RESUMO
Leishmaniasis is a group of diseases caused by a protozoa parasite from one of over 20 Leishmania species. Depending on the tissues infected, these diseases are classified as cutaneous, mucocutaneous and visceral leishmaniasis. For the treatment of leishmaniasis refractory to antimony-based drugs, pentamidine (PTM) is a molecule of great interest. However, PTM displays poor bioavailability through oral routes due to its two strongly basic amidine moieties, which restricts its administration by a parenteral route and limits its clinical use. Among various approaches, nanotechnology-based drug delivery systems (nano-DDS) have potential to overcome the challenges associated with PTM oral administration. Here, we present the development of PTM-loaded PLGA nanoparticles (NPs) with a focus on the characterization of their physicochemical properties and potential application as an oral treatment of leishmaniasis. NPs were prepared by a double emulsion methodology. The physicochemical properties were characterized through the mean particle size, polydispersity index (PdI), zeta potential, entrapment efficiency, yield process, drug loading, morphology, in vitro drug release and in vivo pharmacological activity. The PTM-loaded PLGA NPs presented with a size of 263 ± 5 nm (PdI = 0.17 ± 0.02), an almost neutral charge (-3.2 ± 0.8 mV) and an efficiency for PTM entrapment of 91.5%. The release profile, based on PTM dissolution, could be best described by a zero-order model, followed by a drug diffusion profile that fit to the Higuchi model. In addition, in vivo assay showed the efficacy of orally given PTM-loaded PLGA NPs (0.4 mg kg-1) in infected BALB/c mice, with significant reduction of organ weight and parasite load in spleen (p-value < 0.05). This work successfully reported the oral use of PTM-loaded NPs, with a high potential for the treatment of visceral leishmaniasis, opening a new perspective to utilization of this drug in clinical practice.
Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose/tratamento farmacológico , Pentamidina/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Administração Oral , Animais , Antiprotozoários/química , Antiprotozoários/farmacocinética , Disponibilidade Biológica , Modelos Animais de Doenças , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho do Órgão/efeitos dos fármacos , Carga Parasitária , Tamanho da Partícula , Pentamidina/química , Pentamidina/farmacocinéticaRESUMO
The uptake of [(3)H]pentamidine into wild-type and drug-resistant strains of Leishmania mexicana was compared. Uptake was carrier mediated. Pentamidine-resistant parasites showed cross-resistance to other toxic diamidine derivatives. A substantial decrease in accumulation of the drug accompanied the resistance phenotype, although the apparent affinity for pentamidine by its carrier was not altered when initial uptake velocity was measured. The apparent V(max), however, was reduced. An efflux of pentamidine could be measured in both wild-type and resistant cells. Only a relatively small proportion of the total accumulated pentamidine was available for efflux in wild-type cells, while in resistant cells the majority of loaded pentamidine was available for release. Pharmacological reagents which diminish the mitochondrial membrane potential reduced pentamidine uptake in wild-type parasites, and the mitochondrial membrane potential was shown to be reduced in resistant cells. A fluorescent analogue of pentamidine, 4',6'-diamidino-2-phenylindole, accumulated in the kinetoplast of wild-type but not resistant parasites. These data together indicate that diamidine drugs accumulate in the Leishmania mitochondrion and that the development of the resistance phenotype is accompanied by lack of mitochondrial accumulation of the drug and its exclusion from the parasites.
Assuntos
Antiprotozoários/farmacocinética , Resistência a Múltiplos Medicamentos/fisiologia , Leishmania mexicana/metabolismo , Mitocôndrias/metabolismo , Pentamidina/farmacocinética , Animais , Citometria de Fluxo , Especificidade da EspécieRESUMO
O autor apresenta uma ampla revisäo da literatura sobre as diamidinas aromáticas (Pentamidinas), dando ênfase à terapêutica das leishmanioses, considerando a possibilidade desta droga ser usada como segunda opçäo no tratamento das mesmas. Destaca aspectos relacionados à farmcoadinâmica e efeitos adversos quando do uso clínico do referido medicamento