Pharmacokinetic and pharmacodynamic profile of dronedarone, a new antiarrhythmic agent for the treatment of atrial fibrillation

Rosa, Gian Marco; Bianco, Daniele; Parodi, Antonello; Valbusa, Alberto; Zawaideh, Camilla; Bizzarri, Nicolò; Ferrero, Simone; Brunelli, Claudio

doi:10.1517/17425255.2014.974551

Cited by 15 publications

(12 citation statements)

References 63 publications

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“…Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation (AF) [ 7 ]. It reduces the incidence of recurrences of AF, cardiovascular-related hospitalizations, and death in patients with paroxysmal or persistent AF; however, it is avoided in high-risk patients with permanent AF or patients with unstable chronic heart failure [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Dronedarone produces early regression of myocardial remodelling in structural heart disease

et al. 2017

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Background and aimsLeft ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs).MethodsTen-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content.ResultsThe hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group.ConclusionThe results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.

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Section: Introductionmentioning

confidence: 99%

Dronedarone produces early regression of myocardial remodelling in structural heart disease

et al. 2017

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“…During the last decade, dronedarone has been studied extensively in a wide range of experimental and clinical settings. These studies have revelated that dronedarone is an interesting antiarrhythmic agent for the treatment of atrial fibrillation [31]. Dronedarone reduces cardiovascular morbidity and mortality in clinically stable patients with other risk factors for recurrent atrial fibrillation [23].…”

Section: Discussionmentioning

confidence: 99%

Impact of a Multichannel Blocker in Attenuating Intramyocardial Artery Remodeling in Hypertensive Rats through Increased Nitric Oxide Bioavailability

Quintana‐Villamandos

Delgado-Martos

Delgado-Baeza

2019

BioMed Research International

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Dronedarone is recommended for the treatment of atrial fibrillation. However, we do not know its effect on vascular remodeling. This study was designed to assess whether dronedarone has the potential to improve the intramyocardial artery remodeling induced by chronic hypertension. Ten-month-old male spontaneously hypertensive rats (SHR) were randomly assigned to receive dronedarone (100 mg/kg) or vehicle. Age-matched male Wistar-Kyoto rats served as controls. After 14 days of treatment, we studied the structure (geometry and fibrosis) of the intramyocardial artery using histological analysis. Nitric oxide (NO) in plasma was analyzed. In the untreated SHR, we observed a significant increase in external diameter, lumen diameter, wall width, cross-sectional area, and collagen volume density, as was expected in the experimental model. Dronedarone induced a significant decrease in wall width, cross-sectional area, and collagen volume density in SHR-D in comparison with untreated SHR. The values obtained in SHR-D were similar in the WKY control group. We found significantly higher NO levels in plasma in SHR-D than in untreated SHR. Dronedarone improves the intramyocardial artery remodeling induced by chronic hypertension in SHR through increased nitric oxide bioavailability.

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“…A good example of the importance is the conversion of drug from amiodarone to its derivative dronedarone. Both drugs share the main structure (removed iodine and added methanesulfonyl group) and electropharmacologic profile, with different relative effects on individual ion channels ( Pamukcu and Lip, 2011 ; Rosa et al, 2014 ). Amiodarone accumulates in tissue due to a longer half-life and iodine is known to negatively affect thyroid function ( Cohen-Lehman et al, 2010 ).…”

Section: Computational Pharmacology In Afmentioning

confidence: 99%

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

et al. 2018

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The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.

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Pharmacokinetic and pharmacodynamic profile of dronedarone, a new antiarrhythmic agent for the treatment of atrial fibrillation

Cited by 15 publications

References 63 publications

Dronedarone produces early regression of myocardial remodelling in structural heart disease

Dronedarone produces early regression of myocardial remodelling in structural heart disease

Impact of a Multichannel Blocker in Attenuating Intramyocardial Artery Remodeling in Hypertensive Rats through Increased Nitric Oxide Bioavailability

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

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