RESUMO
Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC50 and CC50, respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 µg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 µg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum-infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.
Assuntos
Antiprotozoários/uso terapêutico , Digitoxigenina/uso terapêutico , Reposicionamento de Medicamentos/métodos , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Poloxâmero/uso terapêutico , Anfotericina B/uso terapêutico , Animais , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Fígado/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Carga Parasitária , Espécies Reativas de Oxigênio , Baço/parasitologiaRESUMO
Amphotericin B deoxycholate is associated with infusion-related toxicity and renal toxicity. Purpose: To evaluate medical indications of this compound in a tertiary care center, analyze adverse reactions, infusion protocols and outcome of treated patients. Patients and methods: Retrospective analysis of 39 treatments indicated in 33 patients during 2007, exploring indications, infusion protocols and renal protective measures, infusion-related adverse reactions, nephrotoxicity, hypokalemia and outcomes. Results: On average, therapy lasted 12 days (2 to 39) and reached 600 mg of accumulated dose (100 to 1950) respectively. 24-hours infusions were applied in 63.2 percent of prescriptions and 35.9 percent received a 4-6 hour infusion schedule. In addition, 36.8 percent received daily a saline infusion before amphotericin. Adverse reactions were observed in 40 percent of treatments, predominating fever (25 percent). Nonetheless, nephrotoxicity was infrequent (9.4 percent), of low magnitude, only affecting patients without previous renal disease, and not requiring dialysis. Hypokalemia developed in 21.6 percent of treatments. More than half of medical indications were empirical (59 percent), for presumed infections by either filamentous fungi or yeasts. In the subgroup with microbiological information, main indications were invasive aspergillosis (15.4 percent of total), systemic candidiasis (12.8 percent) or meningeal cryptococcosis (10.3 percent). A favorable response was registered in 41 percent, and only 48.5 percent of patients survived. In a multivariate analysis, only age > 60 years remained as an independent factor for developing infusion-related adverse reactions. In the same manner, a SOFA score > 3 and corticosteroids administration at the same time than amphotericin B, were independently associated to a fatal outcome. Conclusion: infusion-related adverse reactions are frequent during amphotericin B deoxycholate therapy, but renal...
Anfotericina B deoxicolato se asocia a reacciones adversas durante la infusión y a nefrotoxicidad. Objetivo: Evaluar las indicaciones de anfotericina B deoxicolato en un hospital universitario, las reacciones adversas asociadas, los protocolos de administración y el desenlace de los pacientes tratados. Pacientes y Métodos: Se efectuó un estudio retrospectivo con el total de tratamientos efectuados durante el año 2007 en el Hospital Clínico de la Universidad de Chile, identificando 39 tratamientos en 33 pacientes. Se analizaron las indicaciones, dosis, protocolos de administración, efectos adversos relacionados a la infusión (fiebre, calofríos, vómitos o flebitis), nefrotoxicidad, hipokalemia y además la evolución de los pacientes. Resultados: La duración promedio del tratamiento fue de 12 días (2-39) con una dosis acumulada promedio de 600 mg totales (100-1.950 mg). Un 63,2 por ciento de los tratados recibió infusiones de 24 horas y 35,9 por ciento, infusiones de 4 a 6 horas. Además, 36,8 por ciento fue sometido a precargas salinas. Un 40 por cientoo de los tratamientos se acompañó de reacciones adversas asociadas a la infusión, predominando la fiebre (25 por ciento). Sin embargo, la nefrotoxicidad fue de baja magnitud (9,4 por cientoo), sólo presente en pacientes sin falla renal previa y en ningún caso determinó el inicio de diálisis. La hipokalemia se presentó en ocho tratamientos (21,6 por ciento). Más de la mitad de las indicaciones fueron empíricas (59 por cientoo), ya fuese para el tratamiento presunto de hongos filamentosos (aspergilosis o mucormicosis) o levaduras (candidiasis sistémica). En el subgrupo con datos micro-biológicos, las principales indicaciones fueron aspergilosis invasora (15,4 por ciento de los 39 tratamientos), candidiasis sistémica (12,8 por ciento) o criptococosis meníngea (10,3 por ciento). Un 41 por cientoo de los pacientes tuvo una respuesta favorable a los tratamientos y sólo 48,5 por cientoo sobrevivió...