Exploring the interplay between extracellular pH and Dronedarone's pharmacological effects on cardiac function.

Dronedarone (DRN) is a clinically used drug to mitigate arrhythmias with multichannel block properties, including the sodium channel Nav1.5. Extracellular acidification is known to change the pharmacological properties of several antiarrhythmic drugs. Here, we explore how modification in extracellular pH (pHe) shapes the pharmacological profile of DRN upon Nav1.5 sodium current (INa) and in the ex vivo heart preparation. Embryonic human kidney cells (HEK293T/17) were used to transiently express the human isoform of Nav1.5 α-subunit. Patch-Clamp technique was employed to study INa. Neurotoxin-II (ATX-II) was used to induce the late sodium current (INaLate). Additionally, ex vivo Wistar male rat preparations in the Langendorff system were utilized to study electrocardiogram (ECG) waves. DRN preferentially binds to the closed state inactivation mode of Nav1.5 at pHe 7.0. The recovery from INa inactivation was delayed in the presence of DRN in both pHe 7.0 and 7.4, and the use-dependent properties were distinct at pHe 7.0 and 7.4. However, the potency of DRN upon the peak INa, the voltage dependence for activation, and the steady-state inactivation curves were not altered in both pHe tested. Also, the pHe did not change the ability of DRN to block INaLate. Lastly, DRN in a concentration and pH dependent manner modulated the QRS complex, QT and RR interval in clinically relevant concentration. Thus, the pharmacological properties of DRN upon Nav1.5 and ex vivo heart preparation partially depend on the pHe. The pHe changed the biological effect of DRN in the heart electrical function in relevant clinical concentration.

Effects of amiodarone, amioder, and dronedarone on Trichomonas vaginalis.

Trichomonas vaginalis is a protozoan that causes human trichomoniasis, the most common non-viral sexually transmitted infection (STI) affecting approximately 278 million people worldwide. The current treatment for trichomoniasis is based on 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, known as metronidazole (MTZ). Although effective in clearing the parasite infection, MTZ is related to provoking severe side effects, and it is not recommended during pregnancy. In addition, some strains present resistance to 5'-nitroimidazoles, making urgent the development of alternative drugs for trichomoniasis. Amiodarone, an antiarrhythmic drug, exerts a significant anti-parasite effect, mainly due to its interference with calcium homeostasis and the biosynthesis of sterols. Therefore, we decided to test the effect of amiodarone and two other related compounds (amioder and dronedarone) on T. vaginalis. Our observations show that amiodarone stimulated, rather than inhibited, parasite growth, induced cell aggregation, and glycogen accumulation. Furthermore, the other two compounds displayed anti-parasite activity with IC50 of 3.15 and 11 µM, respectively, and the apoptosis-like process killed the cells. In addition, cells exhibited morphological changes, including an effect on hydrogenosomes structure.

Dronedarone blockage of the tumor-related Kv10.1 channel: a comparison with amiodarone.

Kv10.1 (Eag1, or KCNH1) is a human potassium-selective channel associated with tumor development. In this work, we study the interaction of the drug dronedarone with Kv10.1. Dronedarone presents two chemical modifications aimed to lessen side effects produced by its parent molecule, the antiarrhythmic amiodarone. Hence, our observations are discussed within the framework of a previously reported interaction of amiodarone with Kv10.1. Additionally, we show new data regarding the interaction of amiodarone with the channels. We found that, unexpectedly, the effect of dronedarone on Kv10.1 differs both quantitatively and qualitatively to that of amiodarone. Among other observations, we found that dronedarone seems to be an open-pore blocker, in contrast to the reported behavior of amiodarone, which seems to inhibit from both open and closed states. Additionally, herein we provide evidence showing that, in spite of their chemical similarity, these molecules inhibit the K+ conductance by binding to non-overlapping, independent (non-allosterically related) sites. Also, we show that, while amiodarone inhibits the Cole-Moore shift, dronedarone is unable to inhibit this voltage-dependent characteristic of Kv10.1.

Comparative evaluation of the hepatotoxicity, phototoxicity and photosensitizing potential of dronedarone hydrochloride and its cyclodextrin-based inclusion complexes.

In this study, the hepatotoxicity, phototoxicity and photosensitizing potential of free dronedarone (DRO) and its inclusion complexes with ß-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), prepared by different methods, were investigated by using in vitro cell-based approaches. The results of the 3T3 NRU phototoxicity assay showed that free DRO and the CD-based inclusion complexes did not present any substantial phototoxic potential. The photosensitizing potential was assessed by using THP-1 cells and IL-8 as a biomarker, and the experimental data confirmed that both the free drug and the inclusion complexes are likely to cause skin photosensitization, as they were able to induce IL-8 release after irradiation. Nevertheless, the inclusion complexes obtained by kneading followed by spray-drying induced a lower IL-8 release and also presented a smaller stimulation index in comparison with free DRO, suggesting a reduction in the photosensitizing potential. Finally, the free drug and inclusion complexes were also tested for hepatotoxicity using HepG2 cells. Even though lower IC50 values were found for the inclusion complexes prepared by kneading followed by spray-drying, there was no significant difference, indicating that the complexation of dronedarone did not induce hepatotoxicity. Overall, the obtained data confirmed that the inclusion complexes prepared by kneading followed by spray-drying, especially those based on HP-ß-CD, appeared to be the most promising formulations and, therefore, could be encouragingly explored in the development of novel pharmaceutical dosage forms containing DRO, presumably with reduced side effects and improved safety profile.

Preparation, characterization and in vitro cytotoxicity study of dronedarone hydrochloride inclusion complexes.

Dronedarone is a new antiarrhythmic drug for the treatment of atrial fibrillation. This study investigated the complexation of dronedarone hydrochloride with ß­cyclodextrin (ß-CD) and 2­hydroxypropil­ß­CD (HP-ß-CD) using three different techniques. The complexes in the solid state were characterized by DSC, TGA, PXRD, FT-IR, SEM and 1H NMR, demonstrating the formation of the inclusion complexes and exhibiting different properties from the pure drug. Its aqueous solubility increased about 4.0-fold upon complexation with ß-CD and HP-ß-CD. The dissolution rate of the drug was notably improved in all tested physiological pH values from 1.2 to 6.8 in the presence of both cyclodextrins. Furthermore, an in vitro cytotoxic assay revealed that the inclusion complexes could reduce the cytotoxic effects of the drug on 3T3 cells. The overall results suggest that the inclusion complexes with ß-CD and HP-ß-CD may be potentially useful in the preparation of novel pharmaceutical formulations containing dronedarone hydrochloride.

Comparación de la eficacia y seguridad de flecainida y dronedarona como terapias antiarrítmicas para mantenimiento de ritmo sinusal en fibrilación auricular / Comparison of the efficacy and safety of dronedarone and flecainide as maintenance antiarrhythmic therapy for sinus rhythm in atrial fibrillation

Resumen Introducción y objetivos: Dronedarona y flecainida son antiarrítmicos de primera elección para reducir recurrencias de fibrilación auricular (FA), sin existir estudios que los comparen entre sí. Nuestro objetivo es comparar la eficacia en cuanto a prevención de recurrencias y seguridad de ambos fármacos. Métodos: Estudio retrospectivo en el que se incluyeron 123 pacientes de forma consecutiva en tratamiento con flecainida o dronedarona desde octubre de 2010 hasta febrero de 2013 por FA paroxística (76.4%) y FA persistente (23.6%). Se realizó cardioversión eléctrica en un 7.3% de los pacientes y farmacológica en un 16.3%. La mediana (rango intercuartílico) de seguimiento fue de 301 días (92-474), con una media de 2.8 revisiones por paciente. Se realizó análisis de tiempo hasta el primer evento mediante Kaplan-Meier y regresión de Cox ajustada por un índice de propensión. Resultados: De entre los 123 sujetos incluidos con FA, 71 fueron tratados con flecainida y 52 con dronedarona. Durante el seguimiento se registraron 36 recurrencias y 20 efectos adversos. Se documentaron un 36.6% de recurrencias en los pacientes tratados con flecainida en comparación con un 21% en los tratados con dronedarona (p = 0.073). En el análisis multivariante, dronedarona se mostró al menos tan eficaz como flecainida para prevenir recurrencias de FA (HR: 0.53, IC 95%: 0.20-1.44, p = 0.221) y demostró un perfil de seguridad comparable al de flecainida (HR: 0.68, IC 95%: 0.18-2.53, p = 0.566). Conclusiones: Según nuestra experiencia, dronedarona resulta al menos tan eficaz como flecainida para el mantenimiento de ritmo sinusal, con un buen perfil de tolerabilidad, a pesar de pautarse en pacientes con un perfil clínico más desfavorable.

Abstract Introduction and objectives: Dronedarone and flecainide are the first pharmacological choice to reduce recurrence of atrial fibrillation (AF); however, there are no studies comparing them. A study was performed to compare the efficacy in terms of recurrence of AF and safety of both drugs. Methods: A retrospective cohort study was conducted that included 123 consecutive patients treated with flecainide or dronedarone due to paroxysmal AF (76.4%) or persistent AF (23.6%), from October 2010 to February 2013. Electrical cardioversion was performed in 7.3% of patients and pharmacological cardioversion in 16.3%. The median (interquartile range) follow-up was 301 days (92-474) with a mean of 2.8 reviews per patient. Time to first event analysis was performed using Kaplan-Meier and Cox regression, adjusted for propensity score. Results: Of the 123 consecutive patients with AF included, 71 were on dronedarone and 52 on flecainide. During the follow-up, there were 36 AF recurrences and 20 safety events. There were recurrences in 36.6% of patients treated with flecainide, compared with 21% of those receiving dronedarone (P = .073). Dronedarone showed to be at least as effective as flecainide in preven- ting recurrence of atrial fibrillation (HR: 0.53, 95% CI: 0.20-1.44, P = .221), and demonstrated an acceptable safety profile when compared with flecainide (HR: 0.68, 95% CI: 0.18-2.53, P = .566). Conclusions: In our experience, dronedarone has been at least as effective and safe as flecainide, despite it was most frequently prescribed in patients with worse baseline risk profile.

Anti-Trypanosoma cruzi action of a new benzofuran derivative based on amiodarone structure.

Chagas disease is a neglected tropical affection caused by the protozoan parasite Trypanosoma cruzi. There is no current effective treatment since the only two available drugs have a limited efficacy and produce side effects. Thus, investigation efforts have been directed to the identification of new drug leads. In this context, Ca2+ regulating mechanisms have been postulated as targets for antiparasitic compounds, since they present paramount differences when compared to host cells. Amiodarone is an antiarrhythmic with demonstrated trypanocidal activity acting through the disruption of the parasite intracellular Ca2+ homeostasis. We now report the effect of a benzofuran derivative based on the structure of amiodarone on T. cruzi. This derivative was able to inhibit the growth of epimastigotes in culture and of amastigotes inside infected cells, the clinically relevant phase. We also show that this compound, similarly to amiodarone, disrupts Ca2+ homeostasis in T. cruzi epimastigotes, via two organelles involved in the intracellular Ca2+ regulation and the bioenergetics of the parasite. We demonstrate that the benzofuran derivative was able to totally collapse the membrane potential of the unique giant mitochondrion of the parasite and simultaneously produced the alkalinization of the acidocalcisomes. Both effects are evidenced by a large increase in the intracellular Ca2+ concentration of T. cruzi.

[Comparison of the efficacy and safety of dronedarone and flecainide as maintenance antiarrhythmic therapy for sinus rhythm in atrial fibrillation]. / Comparación de la eficacia y seguridad de flecainida y dronedarona como terapias antiarrítmicas para mantenimiento de ritmo sinusal en fibrilación auricular.

INTRODUCTION AND OBJECTIVES: Dronedarone and flecainide are the first pharmacological choice to reduce recurrence of atrial fibrillation (AF); however, there are no studies comparing them. A study was performed to compare the efficacy in terms of recurrence of AF and safety of both drugs. METHODS: A retrospective cohort study was conducted that included 123 consecutive patients treated with flecainide or dronedarone due to paroxysmal AF (76.4%) or persistent AF (23.6%), from October 2010 to February 2013. Electrical cardioversion was performed in 7.3% of patients and pharmacological cardioversion in 16.3%. The median (interquartile range) follow-up was 301days (92-474) with a mean of 2.8 reviews per patient. Time to first event analysis was performed using Kaplan-Meier and Cox regression, adjusted for propensity score. RESULTS: Of the 123 consecutive patients with AF included, 71 were on dronedarone and 52 on flecainide. During the follow-up, there were 36 AF recurrences and 20 safety events. There were recurrences in 36.6% of patients treated with flecainide, compared with 21% of those receiving dronedarone (P=.073). Dronedarone showed to be at least as effective as flecainide in preventing recurrence of atrial fibrillation (HR: 0.53, 95% CI: 0.20-1.44, P=.221), and demonstrated an acceptable safety profile when compared with flecainide (HR: 0.68, 95% CI: 0.18-2.53, P=.566). CONCLUSIONS: In our experience, dronedarone has been at least as effective and safe as flecainide, despite it was most frequently prescribed in patients with worse baseline risk profile.

Synthesis and characterization of new related substances of the antiarrhythmic drug dronedarone hydrochloride.

Two new potential impurities of antiarrhythmic drug substance Dronedarone Hydrochloride together with debutyldronedarone were detected by LC-MS analysis during process development. A successful synthetic strategy for the synthesis of these potential impurities was developed facilitating the access to new impurity reference standards. Their synthesis and characterization are discussed in detail. The availability of these impurity standards allowed cost reduction through the increase of process control.

Dronedarone, an amiodarone analog with improved anti-Leishmania mexicana efficacy.

Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. They function by disrupting intracellular Ca2+ homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against Leishmania mexicana, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of L. mexicana promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with T. cruzi amastigotes (0.65 nM versus 0.75 µM). As with amiodarone, dronedarone affects intracellular Ca2+ homeostasis in the parasite, inducing an elevation of intracellular Ca2+ levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.

In vitro anti-Trypanosoma cruzi activity of dronedarone, a novel amiodarone derivative with an improved safety profile.

Amiodarone, a commonly used antiarrhythmic, is also a potent and selective anti-Trypanosoma cruzi agent. Dronedarone is an amiodarone derivative in which the 2,5-diiodophenyl moiety of the parental drug has been replaced with an unsubstituted phenyl group aiming to eliminate the thyroid toxicity frequently observed with amiodarone treatment. Dronedarone has been approved by the Food and Drug Administration (FDA), and its use as a safe antiarrhythmic has been extensively documented. We show here that dronedarone also has potent anti-T. cruzi activity, against both extracellular epimastigotes and intracellular amastigotes, the clinically relevant form of the parasite. The 50% inhibitory concentrations against both proliferative stages are lower than those previously reported for amiodarone. The mechanism of action of dronedarone resembles that of amiodarone, as it induces a large increase in the intracellular Ca(2+) concentration of the parasite, which results from the release of this ion from intracellular storage sites, including a direct effect of the drug on the mitochondrial electrochemical potential, and through alkalinization of the acidocalcisomes. Our results suggest a possible future repurposed use of dronedarone for the treatment of Chagas' disease.

[Amiodarone and thyroid dysfunction]. / Amiodarona y disfunción tiroidea.

Amiodarone is a structural analogue of thyroid hormone, and some of its anti-arrhythmic actions and toxicity are attributable to its interaction with nuclear receptors of thyroid hormones. Being highly lipophilic, amiodarone is concentrated in many tissues and is eliminated, consequently, very slowly. It is preferably employed to manage life-threatening arrhythmias, including ventricular fibrillation and unstable ventricular tachycardia. Other indications include atrial fibrillation and flutter, severe congestive heart failure, prevention of atrial fibrillation recurrence, and even in emergency medical situations to prevent sudden cardiac death. The aim of this review is to provide an updated approach on amiodarone and its influence on thyroid physiology and to discuss and analyze in depth its potential and not infrequent thyroidal adverse effects such as hypothyroidism and thyrotoxicosis.

Acute in vitro effects of dronedarone, an iodine-free derivative, and amiodarone, on the rabbit sinoatrial node automaticity: a comparative study.

Amiodarone is a potent antiarrhythmic drug commonly used in the treatment of supraventricular and ventricular arrhythmias. Dronedarone is a recently developed iodine-free compound (Sanofi Recherche), structurally related to amiodarone. Amiodarone and dronedarone have shown similar long-term effects on sinoatrial node automaticity in vivo and in vitro in the rabbit heart. In the present study, we used a microelectrode technique to compare the acute in vitro electrophysiologic effects of amiodarone (100 microM) and dronedarone (100 microM) on the rabbit sinus node. Like amiodarone, dronedarone induces a marked reduction in sinus node automaticity, evidenced by decreases in spontaneous beating rate, action potential amplitude, and slope of phase 4 depolarization. Isoproterenol dose-dependently increases sinus node automaticity in the presence of either amiodarone or dronedarone. The data suggest that dronedarone may be a useful antiarrhythmic alternative to amiodarone in the treatment of supraventricular arrhythmias.

In vitro effects of acute amiodarone and dronedarone on epicardial, endocardial, and M cells of the canine ventricle.

Amiodarone (AM) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias. Dronedarone (DR) is a new compound with a pharmacological profile similar to that of AM, but iodine free. We previously demonstrated that chronic AM treatment reduces transmural dispersion of repolarization (TDR) in the canine heart. We used standard microelectrode technique to evaluate the effects of acute AM (100 microM) and DR (30 microM) on epicardial (EPI), endocardial (ENDO), and M region tissues obtained from the left ventricular wall of the canine heart. Amiodarone (100 microM, 120 min of exposure) produced little change in the action potential duration of ENDO and EPI tissues, but it shortened the action potential of M cells, especially at slow rates, leading to a decrease in TDR. Similar results were observed with DR. Acute AM (100 microM) and DR (30 microM) eliminated d-sotalol-induced early afterdepolarizations (EADs) and triggered activity in 3 of 3 and 2 of 6 M cell preparations, respectively. The reduction of TDR and the elimination of EAD-induced triggered activity differentiates AM and DR from other class III agents. These effects may explain the efficacy and low arrhythmogenicity of acute AM and suggest a potential safe use of DR as an antiarrhythmic agent.