Amphotericin B-Gum Arabic Conjugates: Synthesis, Toxicity, Bioavailability, and Activities Against Leishmania and Fungi

Abstract

The drug conjugates were stable, non-hemolytic and non-toxic to the internal organs of the animal and showed good anti-fungal and anti-leishmanial activity in vitro. In spite of the large molecular weight of the polysaccharide, AmB from the conjugates showed bioavailability after i.v injection. Since the highest concentration of AmB was found in the spleen after a single injection, these conjugates may have potential in anti-leishmanial therapy.

Self-assembled amphotericin B-loaded polyglutamic acid nanoparticles: preparation, characterization and in vitro potential against Candida albicans

“…Investigators have employed different watersoluble polymers to develop encapsulated, conjugated AmBbased delivery systems, but have met with little success. [40][41][42][43][44][45][46][47][48] In some of the earlier efforts, polymers synergized the toxicity of AmB, 49 while in others the AmB was unable to retain the beneficial physicochemical properties associated with its liposomal form (AmB-L). 50 Although, AmB-cyclodextrin complexes showed improved water solubility, 49,51 they were found to be toxic to human red blood cells.…”

Toxicity Mechanisms of Amphotericin B and Its Neutralization by Conjugation with Arabinogalactan

“…However, the infusionrelated and cumulative toxicities, particularly nephrotoxicity (14,20,30), of AMB have resulted in reductions in the routine use of deoxycholate micellar AMB formulations and the development of less-toxic high-cost lipid AMB formulations (16,36). To develop a soluble, less-toxic, and less costly formulation, AMB has been conjugated with various soluble macromolecules (18,37,(47)(48)(49).We conjugated AMB with arabinogalactan (AG) (18), which significantly increased the water solubility of AMB, reduced its toxicity, and resulted in an efficacy similar to that of Fungizone (a deoxycholate micellar formulation) and AmBisome (a lipid-based formulation) (18). AMB-related toxicity is associated with the inductions of interleukin 1␤ (IL-1␤), tumor necrosis factor ␣ (TNF-␣), and apoptosis in organs.…”

“…However, the infusionrelated and cumulative toxicities, particularly nephrotoxicity (14,20,30), of AMB have resulted in reductions in the routine use of deoxycholate micellar AMB formulations and the development of less-toxic high-cost lipid AMB formulations (16,36). To develop a soluble, less-toxic, and less costly formulation, AMB has been conjugated with various soluble macromolecules (18,37,(47)(48)(49).…”

Proteases de Leishmania: novos alvos para o desenvolvimento racional de fármacos

“…Já a L. brasiliensis é resistente ao cetoconazol e susceptível quando ele é usado em combinação com terbinafina. 35,36 O alopurinol, um análogo estrutural da hipoxantina, é hidrolizado a alopurinol ribose, que é então incor porado nos ácidos nucleicos da Leishmania, interferindo assim na síntese de proteí nas do parasito. Sua administração oral tem sido reportada como alter na ti va terapêutica para as leishmanioses do Novo Mundo, mas os resultados terapêu ti cos ainda são muito ambíguos.…”

“…39 O exemplo mais notável é o desenvolvimento de inibidores baseados na estrutura de uma aspártico-protease de HIV, que são eficientes inibidores da replicação viral 36 e têm sido uti li zados clinicamente como medicamentos contra AIDS. 40,41 A atividade proteolítica em parasitos do gênero Leishmania foi primeiramente reportada por Pupkins e Coombs 42 em promastigotas de Leishmania me�i�ana e as cisteíno-proteases foram as prin cipais proteases detectadas, embora também tenham sido observadas atividades proteolíticas em frações sensíveis a inibidores de outras classes de proteases como pepstatina (inibidor de aspártico-protease), 1,10 fenantrolina (inibidor de metaloprotease), antipaína, leupeptina e TLCK que são inibidores de serino-proteases.…”