RESUMO
Miltefosine is the only currently available oral drug for treatment of leishmaniasis. However, information on the pharmacokinetics (PK) of miltefosine is relatively scarce in animals. PK parameters and disposition of the molecule was determined in healthy NMRI mice and Syrian hamsters infected and treated with different miltefosine doses and regimens. Long half-life of the molecule was confirmed and differential pattern of accumulation of the drug was observed in analyzed organs in mice and hamster. Long treatment schedules produced miltefosine levels over IC50 value against L. infantum intracellular amastigotes for at least 24â¯days in spleen and liver of infected hamsters. The observed differential pattern of organ accumulation of the drug in mice and hamster supports the relevance of both species for translational research on chemotherapy of leishmaniasis.
Assuntos
Antiprotozoários/farmacocinética , Leishmaniose Visceral/metabolismo , Fosforilcolina/análogos & derivados , Animais , Antiprotozoários/sangue , Cricetinae , Feminino , Leishmania infantum , Masculino , Camundongos , Fosforilcolina/sangue , Fosforilcolina/farmacocinéticaRESUMO
No disponible
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Hepatite B/induzido quimicamente , Hepatite C Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Hepatite B/complicações , Fibrose/diagnóstico , Fibrose/tratamento farmacológicoAssuntos
Anilidas/efeitos adversos , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Hepatite C Crônica/tratamento farmacológico , Compostos Macrocíclicos/efeitos adversos , Inibidores de Proteases/efeitos adversos , Ritonavir/efeitos adversos , Viremia/tratamento farmacológico , Ativação Viral/efeitos dos fármacos , Anilidas/farmacologia , Anilidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Coinfecção/tratamento farmacológico , Ciclopropanos , Quimioterapia Combinada , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Humanos , Lactamas Macrocíclicas , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Ribavirina/efeitos adversos , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Sulfonamidas , Valina , Carga Viral , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
BACKGROUND: Allicin has shown antileishmanial activity in vitro and in vivo. However the mechanism of action underlying its antiproliferative effect against Leishmania has been virtually unexplored. In this paper, we present the results obtained in L.infantum and a mechanistic basis is proposed. METHODOLOGY/PRINCIPAL FINDING: Exposure of the parasites to allicin led to high Ca2+ levels and mitochondrial reactive oxygen species (ROS), collapse of the mitochondrial membrane potential, reduced production of ATP and elevation of cytosolic ROS. The incubation of the promastigotes with SYTOX Green revealed that decrease of ATP was not associated with plasma membrane permeabilization. Annexin V and propidium iodide (PI) staining indicated that allicin did not induce phospholipids exposure on the plasma membrane. Moreover, DNA agarose gel electrophoresis and TUNEL analysis demonstrated that allicin did not provoke DNA fragmentation. Analysis of the cell cycle with PI staining showed that allicin induced cell cycle arrest in the G2/M phase. CONCLUSIONS/SIGNIFICANCE: We conclude that allicin induces dysregulation of calcium homeostasis and oxidative stress, uncontrolled by the antioxidant defense of the cell, which leads to mitochondrial dysfunction and a bioenergetic catastrophe leading to cell necrosis and cell cycle arrest in the premitotic phase.