title: Amphotericin B molecular organization as an essential factor to improve activity/toxicity ratio in the treatment of visceral leishmaniasis.
abstract: An in vivo study has been performed in order to determine the influence of amphotericin B (AMB) molecular organization on the toxicity and activity of this drug in the treatment of experimental visceral leishmaniasis. Three formulations with similar composition but different drug molecular self-association in aqueous media were prepared. Acute toxicity was evaluated by injecting them in healthy hamsters. Sub-acute toxicity and efficacy were studied administering them to animals previously infected with Leishmania infantum. The preparation with drug molecules completely dissolved into monomers (formulation "C") and produced the highest acute toxicity. The formulation whose AMB molecules were disposed as non-water-soluble multi-aggregates (formulation "B") proved to provide the lowest acute toxicity. This formula also showed an improved activity, mainly in the liver, if compared with the third tested formulation containing AMB molecules disposed as smaller dimerical "water-soluble" aggregates (formulation "A"). As a conclusion, molecular aggregation in biological media should be an important factor to consider when researching or optimizing medicines containing AMB. The liberation of molecules as large dispersed non-water-soluble multi-aggregates seems to improve the narrow therapeutic margin attached to the use of this drug.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Sánchez-Brunete
authors.forename: M A
authors.initials: MA
authors.lastname: Dea
authors.forename: S
authors.initials: S
authors.lastname: Rama
authors.forename: F
authors.initials: F
authors.lastname: Bolás
authors.forename: J M
authors.initials: JM
authors.lastname: Alunda
authors.forename: S
authors.initials: S
authors.lastname: Torrado-Santiago
authors.forename: J J
authors.initials: JJ
authors.lastname: Torrado
mesh_terms: D000666:Amphotericin B / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D006224:Cricetinae; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D018314:Leishmania infantum; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D013056:Spectrophotometry, Ultraviolet; D013154:Spleen / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D007074:Immunoglobulin G; D000666:Amphotericin B