole and nifurtimox) have so far been marketed, and both share various limitations such as variable efficacy, many side effects, and long duration of treatment, thus reducing compliance. The in vitro and in vivo efficacy of poly-aggregated amphotericin B (AmB), encapsulated poly-aggregated AmB in albumin microspheres (AmB-AME), and dimeric AmB-sodium deoxycholate micelles (AmB-NaDC) was evaluated. Dimeric AmB-NaDC exhibited a promising selectivity index (SI = 3164) against amastigotes, which was much higher than those obtained for licensed drugs (benznidazole and nifurtimox). AmB-AME, but not AmB-NaDC, significantly reduced the parasitemia levels (3.6-fold) in comparison to the control group after parenteral administration at day 7 postinfection. However, the oral administration of AmB-NaDC (10-15 mg/kg/day for 10 days) resulted in a 75% reduction of parasitemia levels and prolonged the survival rate in 100% of the tested animals. Thus, the results presented here illustrate for the first time the oral efficacy of AmB in the treatment of trypanosomiasis. AmB-NaDC is an easily scalable, affordable formulation prepared from GRAS excipients, enabling treatment access worldwide, and therefore it can be regarded as a promising therapy for trypanosomiasis.
authors.affiliation: Centro para el Desarrollo de la Investigación Científica (CEDIC) , Manduvirá 635 entre 15 de Agosto y O'Leary, 1255 Asunción, Paraguay.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rolón
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid , Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: Dolores R
authors.initials: DR
authors.lastname: Serrano
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth , St. Michael's Building, White Swan Road, Portsmouth PO1 2DT, U.K.
authors.forename: Aikaterini
authors.identifier: 0000-0003-4791-7468
authors.initials: A
authors.lastname: Lalatsa
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid , Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: de Pablo
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid , Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Torrado
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid , Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: Maria Paloma
authors.initials: MP
authors.lastname: Ballesteros
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Healy
authors.affiliation: Centro para el Desarrollo de la Investigación Científica (CEDIC) , Manduvirá 635 entre 15 de Agosto y O'Leary, 1255 Asunción, Paraguay.
authors.forename: Celeste
authors.initials: C
authors.lastname: Vega
authors.affiliation: Centro para el Desarrollo de la Investigación Científica (CEDIC) , Manduvirá 635 entre 15 de Agosto y O'Leary, 1255 Asunción, Paraguay.
authors.forename: Cathia
authors.initials: C
authors.lastname: Coronel
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid , Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Bolás-Fernández
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera , Edificio Seminario s/n, 46113 Moncada, Valencia, Spain.
authors.forename: Maria Auxiliadora
authors.initials: MA
authors.lastname: Dea-Ayuela
mesh_terms: D000418:Albumins / Q000737:chemistry; D000666:Amphotericin B / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy* / Q000382:microbiology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003840:Deoxycholic Acid / Q000737:chemistry* / Q000494:pharmacology*; D004338:Drug Combinations; D005079:Excipients / Q000737:chemistry; D005260:Female; D008807:Mice, Inbred BALB C; D008823:Micelles; D008863:Microspheres; D010316:Particle Size; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000418:Albumins; D000935:Antifungal Agents; D004338:Drug Combinations; D005079:Excipients; D008823:Micelles; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination
keywords: Trypanosoma cruzi; albumin microspheres; amphotericin B; oral delivery; sodium deoxycholate micelles