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Thomas Jespersen - One of the best experts on this subject based on the ideXlab platform.

  • the kca2 channel inhibitor ap14145 but not Dofetilide or ondansetron provides functional atrial selectivity in guinea pig hearts
    Frontiers in Pharmacology, 2019
    Co-Authors: Jeppe Egedal Kirchhoff, Lea Abildgaard, Thomas Jespersen, Morten Grunnet, Mark Alexander Skarsfeldt, Kalai Mangai Muthukumarasamy, Rafel Simovicens, Sofia Hammami Bomholtz, Ulrik Svane Sorensen, Bo Hjorth Bentzen
    Abstract:

    Background and Purpose: Prolongation of cardiac action potentials is considered antiarrhythmic in the atria but can be proarrhytmic in ventricles if the current carried by Kv11.1-channels (IKr) is inhibited. The current mediated by KCa2-channels, IKCa, is considered a promising new target for treatment of atrial fibrillation (AF). Selective inhibitors of IK (Dofetilide) and IKCa (AP14145) were used to compare the effects on ventricular and atrial repolarisation. Ondansetron which has been reported to be a potent blocker of both IKr and IKCa was included to examine its potential atrial antiarrhythmic properties. Experimental Approach: The expression of KCa2- and Kv11.1-channels in the guinea pig heart was investigated using qPCR. Whole-cell patch clamp technique was used to investigate the effects of Dofetilide, AP14145, and ondansetron on IKCa and/or IKr. The effect of Dofetilide, AP14145, and ondansetron on atrial and ventricular repolarisation was investigated in isolated hearts. A novel atrial paced in vivo guinea pig model was further validated using AP14145 and Dofetilide. Key Results: AP14145 increased AERP without prolonging QTcB both ex vivo and in vivo. In contrast, Dofetilide increased QTcB and, to a lesser extent, AERP in isolated hearts and prolonged QTcB with no effects on AERP in the in vivo guinea pig model. Ondansetron did not inhibit IKCa, but did inhibit IKr in vitro. Ondansetron prolonged ventricular, but not atrial repolarisation ex vivo. Conclusion and Implications: IKCa inhibition by AP14145 selectively increases atrial repolarisation whereas IKr inhibition by Dofetilide and ondansetron increases ventricular repolarisation to a larger extent than atrial repolarisation.

  • effects of Dofetilide and ranolazine on atrial fibrillatory rate in a horse model of acutely induced atrial fibrillation
    Journal of Cardiovascular Electrophysiology, 2019
    Co-Authors: Helena Carstensen, Thomas Jespersen, Steen Pehrson, Eva Zander Hesselkilde, Maria Mathilde Haugaard, Mette Flethoj, Jonas Carlson, Pyotr G Platonov, Rikke Buhl
    Abstract:

    Introduction: The atrial fibrillatory rate is a potential biomarker in the study of antiarrhythmic drug effects on atrial fibrillation (AF). The purpose of this study was to evaluate whether dose-dependent changes in the atrial fibrillatory rate can be monitored on surface electrocardiography (ECG) following treatment with Dofetilide, ranolazine, and a combination of the two in an acute model of AF in horses. Methods and Results: Eight horses were subjected to pacing-induced AF on 4 separate days. Saline (control), Dofetilide, ranolazine, or a combination of Dofetilide and ranolazine was administered in four incremental doses. Atrial fibrillatory activity was extracted from surface ECGs using spatiotemporal QRST cancellation. The mean atrial fibrillatory rate before drug infusion was 297 ± 27 fpm. Dofetilide reduced the atrial fibrillatory rate following the infusion of low doses (0.89 µg/kg, P < 0.05) and within 5 minutes preceding cardioversion (P < 0.05). Cardioversion with ranolazine was preceded by a reduction in the atrial fibrillatory rate in the last minute (P < 0.05). The combination of drugs reduced the atrial fibrillatory rate in a similar manner to Dofetilide used alone. A trend toward a lower atrial fibrillatory rate before drug infusion was found among horses cardioverting on low doses of the drugs. Conclusion: The atrial fibrillatory rate derived from surface ECGs showed a difference in the mode of action on AF between Dofetilide and ranolazine. Dofetilide reduced the atrial fibrillatory rate, whereas ranolazine displayed a cardioverting mechanism that was distinct from a slowing of the fibrillatory process. (Less)

  • antiarrhythmic effects of combining Dofetilide and ranolazine in a model of acutely induced atrial fibrillation in horses
    Journal of Cardiovascular Pharmacology, 2017
    Co-Authors: Helena Carstensen, Steen Pehrson, Eva Zander Hesselkilde, Maria Mathilde Haugaard, Mette Flethoj, Rikke Buhl, Line Kjaer, Jorgen K Kanters, Thomas Jespersen
    Abstract:

    BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

  • antiarrhythmic effect of the ca 2 activated k sk channel inhibitor ica combined with either amiodarone or Dofetilide in an isolated heart model of atrial fibrillation
    Pflügers Archiv: European Journal of Physiology, 2016
    Co-Authors: Jeppe Egedal Kirchhoff, Jonas Goldin Diness, Lea Abildgaard, Morten Grunnet, Majid Sheykhzade, Thomas Jespersen
    Abstract:

    Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics Dofetilide and amiodarone have documented anti-AF effects. While Dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca2+-activated K+ (SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either Dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either Dofetilide or amiodarone when combined with ICA, also at a subefficacious concentration. At a concentration level effective as monotherapy, Dofetilide produced a marked increase in the QT interval. This QT prolonging effect was absent when combined with ICA at non-efficacious monotherapy concentrations. The results thereby reveal that combination of subefficacious concentrations of an SK channel blocker and either Dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced.

Gregory K Feld - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of oral Dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter the symptomatic atrial fibrillation investigative research on Dofetilide safire d study
    Circulation, 2000
    Co-Authors: Steven Singh, Gregory K Feld, Robert G Zoble, Laurence Yellen, Michael A Brodsky, Martin R Berk, Clare B Billing
    Abstract:

    Background—This double-blind, multicenter, placebo-controlled study determined the efficacy and safety of Dofetilide in converting atrial fibrillation (AF) or atrial flutter (AFl) to sinus rhythm (SR) and maintaining SR for 1 year. Methods and Results—Patients with AF or AFl (n=325) were randomized to 125, 250, or 500 μg Dofetilide or placebo twice daily. Dosages were adjusted for QTc response and, after 105 patients were enrolled, for calculated creatinine clearance (ClCr). Pharmacological cardioversion rates for 125, 250, and 500 μg Dofetilide were 6.1%, 9.8%, and 29.9%, respectively, versus 1.2% for placebo (250 and 500 μg versus placebo; P=0.015 and P<0.001, respectively). Seventy percent of pharmacological cardioversions with Dofetilide were achieved in 24 hours and 91% in 36 hours. For the 250 patients who successfully cardioverted pharmacologically or electrically, the probability of remaining in SR at 1 year was 0.40, 0.37, 0.58 for 125, 250, and 500 μg Dofetilide, respectively, and 0.25 for place...

  • electrophysiologic effects of the new class iii antiarrhythmic drug Dofetilide in an experimental canine model of pacing induced atrial fibrillation
    Journal of Cardiovascular Pharmacology and Therapeutics, 1997
    Co-Authors: Gregory K Feld, Yongmei Cha
    Abstract:

    Background: Dofetilide is a new class III antiarrhythmic drug currently under investigation for the treatment of supraventricular arrhythmias in humans. Dofetilide have been previously shown to be ...

  • electrophysiologic effects of the new class iii antiarrhythmic drug Dofetilide compared to the class ia antiarrhythmic drug quinidine in experimental canine atrial flutter role of dispersion of refractoriness in antiarrhythmic efficacy
    Journal of Cardiovascular Electrophysiology, 1996
    Co-Authors: Yongmei Cha, Alan Wales, Paul L Wolf, Shahin Shahrokni, Neil Sawhney, Gregory K Feld
    Abstract:

    Effects of Dofetilide in Canine Atrial Flutter. Introduction: Previous studios that Class III antiarrhythmic drugs are more effective in reentrant arrhythmias because they prolong refractoriness (ERP) and wavelength and reduce dispersion of refractoriness compared to Class IA antiarrhythmic drugs, which slow conduction velocity (CV) in addition to their effects on refractoriness. Methods and Results: To test this hypothesis, the Class III drug Dofetilide and the Class IA drug quinidine were studied in the experimental canine crush-injury model of atrial flutter, utilizing right atrial multipoint programmed stimulation and activation mapping. In seven dogs Dofetilide prolonged ERP by 23%, slowed CV by 9% at 200-msec cycle length (P < 0.001) and by 39% at 150-msec cycle length (P < 0.001), and increased wavelength by 11% (P < 0.02). Dofetilide reduced dispersion of ERP by 20% (P = 0.003) and adjacent electrodes with ERP difference ≥: 20 msec by 76% (P < 0.001). Dofetilide slowed atrial flutter by 37% (P = 0.003) prior to terminating and suppressing it in all dogs. In eight dogs quinidine prolonged ERP by 14% (P < 0.001), slowed CV by 14% at 200-msec cycle length (P < 0.00) and by 19% at 150-msec cycle length (P < 0.001), and reduced wavelength by 2% (P = NS). Quinidine did not reduce dispersion of refractoriness. Quinidine slowed atrial flutter by 57% (P < 0.001), terminating and suppressing it in only three dogs. Efficacy of Dofetilide was greater than quinidine (P = 0.026) and correlated with reduced dispersion of ERP (r = -0.653, P = 0.01), reduced adjacent electrodes with ERP difference ≥ 20 msec (r = -0.637, P = 0.012), and prolonged wavelength (r = 0.61, P = 0.018). Dofetilide and quinidine terminated atrial flutter by similar mechanisms. Myocardial fiber orientation was nonuniform around the crush injury. Conclusions: Antiarrhythmic efficacy of Dofetilide was greater than that of quinidine and correlated with drug-induced prolongation of wavelength and reduction in dispersion of refractoriness, effects produced only by Dofetilide.

Rikke Buhl - One of the best experts on this subject based on the ideXlab platform.

  • effects of Dofetilide and ranolazine on atrial fibrillatory rate in a horse model of acutely induced atrial fibrillation
    Journal of Cardiovascular Electrophysiology, 2019
    Co-Authors: Helena Carstensen, Thomas Jespersen, Steen Pehrson, Eva Zander Hesselkilde, Maria Mathilde Haugaard, Mette Flethoj, Jonas Carlson, Pyotr G Platonov, Rikke Buhl
    Abstract:

    Introduction: The atrial fibrillatory rate is a potential biomarker in the study of antiarrhythmic drug effects on atrial fibrillation (AF). The purpose of this study was to evaluate whether dose-dependent changes in the atrial fibrillatory rate can be monitored on surface electrocardiography (ECG) following treatment with Dofetilide, ranolazine, and a combination of the two in an acute model of AF in horses. Methods and Results: Eight horses were subjected to pacing-induced AF on 4 separate days. Saline (control), Dofetilide, ranolazine, or a combination of Dofetilide and ranolazine was administered in four incremental doses. Atrial fibrillatory activity was extracted from surface ECGs using spatiotemporal QRST cancellation. The mean atrial fibrillatory rate before drug infusion was 297 ± 27 fpm. Dofetilide reduced the atrial fibrillatory rate following the infusion of low doses (0.89 µg/kg, P < 0.05) and within 5 minutes preceding cardioversion (P < 0.05). Cardioversion with ranolazine was preceded by a reduction in the atrial fibrillatory rate in the last minute (P < 0.05). The combination of drugs reduced the atrial fibrillatory rate in a similar manner to Dofetilide used alone. A trend toward a lower atrial fibrillatory rate before drug infusion was found among horses cardioverting on low doses of the drugs. Conclusion: The atrial fibrillatory rate derived from surface ECGs showed a difference in the mode of action on AF between Dofetilide and ranolazine. Dofetilide reduced the atrial fibrillatory rate, whereas ranolazine displayed a cardioverting mechanism that was distinct from a slowing of the fibrillatory process. (Less)

  • antiarrhythmic effects of combining Dofetilide and ranolazine in a model of acutely induced atrial fibrillation in horses
    Journal of Cardiovascular Pharmacology, 2017
    Co-Authors: Helena Carstensen, Steen Pehrson, Eva Zander Hesselkilde, Maria Mathilde Haugaard, Mette Flethoj, Rikke Buhl, Line Kjaer, Jorgen K Kanters, Thomas Jespersen
    Abstract:

    BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Nancy Allen M Lapointe - One of the best experts on this subject based on the ideXlab platform.

  • Dofetilide dose reductions and discontinuations in women compared with men
    Heart Rhythm, 2018
    Co-Authors: Nancy Allen M Lapointe, Sean D Pokorney, Debbie C Yen, Kristen Bova Campbell, Shubin Sheng, Laine Thomas, Tristram D Bahnson, James P Daubert, Jonathan P Picini
    Abstract:

    Background Compared with men, women have longer corrected QT (QTc) intervals, lower clearance of Dofetilide, and higher rates of drug-induced torsades de pointes, but the Dofetilide dosing algorithm is the same for men and women. Objective The purpose of this study was to evaluate the tolerability of the 500 μg twice daily dose of Dofetilide for men and women. Methods Men and women admitted to Duke University Medical Center (January 1, 2006, to October 19, 2012) for the initiation of Dofetilide 500 μg twice daily were matched 1:1 on age and estimated creatinine clearance. Electrocardiograms throughout dosing were analyzed, and rates of Dofetilide discontinuations and dose reductions were compared in unadjusted and adjusted analyses. Results For 220 matched men and women, the median age was 62.5 years (interquartile range 55–69 years) and the median eCrCl was 98.1 mL/min (interquartile range 77.6–126.2 mL/min). Women were less likely than men to have hypertension and interventricular conduction delay but were otherwise similar. During Dofetilide initiation, women were more likely than men to have their Dofetilide dose discontinued or reduced (55% vs 32%; P P Conclusion More than half of women who initiated on 500 μg twice daily of Dofetilide required medication discontinuations or dose reductions, mostly because of QTc prolongation. Additional studies are needed to evaluate the optimal dosing algorithm of Dofetilide in women.

  • evaluation of the Dofetilide risk management program
    American Heart Journal, 2003
    Co-Authors: Nancy Allen M Lapointe, Anita Chen, Bradley G Hammill, Elizabeth R Delong, Judith M Kramer, Robert M Califf
    Abstract:

    Abstract Background Dose-dependent torsades de pointes has been shown to occur with Dofetilide (Tikosyn) and sotalol HCl (Betapace AF); thus, detailed dosing and monitoring recommendations to minimize this risk are included in the product labeling for both drugs. Only Dofetilide, however, has a mandated risk-management program that restricts distribution of the drug and requires prescriber education on the drug. We investigated whether this program improved adherence to dosing and monitoring recommendations for Dofetilide as compared with sotalol. Methods Charts for 47 patients taking Dofetilide and 117 patients taking sotalol were reviewed. Results The recommended starting dose was prescribed more frequently in the Dofetilide group than in the sotalol group (79% vs 35%, P P P P P P P Conclusion Better adherence to several dosing and monitoring recommendations in the Dofetilide group may be caused by the presence of the risk-management program. However, low usage of Dofetilide during the study period may signify an unintended, negative consequence of the risk-management program.

  • new antiarrhythmic agents for atrial fibrillation and atrial flutter united states drug market response as an indicator of acceptance
    Pharmacotherapy, 2003
    Co-Authors: Nancy Allen M Lapointe, Carol Pamer, Judith M Kramer
    Abstract:

    Objective. To determine how well Dofetilide and Betapace AF (sotalol, approved solely for atrial fibrillation and atrial flutter), with their detailed dosing and monitoring guidelines for safety, were accepted into clinical practice during the 2 calendar years after their introduction. Methods and Results. We reviewed the number of new, refill, and total prescriptions of all antiarrhythmic agents in the United States from April 2000-December 2001 to assess use of Dofetilide and Betapace AF in the drug market. Both were prescribed very infrequently throughout the study period. In addition, the infrequent reported use of these drugs for patients with atrial fibrillation and flutter indicated poor acceptance of these agents by prescribing physicians. We speculated that the restricted distribution and required educational program for Dofetilide, as well as the availability of generic sotalol products, may have discouraged physicians from prescribing both Dofetilide and Betapace AF. Conclusion. A common goal for both the Dofetilide risk-management program and the creation of a sotalol product indicated solely for atrial fibrillation and atrial flutter was to provide safer treatment for patients with these arrhythmias. Unfortunately, limited penetration of Dofetilide and Betapace AF into the U.S. market suggests that drugs without a risk-management program or detailed dosing guidelines were more likely than Dofetilide or Betapace AF to be selected for treatment of atrial fibrillation and atrial flutter.

  • practitioner acceptance of the Dofetilide risk management program
    Pharmacotherapy, 2002
    Co-Authors: Nancy Allen M Lapointe, Judith M Kramer, Kevin P Weinfurt, Robert M Califf
    Abstract:

    Study Objective. To assess the opinions and knowledge retention of practitioners after participation in the Dofetilide risk-management program. Design. A 21-item questionnaire. Setting. A large academic medical center. Participants. One hundred forty-six practitioners were given the questionnaire; 91 (62%) completed it. Measurements and Results. The questionnaire assessed practitioners' opinions of the program and guidelines, preparation time for implementing Dofetilide treatment, and retention of facts from the program. Responses were graded on a 5–point Likert scale. Practitioners took a mean of 0.86 ± 0.44 hours to complete the program; physicians took the least time, pharmacists the most. Practitioners agreed the program was necessary but were undecided about whether the guidelines were easily understood or implemented. Nurses answered one of the two knowledge-retention questions incorrectly significantly more often than physicians or pharmacists. Identification of seven drugs that should not be taken with Dofetilide differed significantly (p<0.0001) across groups (mean accuracy score was 41% for nurses, 80% for pharmacists, and 86% for physicians). Conclusion. This risk-management program has been well received by practitioners at our institution. We are gathering data to determine whether the program is effective in reducing inappropriate administration of Dofetilide.

Yongmei Cha - One of the best experts on this subject based on the ideXlab platform.

  • electrophysiologic effects of the new class iii antiarrhythmic drug Dofetilide in an experimental canine model of pacing induced atrial fibrillation
    Journal of Cardiovascular Pharmacology and Therapeutics, 1997
    Co-Authors: Gregory K Feld, Yongmei Cha
    Abstract:

    Background: Dofetilide is a new class III antiarrhythmic drug currently under investigation for the treatment of supraventricular arrhythmias in humans. Dofetilide have been previously shown to be ...

  • electrophysiologic effects of the new class iii antiarrhythmic drug Dofetilide compared to the class ia antiarrhythmic drug quinidine in experimental canine atrial flutter role of dispersion of refractoriness in antiarrhythmic efficacy
    Journal of Cardiovascular Electrophysiology, 1996
    Co-Authors: Yongmei Cha, Alan Wales, Paul L Wolf, Shahin Shahrokni, Neil Sawhney, Gregory K Feld
    Abstract:

    Effects of Dofetilide in Canine Atrial Flutter. Introduction: Previous studios that Class III antiarrhythmic drugs are more effective in reentrant arrhythmias because they prolong refractoriness (ERP) and wavelength and reduce dispersion of refractoriness compared to Class IA antiarrhythmic drugs, which slow conduction velocity (CV) in addition to their effects on refractoriness. Methods and Results: To test this hypothesis, the Class III drug Dofetilide and the Class IA drug quinidine were studied in the experimental canine crush-injury model of atrial flutter, utilizing right atrial multipoint programmed stimulation and activation mapping. In seven dogs Dofetilide prolonged ERP by 23%, slowed CV by 9% at 200-msec cycle length (P < 0.001) and by 39% at 150-msec cycle length (P < 0.001), and increased wavelength by 11% (P < 0.02). Dofetilide reduced dispersion of ERP by 20% (P = 0.003) and adjacent electrodes with ERP difference ≥: 20 msec by 76% (P < 0.001). Dofetilide slowed atrial flutter by 37% (P = 0.003) prior to terminating and suppressing it in all dogs. In eight dogs quinidine prolonged ERP by 14% (P < 0.001), slowed CV by 14% at 200-msec cycle length (P < 0.00) and by 19% at 150-msec cycle length (P < 0.001), and reduced wavelength by 2% (P = NS). Quinidine did not reduce dispersion of refractoriness. Quinidine slowed atrial flutter by 57% (P < 0.001), terminating and suppressing it in only three dogs. Efficacy of Dofetilide was greater than quinidine (P = 0.026) and correlated with reduced dispersion of ERP (r = -0.653, P = 0.01), reduced adjacent electrodes with ERP difference ≥ 20 msec (r = -0.637, P = 0.012), and prolonged wavelength (r = 0.61, P = 0.018). Dofetilide and quinidine terminated atrial flutter by similar mechanisms. Myocardial fiber orientation was nonuniform around the crush injury. Conclusions: Antiarrhythmic efficacy of Dofetilide was greater than that of quinidine and correlated with drug-induced prolongation of wavelength and reduction in dispersion of refractoriness, effects produced only by Dofetilide.