Role of dofetilide in patients with ventricular arrhythmias

Shantha, Ghanshyam Palamaner Subash; Singleton, Matthew J.; Kozák, P; Bodziock, George; Atreya, Auras R.; Narasimhan, Bharat; Deshmukh, Abhishek; Liang, Jackson J.; Hranitzky, Patrick; Whalen, Patrick; Bhave, Prashant D.

doi:10.1007/s10840-023-01578-w

Cited by 2 publications

(1 citation statement)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some of these examples are trying to identify highly specific and more potent drug-like compounds to target defined human Kir channels, including repurposing of approved drugs. Public examples of approved drugs presently being tested to control human channelopathies are for instance, Retigabine (tested as antiepileptic drug [23][24][25] ), Dofetilide (tested as antiarrhythmic for atrial fibrillation [26][27][28][29] , and Senicapoc (tested against ischemic stroke 30 despite showing off-target effects 31 ). Future research may lead to new discoverings in the anti-channelopathies research field, but progress is slow mostly due to the small amount of drug-like compound alternatives and to the extensive clinical tests required for each possibility.…”

Section: Introductionmentioning

confidence: 99%

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

coll

2024

Preprint

View full text Add to dashboard Cite

Human potassium channels (Kir) are implicated in numerous dysfunction diseases genetically affecting cardiovascular, skeletal-muscle and/or synaptic-neuronal functions. Variations in Kir sequences, organ distribution differences and toxicity of some of their known inhibitors, require alternative drugs to interfere specifically with each human Kir molecular species. In this work, a prokaryotic asymmetric transmembrane homotetramer potassium (K+) channel protein highly homologous to Kirs has been used as their model. Computational methods combining molecular parent co-evolutions confirmed by consensus docking, were explored as possible prove-of-concept to generate rather than screen for numerous KcsA docking-ligands. The explorations of the KcsA central cavity and of their interface lipid-binding shallow-grooves, predicted highly specific novel scaffolds with low-toxicity risks, displaying hundreds of molecular variations of new scaffolds within nanoMolar-ranged affinities. Experimental validation and/or additional computational research on human Kirs could be attempted in the future.

show abstract

Section: Introductionmentioning

confidence: 99%

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

coll

2024

Preprint

View full text Add to dashboard Cite

show abstract

Dofetilide for the treatment of premature ventricular complexes and ventricular tachycardia in patients with structural heart disease

Deshmukh,

Yokokawa,

McBride

et al. 2024

Cardiovasc electrophysiol

View full text Add to dashboard Cite

BackgroundDofetilide is a class III antiarrhythmic agent approved for the treatment of atrial fibrillation and atrial flutter. Given the efficacy of other class III agents, it has been used off‐label for the treatment of premature ventricular complexes (PVCs) and ventricular tachycardias (VTs).ObjectiveThe purpose of this study was to determine the efficacy and safety of dofetilide for ventricular arrythmias (VAs).MethodsIn this retrospective cohort study, 81 patients (59 men; age = 60 ± 14 years; LVEF = 0.34 ± 0.16) were admitted for dofetilide initiation to treat PVCs (29), VTs (42) or both (10). A ≥ 80% decrease in PVC burden was defined as a satisfactory response. An ICD was present in 72 patients (89%). Another antiarrhythmic was previously used in 50 patients (62%). Prior catheter ablation had been performed in 33 patients (41%).ResultsDuring intitiation, dofetilide was discontinued in 12 patients (15%) due to QT prolongation (8) and inefficacy to suppress VAs (4). Among the 32 patients with PVCs who successfully started dofetilide, the mean PVC burden decreased from 20 ± 10% to 8 ± 8% at a median follow‐up of 2.6 months (p < .001). PVC burden was reduced by ≥80% in only 11/32 patients (34%). During 7 ± 1 years of follow‐up, 41/69 patients (59%) continued to have VAs and received appropriate ICD therapies for monomorphic VTs (35) and polymorphic VT/VF (6) at a median of 8.0 (IQR 2.6–33.2) months. Dofetilide had to be discontinued in 50/69 patients (72%) due to inefficacy or intolerance. The composite outcome of VT/VF recurrence, heart transplantation, or death occurred in 6/12 patients (50%) without dofetilide and 49/69 patients (71%) with dofetilide. The event free survival was similar between patients treated with and without dofetilide (log‐rank p = .55).ConclusionsTreatment with dofetilide was associated with a decrease in PVCs, however clinically significant suppression occurred in a minority of patients. Dofetilide failed to suppress the occurrence of VTs in a majority of patients.

show abstract

Role of dofetilide in patients with ventricular arrhythmias

Cited by 2 publications

References 19 publications

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

Dofetilide for the treatment of premature ventricular complexes and ventricular tachycardia in patients with structural heart disease

Contact Info

Product

Resources

About