Engineering oral and parenteral amorphous amphotericin B formulations against experimental Trypanosoma cruzi infections

Rolón, Miriam and Serrano, Dolores R. and Lalatsa, Aikaterini and De Pablo, Esther and Torrado, Juan Jose and Ballesteros, Maria Paloma and Healy, Anne Marie and Vega, Celeste and Coronel, Cathia and Bolás-Fernández, Francisco and Dea-Ayuela, Maria Auxiliadora (2017) Engineering oral and parenteral amorphous amphotericin B formulations against experimental Trypanosoma cruzi infections. Molecular Pharmaceutics, 14 (4). pp. 1095-1106. ISSN 1543-8384 (https://doi.org/10.1021/acs.molpharmaceut.6b01034)

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Abstract

(Figure Presented) 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.

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