title: Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices.
abstract: The main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-epsilon-caprolactone nanocapsules (NC). The acute lethal dose (LD(100)) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD(50) was 154 mg/kg. In contrast, the LD(100) for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl. The calculated LD(50) was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused 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 and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.
authors.affiliation: Núcleo de Pesquisa em Ciências Biológicas, ICEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Elaine Amaral
authors.initials: EA
authors.lastname: Leite
authors.forename: Andrea
authors.initials: A
authors.lastname: Grabe-Guimarães
authors.forename: Homero Nogueira
authors.initials: HN
authors.lastname: Guimarães
authors.forename: George Luiz Lins
authors.initials: GL
authors.lastname: Machado-Coelho
authors.forename: Gillian
authors.initials: G
authors.lastname: Barratt
authors.forename: Vanessa C F
authors.initials: VC
authors.lastname: Mosqueira
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000633:toxicity*; D001919:Bradycardia / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D007928:Lethal Dose 50; D008133:Long QT Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D053769:Nanocapsules; D010616:Phenanthrenes / Q000008:administration & dosage / Q000633:toxicity*; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000962:Antimalarials; D053769:Nanocapsules; D010616:Phenanthrenes; C023768:halofantrine