Antiarrhythmic Effects of Combining Dofetilide and Ranolazine in a Model of Acutely Induced Atrial Fibrillation in Horses.
Abstract: Antiarrhythmic compounds against atrial fibrillation (AF) often have reduced efficacy and may display cardiac and/or noncardiac toxicity. Efficacy can be improved by combining 2 compounds with distinct mechanisms, and it may be possible to use lower doses of each compound, thereby reducing the likelihood of adverse side effects. The purpose of this study was to investigate whether the effective doses of dofetilide and ranolazine can be reduced if the drugs are combined. Dofetilide, ranolazine, and a combination of these were administered in 4 incremental dosing regimens to horses with acutely pacing-induced AF. Time to cardioversion, atrial effective refractory period, and AF vulnerability and duration were assessed. Of 8 horses, 6 cardioverted to sinus rhythm after infusion with a combination of 0.889 μg/kg dofetilide and 0.104 mg/kg ranolazine. Two horses cardioverted with 0.104 mg/kg ranolazine alone, and 3 cardioverted with 0.889 μg/kg dofetilide alone. The combination therapy decreased AF vulnerability (P < 0.05) and AF duration (P < 0.05). No change in atrial effective refractory period was detected with any of the drugs. The combination of dofetilide and ranolazine showed increased antiarrhythmic effects on acutely induced AF in horses, affecting time to cardioversion, AF vulnerability, and AF duration.
Publication Date: 2017-10-27 PubMed ID: 29068807PubMed Central: PMC5768216DOI: 10.1097/FJC.0000000000000541Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The study investigates the improved effectiveness of the combined use of antiarrhythmic drugs, dofetilide and ranolazine, in treating pacing-induced atrial fibrillation in horses, potentially reducing the necessary dosage and decreasing the likelihood of adverse effects.
Introduction to the Research
- The study focuses on the medical condition called atrial fibrillation (AF), a common cardiac arrhythmia i.e., irregular heart rhythm, which can lead to various complications like stroke or heart failure.
- Currently, the antiarrhythmic compounds used to treat AF often have reduced effectiveness and are associated with cardiac and/or noncardiac toxicity. The researchers hypothesized that combining two drugs with distinct mechanisms can increase efficacy and potentially allow for lower dosages to reduce side effects.
Methodology of the Study
- The researchers chose two drugs, dofetilide and ranolazine, for the study. These drugs were administered in four different incremental dosing regimens to horses suffering from acutely pacing-induced AF. Pacing-induced AF refers to AF that is brought on by stimulating the heart to beat at an elevated rate.
- The effectiveness of these drugs was evaluated based on various criteria such as time to cardioversion, AF vulnerability, atrial effective refractory period, and duration of AF. Cardioversion refers to the restoration of normal heart rhythm, and the atrial effective refractory period is the phase during which the heart’s atria are not susceptible to new electrical signals.
Key Findings of the Study
- Out of the eight horses, six experienced restored sinus rhythm (normal heart rhythm) after an infusion with a combination of 0.889 μg/kg dofetilide and 0.104 mg/kg ranolazine. By contrast, only two horses cardioverted with 0.104 mg/kg ranolazine alone and only three with 0.889 μg/kg dofetilide alone.
- The mixture of both drugs resulted in a decrease in AF vulnerability i.e., the probability of AF onset, and a reduction in AF’s duration.
- None of the drugs caused any change in the atrial effective refractory period.
Significance of the Research Paper
- The findings suggest that combining dofetilide and ranolazine enhances the antiarrhythmic effects against acutely induced AF in horses by improving time to cardioversion, reducing vulnerability to AF, and shortening the period of AF.
- This research can potentially form a base for more detailed studies around the combined use of dofetilide and ranolazine or other drugs in the treatment of AF not only in animals but also in humans.
Cite This Article
APA
Carstensen H, Kjær L, Haugaard MM, Flethøj M, Hesselkilde EZ, Kanters JK, Pehrson S, Buhl R, Jespersen T.
(2017).
Antiarrhythmic Effects of Combining Dofetilide and Ranolazine in a Model of Acutely Induced Atrial Fibrillation in Horses.
J Cardiovasc Pharmacol, 71(1), 26-35.
https://doi.org/10.1097/FJC.0000000000000541 Publication
Researcher Affiliations
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark. Dr. Haugaard is now with Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark. Dr. Haugaard is now with Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark. Dr. Haugaard is now with Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark. Dr. Haugaard is now with Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark. Dr. Haugaard is now with Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark. Dr. Haugaard is now with Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
MeSH Terms
- Animals
- Anti-Arrhythmia Agents / administration & dosage
- Atrial Fibrillation / diagnosis
- Atrial Fibrillation / drug therapy
- Atrial Fibrillation / physiopathology
- Disease Models, Animal
- Drug Combinations
- Female
- Heart Rate / drug effects
- Horses
- Infusions, Intravenous
- Male
- Phenethylamines / administration & dosage
- Ranolazine / administration & dosage
- Sulfonamides / administration & dosage
Conflict of Interest Statement
The authors report no conflicts of interest.
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