Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro

Abstract

Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halothane-anesthetized dogs (n = 4) and isolated left atrium of guinea pigs (n = 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.v.) or pilsicainide (1 and 3 mg/kg, i.v.) was additionally administered to the dogs. The low dose of oseltamivir provided clinically relevant plasma concentrations with C max of 4 μM. The low and middle doses of oseltamivir increased cardiac output, whereas the middle dose increased blood pressure and delayed intra-atrial conduction and ventricular repolarization. The high dose of oseltamivir exerted negative chronotropic, inotropic and hypotensive effects, while it delayed intra-atrial, atrioventricular nodal and intra-ventricular conduction and ventricular repolarization. Use-dependent delay of ventricular repolarization was observed after oseltamivir, whereas reverse use-dependent prolongation was induced by pilsicainide. Moreover, oseltamivir more selectively suppressed intra-atrial conduction than intra-ventricular conduction, which was less selective for pilsicainide. Action potential assay using isolated atrium indicated that oseltamivir (10 μM) decreased V max more than pilsicainide (10 μM) and that oseltamivir (10-100 μM) prolonged action potential duration, which was not induced by pilsicainide (1-10 μM). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10-100 times higher doses possess unique electrophysiological profile.

Antiviral drug vidarabine possessing cardiac type 5 adenylyl cyclase inhibitory property did not affect cardiohemodynamic or electrophysiological variables in the halothane-anesthetized dogs

“…Based on our previous knowledge with the halothane-anesthetized canine model (Kise et al, 2010;Kitahara et al, 2013;Yamazaki-Hashimoto et al, 2015), the peak plasma concentration after the administration of 1, 10 and 100 mg/kg/10 min of a drug could be estimated to be approximately 1, 10 and 100 μg/mL, respectively. Mean- while, the peak plasma concentration of vidarabine after the intravenous administration in a dose of 10 mg/kg for 3 hr to healthy human subjects has been shown to be 0.2 μg/mL (0.75 μM) in the interview form from the manufacturer.…”

Assessment of drug‐induced proarrhythmias due to pilsicainide in patients with atrial tachyarrhythmias

“…However, in basic studies, pilsicainide was shown to block also the K + channels. Pilsicainide blocks the K + channel current in the human ether‐a‐go‐go‐related gene (HERG) with a preferential affinity for the open state of the channel, and shows a fast access to the binding site [18–20]. As a result, the K + channel blocking action of pilsicainide prolonged the QTc interval in patients presenting with very high pilsicainide concentrations.…”

COVID-19 Pandemic and Cardiovascular Disease

“…Oseltamivir is fairly cardio-benign, and in fact in animal models has been shown to reduce the risk of atrial and ventricular arrhythmias. 22,23 Anti-malarial Drugs Chloroquine, a widely used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad-spectrum anti-viral drug. 24,25 Chloroquine is known to block virus infection by increasing the endosomal pH required for virus/cell fusion and interfering with the glycosylation of cellular receptors of SARS-CoV.…”