ABSTRACT
Amphotericin B remains the drug of choice for the treatment of most of the systemic fungal infections in immunodeficient patients. Because of the high incidence of adverse drug reactions the clinical use of Amphotericin B is rather limited. To reduce its toxicity new drug delivery systems has been suggested. Nevertheless, these carriers present several technological drawbacks that impair the development of a marketable product. The aim of this work was to develop an Amphotericin B microemulsion in order to increase its efficacy and decrease its toxicity compared to Fungizon, the widely know inexpensive micellar system of Amphotericin B. Amphotericin B loaded microemulsion showed an average size close to 300 nm by photon correlation spectroscopy. In the UV spectrum, the observation of the monomeric peak at 405 nm, which was independent of the sample dilution, revealed that the Amphotericin B molecules were strongly and individually bound to the microemulsion droplets. The new microemulsion formulation had the same efficacy than Fungizon against C. albicans. Concerning toxicity, Amphotericin B loaded microemulsion showed lower toxicity against human red blood cells compared to the commercial product. Taken together, these results suggested that microemulsion is an eligible drug carrier for Amphotericin B or other water insoluble molecules, and it has potential applications to targeting fungal cells. Additionally, a novel formulation of Amphotericin B-loaded microemulsion was prepared by a straightforward and fast procedure.
Subject(s)
Amphotericin B/chemistry , Amphotericin B/toxicity , Antifungal Agents/chemistry , Antifungal Agents/toxicity , Drug Carriers/chemistry , Drug Carriers/toxicity , Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Candida albicans/drug effects , Cell Survival/drug effects , Drug Carriers/pharmacology , Emulsions/chemistry , Emulsions/pharmacology , Emulsions/toxicity , Erythrocytes/drug effects , Erythrocytes/metabolism , Hemoglobins/metabolism , Humans , Linear Models , Male , Nanoparticles/adverse effects , Nanoparticles/chemistry , Nanoparticles/toxicity , Particle Size , Potassium/blood , SpectrophotometryABSTRACT
PURPOSE: Amphotericin B (AmB), an antifungal agent that presents a broad spectrum of activity, remains the gold standard in the antifungal therapy. However, sometimes the high level of toxicity forbids its clinical use. The aim of this work was to evaluate and compare the efficacy and toxicity in vitro of Fungizon (AmB-D) and two new different AmB formulations. METHODS: three products were studied: Fungizon, and two Fungizon /Lipofundin admixtures, which were diluted through two methods: in the first one, Fungizon was previously diluted with water for injection and then, in Lipofundin (AmB-DAL); the second method consisted of a primary dilution of AmB-D as a powder in the referred emulsion (AmB-DL). For the in vitro assay, two cell models were used: Red Blood Cells (RBC) from human donors and Candida tropicallis (Ct). The in vitro evaluation (K+ leakage, hemoglobin leakage and cell survival rate-CSR) was performed at four AmB concentrations (from 50 to 0.05 mg x L(-1)). RESULTS: The results showed that the action of AmB was not only concentration dependent, but also cellular type and vehicle kind dependent. At AmB concentrations of 50 mg x L(-1), although the hemoglobin leakage for AmB-D was almost complete (99.51), for AmB-DAL and AmB-DL this value tended to zero. The p = 0.000 showed that AmB-D was significantly more hemolytic. CONCLUSION: The Fungizon-Lipofundin admixtures seem to be the more valuable AmB carrier systems due to their best therapeutic index presented.
Subject(s)
Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Parenteral Nutrition/standards , Phospholipids/pharmacology , Sorbitol/pharmacology , Amphotericin B/adverse effects , Analysis of Variance , Antifungal Agents/adverse effects , Candida tropicalis/drug effects , Drug Carriers , Drug Combinations , Erythrocytes/drug effects , Female , Hemoglobins/drug effects , Humans , In Vitro Techniques , Models, Biological , Phospholipids/adverse effects , Potassium/blood , Sorbitol/adverse effects , Treatment OutcomeABSTRACT
OBJETIVO: A anfotericina B é um agente antifúngico de largo espectro bastante empregado na terapia antifúngica. Entretanto, esta molécula apresenta um alto nível de toxicidade que, na maioria das vezes, impede o seu uso contínuo na terapêutica médica. O objetivo deste artigo foi comparar a eficácia e a toxicidade in vitro do Fungizon (AmB-D) e de dois sistemas carreadores de AmB. MÉTODOS: Três produtos foram avaliados: o Fungizon , e dois sistemas oriundos da mistura entre o Fungizon e o Lipofundin , uma emulsão de uso parenteral. Tais sistemas foram obtidos por duas técnicas: Na primeira diluiu-se previamanete o Fungizon com água para injetáveis e em seguida inseriu-se o Lipofundin (AmB-DAL); o segundo método consistiu na diluíção extemporânea do Fungizon com a referida emulsão (AmB-DL). Dois modelos celulares foram empregados no estudo: os eritrócitos (RBC) oriundos de doadores humanos e a Candida tropicalis (Ct). A avaliação in vitro (liberação de K+ e hemoglobina, e o índice de sobrevivência celular-CSR) foi realizado com quatro concentrações de AmB (entre 50 e 0.05mg.L-1). RESULTADOS: Os resultados demonstram que a ação da AmB não só foi dependente da concentração como também variou de acordo com o modelo celular e o veículo que diluiu o Fungizon . Nas concentrações de 50 mg.L-1, apesar da liberação de hemoglobina ser quase que total para AmB-D (99.51), para a AmB-DAL e AmB-DL este valor tendeu a zero. Um p = 0.000 demonstrou que AmB-D foi significativamente mais hemolítico. CONCLUSÃO: A mistura Fungizon -Lipofundin aparenta ser um bom sistema para carrear a AmB tendo em vista seu elevado índice terapêutico demonstrado.
