vernakalant and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Evidence has emerged that small-conductance Ca. A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs.. SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

Topics: Acetamides; Animals; Anisoles; Atrial Fibrillation; Cardiac Pacing, Artificial; Disease Models, Animal; Disease Progression; Patch-Clamp Techniques; Pyrrolidines; Refractory Period, Electrophysiological; Small-Conductance Calcium-Activated Potassium Channels; Swine

The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS).. Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0.5 µM, n = 14) after obtaining baseline data. Thereafter, vernakalant (10 µM) was additionally infused. Infusion of erythromycin or veratridine significantly increased action potential duration (APD90) and QT interval. Erythromycin and veratridine also significantly augmented spatial dispersion of repolarization (erythromycin: +43 ms; veratridine: +55 ms, P < 0.01, respectively) and temporal dispersion of repolarization. After lowering extracellular [K+] in bradycardic hearts, 11 of 15 erythromycin-treated hearts and 4 of 14 veratridine-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with vernakalant resulted in a significant reduction of spatial dispersion of spatial dispersion in both groups (erythromycin: -32 ms; veratridine: -35 ms, P < 0.05 each) and a stabilization of temporal dispersion. After additional treatment with vernakalant, only 5 of 15 erythromycin-treated hearts (P = 0.07) and 1 of 14 veratridine-treated hearts (P = 0.32) presented polymorphic VT.. Vernakalant has antiarrhythmic effects in this experimental model of acquired LQTS. A reduction of spatial dispersion of repolarization and a stabilization of temporal dispersion in hearts showing polymorphic VT represent the major underlying electrophysiological mechanisms.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Conduction System; In Vitro Techniques; Long QT Syndrome; Pyrrolidines; Rabbits; Tachycardia, Ventricular; Treatment Outcome

Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current.. The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria.. Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia.. Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing.. The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria.

Topics: Action Potentials; Animals; Anisoles; Atrial Fibrillation; Atrial Remodeling; Disease Models, Animal; Goats; Heart Atria; Pyrrolidines; Refractory Period, Electrophysiological

Electrical remodeling plays a pivotal role in maintaining the reentry during atrial fibrillation. In this study, we assessed influence of electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. We used an atrial electrical remodeling model of the rabbit, subjected to rapid atrial pacing (RAP; 600 beats/min) for 2-4 weeks, leading to shortening of atrial effective refractory period (AERP). Intravenous administration of dl-sotalol (6 mg/kg), bepridil (1 mg/kg), amiodarone (10 mg/kg) or vernakalant (3 mg/kg) significantly prolonged the AERP both in the control and RAP rabbits. The extents in the RAP rabbits were similar to those in the control animals. On the other hand, prolonging effects of intravenously administered ranolazine (10 mg/kg) or tertiapin-Q (0.03 mg/kg) on the AERP in the RAP rabbits were more potent than those in the control animals. These results suggest that rapid pacing-induced electrical remodeling effectively modified the prolonging effects of ranolazine and tertiapin-Q on the AERP in contrast to those of clinically available antiarrhythmic drugs, dl-sotalol, bepridil amiodarone and vernakalant.

Topics: Amiodarone; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Remodeling; Bepridil; Cardiac Pacing, Artificial; Disease Models, Animal; Infusions, Intravenous; Male; Pyrrolidines; Rabbits; Sotalol

Ranolazine has been reported to have an antiarrhythmic potential. The aim of this study was to assess the electrophysiologic effects of ranolazine and to compare its effects to vernakalant in an experimental whole-heart model of short-QT syndrome.. Rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an IK. Endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (- 34 milliseconds, P < 0.05) and action potential duration (APD. In the present pharmacologic model of short QT syndrome treatment with pinacidil led to an increased inducibility of VF in association with a reduction in ERP. Additional treatment with ranolazine or vernakalant reversed this effect and demonstrated potent antiarrhythmic properties based on an increase of ERP.

Topics: Action Potentials; Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Disease Models, Animal; Electrocardiography; Heart Rate; Isolated Heart Preparation; Pinacidil; Pyrrolidines; Rabbits; Ranolazine; Sodium Channel Blockers; Time Factors; Ventricular Fibrillation

About one-third of patients with mild dyssynchronous heart failure suffer from atrial fibrillation (AF). Drugs that convert AF to sinus rhythm may further slowdown ventricular conduction. We aimed to investigate the electrophysiological and haemodynamic effects of vernakalant and flecainide in a canine model of chronic left bundle branch block (LBBB).. Left bundle branch block was induced in 12 canines. Four months later, vernakalant or flecainide was administered using a regime, designed to achieve clinically used plasma concentrations of the drugs, n = 6 for each drug. Epicardial electrical contact mapping showed that both drugs uniformly prolonged myocardial conduction time. Vernakalant increased QRS width significantly less than flecainide (17 ± 13 vs. 34 ± 15%, respectively). Nevertheless, both drugs equally decreased LVdP/dtmax by ∼15%, LVdP/dtmin by ∼10%, and left ventricular systolic blood pressure by ∼5% (P = n.s. between drugs).. Vernakalant prolongs ventricular conduction less than flecainide, but both drugs had a similar, moderate negative effect on ventricular contractility and relaxation. Part of these reductions seems to be related to the increase in dyssynchrony.

Topics: Action Potentials; Animals; Anisoles; Anti-Arrhythmia Agents; Blood Pressure; Bundle-Branch Block; Chronic Disease; Disease Models, Animal; Dogs; Electrophysiologic Techniques, Cardiac; Female; Flecainide; Heart Conduction System; Hemodynamics; Male; Myocardial Contraction; Pyrrolidines; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

The present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF).. In 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD90) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K+ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias.. In the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Resynchronization Therapy; Disease Models, Animal; Electrocardiography; Female; Heart Conduction System; Heart Failure; Heart Ventricles; Models, Cardiovascular; Pyrrolidines; Rabbits

The anesthetized chronic AV-blocked dog (cAVB) and methoxamine-sensitized rabbit model are widely used to determine pro-arrhythmic properties of drugs. In general, both models show similar results. However, conflicting data have also been reported; K201 and AZD1305 induced Torsade de Pointes (TdP) exclusively in cAVB dogs. Vernakalant, an antiarrhythmic drug that blocks several ion channels has been approved only in Europe. Its propensity to induce repolarization-dependent TdP arrhythmias has been evaluated solely in the methoxamine-sensitized rabbits. We therefore assessed the proarrhythmic potential of vernakalant in the cAVB dog model. Vernakalant was evaluated in 10 mongrel dogs (sinus rhythm (SR) 2mg/kg; chronic AV block (cAVB) 2+3mg/kg). The same dogs were challenged with dofetilide (25 μg/kg) to evaluate TdP inducibility. During the serial experiments the animals were paced from the right ventricular apex (60 beats/min). Short-term variability of repolarization (STV) was quantified for proarrhythmic risk. In SR (n=8) vernakalant prolonged QT (265 ± 11 to 311 ± 18 ms P<0.01(**)) but not PQ or QRS. In cAVB (n=8), 2mg/kg vernakalant prolonged QT (391 ± 43 to 519 ± 73 ms(**)) and QRS (103 ± 24 to 108 ± 23 ms(**)). After a 30 min lag-time, 3mg/kg vernakalant (n=4) increased QT to a lesser extent (413 ± 34 to 454 ± 27 ms(**)) while maintaining QRS prolongation (114 ± 18 to 122 ± 20 ms(**)). Neither dose increased STV or caused arrhythmias. Dofetilide prolonged QT (398 ± 51 to 615 ± 71 ms(**)), increased STV (1.0 ± 0.4 to 2.2 ± 1.0 ms P<0.05(⁎)) and induced TdP arrhythmias in 6/8(⁎) cAVB dogs. Vernakalant did not induce arrhythmias in the cAVB dog model. Higher dosages (3mg/kg) did not prolong repolarization further whereas negative inotropic effects were starting to become apparent precluding further increases in dose.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrioventricular Block; Disease Models, Animal; Dogs; Female; Male; Phenethylamines; Pyrrolidines; Sulfonamides; Torsades de Pointes

Vernakalant is a novel antiarrhythmic agent that has demonstrated clinical efficacy for the treatment of atrial fibrillation. Vernakalant blocks, to various degrees, cardiac sodium and potassium channels with a pattern that suggests atrial selectivity. We hypothesized, therefore, that vernakalant would affect atrial more than ventricular effective refractory period (ERP) and have little or no effect on ventricular defibrillation threshold (DFT). Atrial and ventricular ERP and ventricular DFT were determined before and after treatment with vernakalant or vehicle in 23 anesthetized male mixed-breed pigs. Vernakalant was infused at a rate designed to achieve stable plasma levels similar to those in human clinical trials. Atrial and ventricular ERP were determined by endocardial extrastimuli delivered to the right atria or right ventricle. Defibrillation was achieved using external biphasic shocks delivered through adhesive defibrillation patches placed on the thorax after 10 seconds of electrically induced ventricular fibrillation. The DFT was estimated using the Dixon "up-and-down" method. Vernakalant significantly increased atrial ERP compared with vehicle controls (34 ± 8 versus 9 ± 7 msec, respectively) without significantly affecting ventricular ERP or DFT. This is consistent with atrial selective actions and supports the conclusion that vernakalant does not alter the efficacy of electrical defibrillation.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Electric Countershock; Heart Atria; Humans; Male; Potassium Channels; Pyrrolidines; Refractory Period, Electrophysiological; Sodium Channels; Swine; Ventricular Function

A series of in vivo experiments were conducted to compare the hemodynamic actions of vernakalant (a novel, relatively atrial selective, antiarrhythmic drug) to flecainide after infusion into the peripheral vasculature. Anesthetized rats were surgically prepared to have an extracorporeal perfusion circuit whereby blood in the abdominal aorta (distal to the renal arteries) was diverted to a constant flow pump and returned to the abdominal aorta at the same level allowing measurement of hindlimb vascular resistance. The effects of cumulative, ascending doses of intravenous vernakalant and flecainide on vascular resistance, after arterial pressures, and heart rate were measured. Blood samples were drawn following each dose to determine drug plasma concentrations. Vernakalant had no significant vasomotor effects on peripheral or systemic vasculature. In contrast, flecainide decreased peripheral vascular resistance (15% at 0.8 μg/mL) and systemic pressures (32% mean arterial pressure at 0.8 μg/mL) in a dose-dependent manner. At therapeutic plasma concentrations, vernakalant (1 μg/mL) had little effect on heart rate (-24 beats/min) or QRS intervals (+3.4 msec), whereas flecainide (0.8 μg/mL) significantly decreased heart rate (55 beats/min) and increased QRS intervals (9.9 msec). In conclusion, vernakalant did not have negative hemodynamic effects at therapeutic plasma concentrations in a rat hindlimb perfusion model.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Aorta, Abdominal; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Flecainide; Hindlimb; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Vascular Resistance

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmia, Sinus; Atrial Fibrillation; Disease Models, Animal; Humans; Pyrrolidines; Randomized Controlled Trials as Topic