Halofantrine poly-&-caprolactone nanocapsules: development, characterization and cardiotoxicity study / NANOCÁPSULAS DE POLI--CAPROLACTONA CONTENDO HALOFANTRINO: DESENVOLVIMENTO, CARACTERIZAÇÃO E ESTUDO DA CARDIOTOXICIDADE.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2006

RESUMO

Malaria is one of the worlds most important parasitic infections. Severe malaria is one of complicated form of Plasmodium falciparum infection which intravenous antimalarial drug administration is always necessary. In this case, the halofantrine (Hf) could be a good alternative for treatment of severe malaria because it is highly active against drug resistant P. falciparum. However, it is an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram. In this study, the more lipophilic Hf free base was entrapped in nanostructured oil-filled colloidal carrier, named nanocapsules (NCs), composed by biodegradable polymer such as poly--caprolactone. The polydispersity index of the population and nanoparticles mean size were determined by photon correlation spectroscopy (PCS) and nanoparticles zeta potential by electrophoretic mobility. The morphology and structural organization of NCs were evaluated by atomic force microscopy (AFM) technique, searching to analysed and understand possible alterations induced by the drug inclusion in these nanostructures. The main goal of the present work was to assess and evaluate electrocardiographic and arterial blood pressure changes, particularly QT interval prolongation, in anaesthetized Wistar rats healthy or rats infected with Plasmodium berghei, followed by i.v. administration of a single high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. The mean diameter for NC unloaded, obtained by AFM, was between 222 and 550 nm, however, the mean diameter of this same sample determined by PCS was 245 nm. The mean diameter of Hf-NC determined by AFM was 475  153 nm and 309  97 nm for 0.1 e 1.0 mg base Hf/mL colloidal suspension. The analysis of the data showed that the diameter of NC is much larger than their height, with diameter/height mean ratio around 10. The acute lethal dose (LD100) of Hf.HCl experimentally observed was 200 mg/kg and the calculated LD50 was 154 mg/kg. In contrast, the LD100 for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl and the calculated LD50 was 249 mg/kg for Hf-NC. It was observed, in short term experiments of cardiotoxicity studies, that Hf caused a dose-dependent prolongation of the QT and PR intervals of the ECG, however, this effect was significantly (P <0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia, followed by a continuous decrease of heart rate and severe hypotension leading the animals to death. No changes in any of these parameters were observed in animals that received Hf solution vehicle and NCs excipients at equivalent time intervals and volume. Hf associated with NCs reduced the QT prolongation by 77% and 85% at 5 min after the injection of 100 and 150 mg/kg, respectively. The evaluation of long term showed equivalent increases for the interval QT and QTc when Hf was administered as Hf-NC (150 mg/kg) compared with the same dose of the free Hf up to 30 minutes, but the maximum alteration was observed only 2 hours after the injection. However, the toxicity induced by Hf-NC was less pronounced because all the animals survived during all experimental period (48 h). On the other hand, the Hf.HCl provokes death in 83% of the animals, 30 min after administration. It was observed a alteration of QT interval in 24 hours after the administration of Hf-NC that could be attributed to the Hf amount accumulated in the cells of mononuclear phagocytic system. The evaluation of the cardiotoxicity in Plasmodium berghei infected rats demonstrated that Hf-NC induced variations of the cardiovascular parameters similar to Hf.HCl, indicating that in infected animals, the Hf associated to the NCs is available for interaction with the heart cells of the same way that the Hf in solution. However, in all experiments performed with healthy or parasitized animals, it was observed that encapsulation of Hf altered its biological response, probably by modulating the distribution of the drug in the body.

ASSUNTO(S)

liberação controlada malária polímeros na medicina imunologia nanopartículas efeito das drogas sistema cardiovascular fármacos

ACESSO AO ARTIGO

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