Avaliação da atividade cardioprotetora da piridostigmina veiculada em lipossomas

AUTOR(ES)
DATA DE PUBLICAÇÃO

2009

RESUMO

The demonstration of the benefits of vagal stimulation in patients with cardiovascular diseases suggests that cholinergic drugs may have similar protective effects. Pyridostigmine, a reversible anticholinesterase agent, has benefits demonstrated in patients with cardiac failure. However, its short half-life of elimination and the incidence of adverse effects are factors that limit its use. The development of dosage forms such as long-circulating liposome may prolong the release of drugs into tissues and reduce their toxicity, and liposomes accumulation into ischemic myocardium has been demonstrated. The main goal of the present work was to investigate the cardioprotective action of Pyridostigmine encapsulated in long-circulating liposomes. The encapsulation of Pyridostigmine was carried out by freeze-thawed and extrusion. The formulation obtained was characterized and administrated in the doses of 0.1, 0.3 and 1.0 mg/kg to male Wistar rats, which after 1, 2, 4 or 6 hours were submitted to sympathetic stimulation by administration of 1 or 3 μg of noradrenaline (NA). The signals of arterial pressure (AP) and electrocardiogram (ECG) were obtained, and the cardiovascular parameters were compared to the animals that received Pyridostigmine in free form or saline. The encapsulation efficiency of 15,5% of Pyridostigmine into liposomes was obtained, with a medium size of 174 nm, polydispersity index of 0.06 and zeta potential -50 mV. In animals that received saline, the NA induced significant increases in systolic and diastolic AP, with the highest increases observed after administration of 3μg solution (76 and 70% respectively). The PR and QRS intervals of ECG were not significantly changed, while on the QT interval were observed increases of 22% in animals that received saline, compared to the control period. The administration of Pyridostigmine in free and liposomal forms was not able to inhibit the increases of AP. The animals treated with Pyridostigmine presented a significant reduction of QT interval increases resulting from sympathetic stimulation. The maximum effect of free Pyridostigmine to prevent the QT increases was observed after 1 hour of its administration (6.6% to the dose of 0.3 mg/kg) but it was not maintained after 2 hours of the treatment. The maximum effect of liposomal formulation to prevent the prolongation of the QT interval was observed 2 hours after treatment (8.5% to the dose of 1.0 mg/kg) and this effect was maintained until 6 hours after its administration. The administration of free Pyridostigmine at 1.0 mg/kg caused to the animals toxic effects characteristic of cholinergic hyperstimulation, which was not observed for the same dose of liposomal Pyridostigmine. Thus we can conclude that the encapsulation of Pyridostigmine in long-circulating liposomes may be a potential therapeutic alternative in preventing cardiovascular complications resulting from sympathetic hyperactivity in patients with ischemic cardiac disease.

ASSUNTO(S)

lipossomos eletrocardiograma farmacologia cardiorenal

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