Electropharmacological effects of amantadine on cardiovascular system assessed with J-T_peak and T_peak-T_end analysis in the halothane-anesthetized beagle dogs

Abstract

-Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-T peak and T peak -T end were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-T peak , but prolonged the T peak -T end . Amantadine can be considered to stimulate Ca 2+ channel but inhibit Na + and K + channels in the in situ heart. J-T peak and T peak -T end analysis suggests that amantadine may possess modest risk for arrhythmia.

Amantadine-Induced Cardiac Arrest in a Patient With COVID-19

“…Cao X et al have proposed that amantadine may block Na+ and K+ channels and induce Ca2+ channels in the heart in vivo. In addition, proarrhythmic properties of amantadine may be between E-4031 (a human ether-a-go-go related gene potassium channel blocker) and amiodarone [16].…”

A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium

“…Heart rate correction of ECG parameters has a long clinical and nonclinical history, 14 -16 with standard approaches that suffer from substantial intersubject variability in healthy volunteers. 17 In nonclinical studies, the QT–HR relationship has been characterized in canines, 18 minipigs, guinea pigs, and nonhuman primates.…”

“…12 The JTp and Tpe from anesthetized dogs were previously considered to assess inward and outward current modifications, 13 but overall, limited data are available from conscious nonclinical models. Heart rate correction of ECG parameters has a long clinical and nonclinical history, [14][15][16] with standard approaches that suffer from substantial intersubject variability in healthy volunteers. 17 In nonclinical studies, the QT-HR relationship has been characterized in canines, 18 minipigs, guinea pigs, and nonhuman primates.…”

Cardiovascular safety pharmacology of ivermectin assessed using the isoflurane-anesthetized beagle dogs: ICH S7B follow-up study

“…In order to better characterize the proarrhythmic potential of ivermectin, we compared eff ects of the high dose of ivermectin on the proarrhythmic surrogate markers with those of supratherapeutic doses of aciclovir, amantadine and oseltamivir in our previous studies assessed under the halothane anesthesia ( Cao et al . , 2016 ;Kitahara et al .…”

“…The terminal repolarization period was calculated by the difference between the duration of MAP and the ventricular effective refractory period (VERP) at the same site, which could reflect the magnitude of local electrical vulnerability, providing "substrate" for the perpetuation of spiral reentry (Sugiyama and Hashimoto, 2002). Finally, we compared the current results of ivermectin on these proarrhythmic surrogate markers with those of typical antiviral drugs (Cao et al, 2016;Kitahara et al, 2013;Kondo et al, 2020) to better characterize the cardiac safety profile of ivermectin.…”