Vernakalant 500mg/25ml solution for infusion vials

Abstract Objective To conduct a randomised, open label comparison of the effectiveness and safety of intravenous vernakalant and intravenous procainamide for the management of acute atrial fibrillation in the emergency department. Design Randomised clinical trial (RAFF4 trial). Setting 12 tertiary care emergency departments in Canada. Participants Patients with acute atrial fibrillation for whom acute rhythm control was a safe option. Interventions Patients were randomised (1:1) to an intravenous infusion of vernakalant or procainamide; when rapid conversion did not occur, patients were offered electrical cardioversion. Main outcomes and measures The primary outcome was conversion to sinus rhythm within 30 minutes of drug infusion completion. Secondary outcomes included time to conversion to sinus rhythm and whether the patient required electrical cardioversion. Results Of the 350 enrolled eligible patients, baseline characteristics were similar in the procainamide (n=172) and vernakalant (n=178) groups. For the primary outcome of conversion success, vernakalant was more effective (62.4% v 48.3%; adjusted absolute difference 15.0%, 95% confidence interval 4.6% to 25.0%, P=0.005; adjusted odds ratio 1.87, 95% confidence interval 1.2 to 2.9, P=0.006). With vernakalant, time to conversion was faster (21.8 v 44.7 minutes; mean difference −22.9, 95% confidence interval −29.9 to −16.0, P<0.001), and fewer patients underwent attempted electrical cardioversion (33.7% v 44.2%; odds ratio 0.62, 95% confidence interval 0.39 to 0.96, P=0.033). Adverse events were similar in both groups, were generally mild and brief, and most patients were discharged home. Subgroup analysis strongly favoured vernakalant for conversion in patients younger than 70 years (73.3% v 47.2%; adjusted odds ratio 3.1, 95% confidence interval 1.7 to 5.5, P=0.001, interaction P=0.005). Conclusions In this head-to-head comparison, vernakalant was superior to procainamide for patients with higher conversion rates and faster times to conversion. Therefore, vernakalant is a safe and highly effective intravenous alternative for the rapid cardioversion and discharge home of patients with acute atrial fibrillation. Trial registration ClinicalTrials.gov NCT04485195

Abstract licence: CC BY-NC

ABSTRACT Background Atrial fibrillation (AF) and obesity coexist in approximately 37.6 million and 650 million people globally, respectively. The anatomical and physiological changes in individuals with obesity may influence the pharmacokinetic properties of drugs. Aim This review aimed to describe the evidence of the effect of obesity on the pharmacokinetics of antiarrhythmics in people with AF. Methods Three databases were searched from inception to June 2023. Original studies that addressed the use of antiarrhythmics in adults with AF and concomitant obesity were included. Results A total of 4549 de‐duplicated articles were screened, and 114 articles underwent full‐text review. Ten studies were included in this narrative synthesis: seven cohort studies, two pharmacokinetic studies, and a single case report. Samples ranged from 1 to 371 participants, predominately males (41%–85%), aged 59–75 years, with a body mass index (BMI) of 23–66 kg/m 2 . The two most frequently investigated antiarrhythmics were amiodarone and dofetilide. Other drugs investigated included diltiazem, flecainide, disopyramide, propafenone, dronedarone, sotalol, vernakalant, and ibutilide. Findings indicate that obesity may affect the pharmacokinetics of amiodarone and sodium channel blockers (e.g., flecainide, disopyramide, and propafenone). Factors such as drug lipophilicity may also influence the pharmacokinetics of the drug and the need for dose modification. Discussion Antiarrhythmics are not uniformly affected by obesity. This observation is based on heterogeneous studies of participants with an average BMI and poorly controlled confounding factors such as multimorbidity, concomitant medications, varying routes of administration, and assessment of obesity. Controlled trials with stratification at the time of recruitment for obesity are necessary to determine the significance of these findings.

Abstract licence: CC BY

Atrial fibrillation is the most common sustained cardiac arrhythmia, and its prevalence is increasing with age; also it is associated with significant morbidity and mortality. Rhythm control is advised in recent-onset atrial fibrillation, and in highly symptomatic patients, also in young and active individuals. Moreover, rhythm control is associated with lower incidence of progression to permanent atrial fibrillation. Vernakalant is a relatively new anti-arrhythmic drug that showed efficacy and safety in recent-onset atrial fibrillation. Vernakalant is indicated in atrial fibrillation (⩽7 days) in patients with no heart disease (class I, level A) or in patients with mild or moderate structural heart disease (class IIb, level B). Moreover, Vernakalant may be considered for recent-onset atrial fibrillation (⩽3 days) post cardiac surgery (class IIb, level B). Although it is mainly indicated in patients with recent-onset atrial fibrillation and with no structural heart disease, it can be given in moderate stable cardiac disease as alternative to Amiodarone. Similarly to electrical cardioversion, pharmacological cardioversion requires a minimal evaluation and cardioversion should be included in a comprehensive management strategy for better outcome.

Abstract licence: CC BY-NC

BACKGROUND: (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Abstract licence: CC BY

BACKGROUND: Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for cardiac disease modelling, drug discovery and regenerative medicine. Despite the advancement in various differentiation protocols, the heterogeneity of the generated population composed of diverse cardiac subtypes poses a significant challenge to their practical applications. Mixed populations of cardiac subtypes can compromise disease modelling and drug discovery, while transplanting them may lead to undesired arrhythmias as they may not integrate and synchronize with the host tissue's contractility. It is therefore crucial to identify cell surface markers that could enable high purity of ventricular CMs for subsequent applications. METHODS: By exploiting the fact that immature CMs expressing myosin light chain 2A (MLC2A) will gradually express myosin light chain 2 V (MLC2V) protein as they mature towards ventricular fate, we isolated signal regulatory protein alpha (SIRPA)-positive CMs expressing intracellular MLC2A or MLC2V using MARIS (method for analysing RNA following intracellular sorting). Subsequently, RNA sequencing analysis was performed to examine the gene expression profile of MLC2A + and MLC2V + sorted CMs. We identified genes that were significantly up-regulated in MLC2V + samples to be potential surface marker candidates for ventricular specification. To validate these surface markers, we performed immunostaining and western blot analysis to measure MLC2A and MLC2V protein expressions in SIRPA + CMs that were either positive or negative for the putative surface markers, JAK2 (Janus kinase 2) or CD200. We then characterized the electrophysiological properties of surface marker-sorted CMs, using fluo-4 AM, a green-fluorescent calcium indicator, to measure the cellular calcium transient at the single cell level. For functional validation, we investigated the response of the surface marker-sorted CMs to vernakalant, an atrial-selective anti-arrhythmic agent. RESULTS: In this study, while JAK2 and CD200 were identified as potential surface markers for the purification of ventricular-like CMs, the SIRPA+/JAK2+ population showed a higher percentage of MLC2V-expressing cells (~ 90%) compared to SIRPA+/CD200+ population (~ 75%). SIRPA+/JAK2+ sorted CMs exhibited ventricular-like electrophysiological properties, including slower beating rate, slower calcium depolarization and longer calcium repolarization duration. Importantly, vernakalant had limited to no significant effect on the calcium repolarization duration of SIRPA+/JAK2+ population, indicating their enrichment for ventricular-like CMs. CONCLUSION: Our study lays the groundwork for the identification of cardiac subtype surface markers that allow purification of cardiomyocyte sub-populations. Our findings suggest that JAK2 can be employed as a cell surface marker for enrichment of hPSC-derived ventricular-like CMs.

Abstract licence: CC BY

Introduction: The mechanisms leading to the conversion of atrial fibrillation (AF) to sinus rhythm are poorly understood. This study describes the dynamic behavior of electrophysiological parameters and conduction patterns leading to spontaneous and pharmacological AF termination. Methods: Five independent groups of goats were investigated: (1) spontaneous termination of AF, and drug-induced terminations of AF by various potassium channel inhibitors: (2) AP14145, (3) PA-6, (4) XAF-1407, and (5) vernakalant. Bi-atrial contact mapping was performed during an open chest surgery and intervals with continuous and discrete atrial activity were determined. AF cycle length (AFCL), conduction velocity and path length were calculated for each interval, and the final conduction pattern preceding AF termination was evaluated. Results: AF termination was preceded by a sudden episode of discrete activity both in the presence and absence of an antiarrhythmic drug. This episode was accompanied by substantial increases in AFCL and conduction velocity, resulting in prolongation of path length. In 77% ± 4% of all terminations the conduction pattern preceding AF termination involved medial to lateral conduction along Bachmann's bundle into both atria, followed by anterior to posterior conduction. This finding suggests conduction block in the interatrial septum and/or pulmonary vein area as final step of AF termination. Conclusion: AF termination is preceded by an increased organization of fibrillatory conduction. The termination itself is a sudden process with a critical role for the interplay between spatiotemporal organization and anatomical structure.

Abstract licence: CC BY

BACKGROUND: Pancreatic cancer (PanCa) is one of the most lethal cancers (survival ~ 12%). As the conventional therapeutic interventions are mostly futile, a deep understanding of the disease pathophysiology is an urgent need. Ion channels, located on cell membrane, contribute significantly to cancer hallmarks, through dysregulation of various ion translocation; however, the fundamental mechanisms remain uncertain. METHODS: To identify these oncochannels in Indian cohort of PanCa, we utilized 450 K data, published in our previous study, and identified potential pathways involved. Their expressions were evaluated using TCGA data and an independent Indian paired patient cohort (n = 20). The top genes were further validated using GEO and ScRNA seq dataset. Potential target ability of KCNJ5 was identified through molecular dynamic based drug designing. RESULTS: A set of 7 differentially methylated and differentially expressed genes of ion-channel proteins namely KCNJ5, CACNB2, KCNA3, KCNA6, RASA3, GABBR2 and CLIC5 were identified in Indian PanCa cohort only. KCNJ5 was significantly upregulated and associated with worse survival in Indian cohort, whereas downregulated in TCGA and other Caucasians patient populations. Two TFs controlling the KCNJ5 expression are POU2F1 and POU3F1. Few predicted small molecules targeting Kcnj5 are, Amiloride, Vernakalant hydrochloride, Dalfampridine, Glyburide and Levcromakalim. It also showed notable interactions with a steroidal anticancer agent, protodioscin. CONCLUSION: An onco-channel gene, KCNJ5 significantly upregulated, and showing adverse survival in highly expressed KCNJ5 group in Indian cohort of PanCa, can be targeted with Amiloride, Vernakalant hydrochloride, Dalfampridine, Glyburide Levcromakalim and protodioscin. This understanding can lead to novel target identification for PanCa therapy development.

Abstract licence: CC BY-NC-ND