Study on the interaction between erythrosine B and the cardiac drug amiodarone using fluorescence, scattering, and absorbance spectra and their analytical application.

In an acidic buffered solution, erythrosine B can react with amiodarone to form an association complex, which not only generates great enhancement in resonance Rayleigh scattering (RRS) spectrum of erythrosine B at 346.5 nm but also results in quenching of fluorescence spectra of erythrosine B at λemission = 550.4 nm/λexcitation = 528.5 nm. In addition, the formed erythrosine B-amiodarone complex produces a new absorbance peak at 555 nm. The spectral characteristics of the RRS, absorbance, and fluorescence spectra, as well as the optimum analytical conditions, were studied and investigated. As a result, new spectroscopic methods were developed to determine amiodarone by utilizing erythrosine B as a probe. Moreover, the ICH guidelines were used to validate the developed RRS, photometric, and fluorimetric methods. The enhancements in the absorbance and the RRS intensity and the decrease in the fluorescence intensity of the used probe were proportional to the concentration of amiodarone in ranges of 2.5-20.0, 0.2-2.5, and 0.25-1.75 µg/mL, respectively. Furthermore, limit of detection values were 0.52 ng/mL for the spectrophotometric method, 0.051 µg/mL for the RRS method, and 0.075 µg/mL for the fluorimetric method. Moreover, with good recoveries, the developed spectroscopic procedures were applied to analyze amiodarone in its commercial tablets.

Analysis of a Serious Adverse Reaction of Pulmonary Fibrosis Caused by Dronedarone.

Objective: This study aims to analyze a severe adverse reaction of pulmonary fibrosis induced by dronedarone hydrochloride tablets, and to provide a reference for clinical rational medication through drug precautions. Methods: A case of pulmonary fibrosis induced by dronedarone hydrochloride tablets, along with related literature was retrospectively analyzed. Results: Patients over 65 years old with a history of exposure to amiodarone may increase the incidence of pulmonary toxicity induced by dronedarone, and dronedarone should not be selected as a substitute treatment drug for patients with amiodarone-induced pulmonary toxicity. Conclusions: It is recommended that clinicians monitor the diffusion capacity of carbon monoxide and lung ventilation function of patients before and after using dronedarone for treatment. For patients with a history of amiodarone exposure, intermittent monitoring of chest X-rays and lung function is necessary. If lung function decreases, dronedarone should be immediately discontinued.

Formulation and characterization of amiodarone-methyl-beta-cyclodextrin inclusion complexes: A molecular modelling perspective.

This study aimed to develop immediate-release tablets containing amiodarone hydrochloride (AM). AM is a BCS class II compound, i.e., high permeable, and poorly soluble. The interactions between amiodarone and methyl-ß-cyclodextrin were DFT-based, theoretically measured, supporting the complexation of AM with cyclodextrin by using methyl-ß-cyclodextrin through a spray-drying process. Thus, increasing substantially the drug solubility to 93.31% and 87.14%, respectively. Solubility studies demonstrated the formation of the Drug-Methyl-ß-cyclodextrin inclusion complex with 1:1 stoichiometry. The complex formation was characterized by SBET, XRD, DSC, SEM, FTIR, and 1H NMR. Complementing, immediate-release tablets containing the inclusion complex were developed by direct compression, and in vitro dissolution studies were performed in gastrointestinal fluids using USP Pharmacopeia standard dissolution rate testing equipment. The dissolution rate of immediate-release tablets was substantially higher than the pristine drug in all mediums evaluated. These results confirm the application of methyl-ß-cyclodextrin as an effective excipient for incorporation in novel dosage forms to increase the solubility of poorly soluble drugs.

Conjugation of amiodarone to a novel cardiomyocyte cell penetrating peptide for potential targeted delivery to the heart.

Modern medicine has developed a myriad of therapeutic drugs against a wide range of human diseases leading to increased life expectancy and better quality of life for millions of people. Despite the undeniable benefit of medical advancements in pharmaceutical technology, many of the most effective drugs currently in use have serious limitations such as off target side effects resulting in systemic toxicity. New generations of specialized drug constructs will enhance targeted therapeutic efficacy of existing and new drugs leading to safer and more effective treatment options for a variety of human ailments. As one of the most efficient drugs known for the treatment of cardiac arrhythmia, Amiodarone presents the same conundrum of serious systemic side effects associated with long term treatment. In this article we present the synthesis of a next-generation prodrug construct of amiodarone for the purpose of advanced targeting of cardiac arrhythmias by delivering the drug to cardiomyocytes using a novel cardiac targeting peptide, a cardiomyocyte-specific cell penetrating peptide. Our in vivo studies in guinea pigs indicate that cardiac targeting peptide-amiodarone conjugate is able to have similar effects on calcium handling as amiodarone at 1/15th the total molar dose of amiodarone. Further studies are warranted in animal models of atrial fibrillation to show efficacy of this conjugate.

The Influence of the Polymer Type on the Quality of Newly Developed Oral Immediate-Release Tablets Containing Amiodarone Solid Dispersions Obtained by Hot-Melt Extrusion.

The present study aims to demonstrate the influence of the polymer-carrier type and proportion on the quality performance of newly developed oral immediate-release tablets containing amiodarone solid dispersions obtained by hot-melt extrusion. Twelve solid dispersions including amiodarone and different polymers (PEG 1500, PEG 4000; PEG 8000, Soluplus®, and Kolliphor® 188) were developed and prepared by hot-melt extrusion using a horizontal extruder realized by the authors in their own laboratory. Only eleven of the dispersions presented suitable physical characteristics and they were used as active ingredients in eleven tablet formulations that contain the same amounts of the same excipients, varying only in solid dispersion type. The solid dispersions' properties were established by optical microscopy with reflected light, volumetric controls and particle size evaluation. In order to prove that the complex powders have appropriate physical characteristics for the direct compression process, they were subjected to different analyses regarding their flowability and compressibility behavior. Additionally, the Fourier transform infrared spectroscopy and X-ray diffraction analysis were performed on the obtained solid dispersions. After confirming the proper physical attributes for all blends, they were processed into the form of tablets by direct compression technology. The manufactured tablets were evaluated for pharmacotechnical (dimensions-diameter and thickness, mass uniformity, hardness and friability) and in vitro biopharmaceutical (disintegration time and drug release) performances. Furthermore, the influence of the polymer matrix on their quality was determined. The high differences in flow and compression performances of the solid dispersions prove the relevant influence of the polymer type and their concentration-dependent plasticizing properties. The increase in flowability and compressibility characteristics of the solid dispersions could be noticed after combining them with direct compression excipients owning superior mechanical qualities. The influence of the polymer type is best detected in the disintegration test, where the obtained values are quite different between the studied formulations. The use of PEG 1500 alone or combined in various proportions with Soluplus® leads to rapid disintegration. In contrast, the mixture of PEG 4000 and Poloxamer 188 in equal proportions determined the increase in disintegration time to 120 s. The use of Poloxamer 188 alone and a 3:1 combination of PEG 4000 and Soluplus® also generates a prolonged disintegration time for the tablets.

Investigation of the arcane inhibition of human organic anion transporter 3 by benzofuran antiarrhythmic agents.

The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected Ki values of 0.042, 0.019, 0.028 and 0.0046 µM respectively. Protein binding effects and probe substrate dependency were accounted for in our assays. Static modelling predicted 1.29-, 1.01-, 1.29- and 1.16-fold increase in rivaroxaban exposure, culminating in a predicted 1.29-, 1.01-, 1.28- and 1.15-fold increase in major bleeding risk respectively, suggesting potential OAT3-mediated DDI between amiodarone and rivaroxaban. Future work involving physiologically-based pharmacokinetic modelling is crucial in holistically predicting the complex DDIs between the benzofuran antiarrhythmic agents and rivaroxaban.

[Examples of Malfunction Occurred by Interactions between Pharmaceutical Products and Medical Devices That Pharmacists Should Be Aware of].

There have been a number of reports of medical device materials becoming denatured or damaged by interactions with pharmaceutical products. For example, the polycarbonate (PC) resin that is widely used in medical devices has the shortcoming of weak chemical resistance, and in more than one case, three-way stopcocks made of PC resin have been damaged when drugs like propofol are used. There have also been reports where concomitant use of pharmaceutical products prevented medical devices from exerting their effect properly. For example, owing to the heart-slowing action of amiodarone hydrochloride, a dose increase in a patient with an implantable cardioverter-defibrillator caused the device to fail to detect a sustained tachycardia attack, as a consequence of which defibrillation therapy was not administered. These are but a few of the numerous and varied interactions between pharmaceutical products and medical devices. We introduce the drug-medical device interactions that have been reported to Pharmaceuticals and Medical Devices Agency (PMDA) thus far.

Stability-indicating HPLC method for determination of amiodarone hydrochloride and its impurities in tablets: a detailed forced degradation study

Resumo Amiodarone hydrochloride is one of the most important drugs used to treat arrhythmias. The USP monograph for amiodarone hydrochloride describes an HPLC method for the quantification of seven impurities, however, this method shows problems that result in unresolved peaks. Moreover, there is no monograph for tablets in this compendium. Thus, a stability indicating HPLC method was developed for the determination of amiodarone, its known impurities and degradation products in tablets. A detailed forced degradation study was performed submitting amiodarone API, tablets and placebo to different stress conditions: acid and alkaline hydrolysis, oxidation, metal ions, heat, humidity, and light. Amiodarone hydrochloride API was susceptible to degradation in all stress conditions. The tablets also showed degradation in all environments, except in acidic condition. The analytes separation and quantification were achieved on an Agilent Zorbax Eclipse XDB-C18 column (100 x 3.0 mm, 3.5 µm). The mobile phase was composed of 50 mM acetate buffer pH 5.5 (A) and a mixture of methanol-acetonitrile (3:4, v/v) (B) in gradient elution. The method was validated in the range of 350-650 µg/mL for assay and 10-24 µg/mL for impurities determination. Therefore, this method can be used both for stability studies and routine quality control analyses.

Evaluation of in vitro anti-Trypanosoma cruzi activity of medications benznidazole, amiodarone hydrochloride, and their combination

Abstract INTRODUCTION: Approximately seven to eight million people worldwide have Chagas disease. In Brazil, benznidazole is the most commonly used active drug against Trypanosoma cruzi; however, its efficacy is limited, and side effects are frequent. Recent studies suggest that amiodarone may be beneficial in the treatment of this disease, by exerting anti-T. cruzi action. This study evaluated changes in T. cruzi cell count in in vitro cultures subjected to different doses of benznidazole, amiodarone, and their combination. METHODS: T. cruzi (Y strain) cultures containing approximately 100,000 cells were treated with either 100mg, 50mg, 25mg, 12.5mg, or 10mg of benznidazole, amiodarone, or their combination. On the 4th day, cell count was compared to the baseline data. RESULTS: On the 4th day, no parasites were observed in any of the treated cultures. CONCLUSIONS: Benznidazole and amiodarone were equally effective in eliminating T. cruzi in culture. The combination of the two drugs was also equally effective, but our data cannot demonstrate synergism, as similar results were obtained when the drugs were tested individually or in combination. It is suggested that this study be repeated with other T. cruzi strains to determine whether similar results can be obtained again.

Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators.

A new series of 2-alkyloxy-pyridine-3-carbonitrile-benzofuran hybrids (4a-x) was synthesized. All the new derivatives were examined via the standard technique for their vasodilation activity. Some of the investigated compounds exhibited a remarkable activity, with compounds 4w, 4e, 4r, 4s, 4f and 4g believed to be the most active hits in this study with IC50 values 0.223, 0.253, 0.254, 0.268, 0.267 and 0.275 mM, respectively, compared with amiodarone hydrochloride, the reference standard used (IC50 = 0.300 mM). CODESSA PRO was employed to obtain a statistically significant 2-Dimensional Quantitative Structure Activity Relationship (2D-QSAR) model describing the bioactivity of the newly synthesized analogs (N = 24, n = 4, R² = 0.816, R²cvOO = 0.731, R²cvMO = 0.772, F = 21.103, s² = 6.191 × 10-8).

Effects of dronedarone, amiodarone and their active metabolites on sequential metabolism of arachidonic acid to epoxyeicosatrienoic and dihydroxyeicosatrienoic acids.

Cardiac enzymes such as cytochrome P450 2J2 (CYP2J2) metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs), which in turn are metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). As EETs and less potent DHETs exhibit cardioprotective and vasoprotective functions, optimum levels of cardiac EETs are paramount in cardiac homeostasis. Previously, we demonstrated that dronedarone, amiodarone and their main metabolites, namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA), potently inhibit human cardiac CYP2J2-mediated astemizole metabolism in vitro. In this study, we investigated the inhibition of recombinant human CYP450 enzymes (rhCYP2J2, rhCYP2C8, rhCYP2C9)-mediated AA metabolism and human recombinant sEH (rhsEH)-mediated EET metabolism by dronedarone, amiodarone, NDBD and NDEA. A static model describing sequential metabolism was further developed to predict the aggregate effect of dual-inhibition of rhCYP2J2 and rhsEH on the fold-of 14,15-EET level (CEET'/CEET). Dronedarone, amiodarone and NDBD inhibit rhCYP2J2-mediated metabolism of AA to 14,15-EET with Ki values of 3.25, 5.48, 1.39µM respectively. Additionally, dronedarone, amiodarone, NDBD and NDEA inhibit rhsEH-mediated metabolism of 14,15-EET to 14,15-DHET with Ki values of 5.10, 13.08, 2.04, 1.88µM respectively. Based on static sequential metabolism modelling, dronedarone (CEET'/CEET=0.85), amiodarone (CEET'/CEET=0.48) and NDBD (CEET'/CEET=0.76) were predicted to decrease cardiac 14,15-EET level whereas NDEA (CEET'/CEET>35.5) was predicted to elevate it. Based on our novel findings, we postulate the differential cardiac exacerbation potential of dronedarone and amiodarone is partly associated with their differential inhibition potencies of cardiac CYP2J2 and sEH.

Effect of antiarrhythmic drugs on small conductance calcium - activated potassium channels.

Atrial fibrillation (AF) is the most common type of arrhythmia. Current pharmacological treatment for AF is moderately effective and/or increases the risk of serious ventricular adverse effects. To avoid ventricular adverse effects, a new target has been considered, the small conductance calcium-activated K+ channels (KCa2.X, SK channels). In the heart, KCa2.X channels are functionally more important in atria compared to ventricles, and pharmacological inhibition of the channel confers atrial selective prolongation of the cardiac action potential and converts AF to sinus rhythm in animal models of AF. Whether antiarrhythmic drugs (AADs) recommended for treating AF target KCa2.X channels is unknown. To this end, we tested a large number of AADs on the human KCa2.2 and KCa2.3 channels to assess their effect on this new target using automated whole-cell patch clamp. Of the AADs recommended for treatment of AF only dofetilide and propafenone inhibited hKCa2.X channels, with no subtype selectivity. The calculated IC50 were 90±10µmol/l vs 60±10µmol/l for dofetilide and 42±4µmol/l vs 80±20µmol/l for propafenone (hKCa2.3 vs hKCa2.2). Whether this inhibition has clinical importance for their antiarrhythmic effect is unlikely, as the calculated IC50 values are very high compared to the effective free therapeutic plasma concentration of the drugs when used for AF treatment, 40,000-fold for dofetilide and 140-fold higher for propafenone.

Preparation and Characterization of the Sulfobutylether-ß-Cyclodextrin Inclusion Complex of Amiodarone Hydrochloride with Enhanced Oral Bioavailability in Fasted State.

Amiodarone hydrochloride (AMD) is used in the treatment of a wide range of cardiac tachyarrhythmias, including both ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT). The objectives of this study were to improve the solubility and bioavailability in fasted state and to reduce the food effect of AMD by producing its inclusion complex with sulfobutylether-ß-cyclodextrin (SBE-ß-CD). The complex was prepared through a saturated water solution combined with the freeze-drying method and then characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and differential scanning calorimetry. The solubilities of AMD and its complex were 0.35 and 68.62 mg/mL, respectively, and the value of the inclusion complex was significantly improved by 196-fold compared with the solubility of free AMD. The dissolution of the AMD-SBE-ß-CD inclusion complex in four different dissolution media was larger than that of the commercial product. The cumulative dissolution was more than 85% in water, pH 4.5 NaAc-HAC buffer, and pH 1.2 HCl aqueous solution. Moreover, the pharmacokinetic study found that the C max, AUC(0-t), and AUC(0-∞) of the AMI-SBE-ß-CD inclusion complex had no significant difference in fasted and fed state, which indicated that the absorption of the AMI-SBE-ß-CD inclusion complex in fasted state was increased and not affected by food.

Effects of amiodarone combined with succinylmetroprolol sustained-release tablets on cardiac function in patients with atrial fibrillation and congestive heart failure / 中国生化药物杂志

Objective To investigate the clinical efficacy of amiodarone combined with succinylmetroprolol sustained-release tablets in patients with atrial fibrillation and congestive heart failure (CHF) complicated with atrial fibrillation (AF), and to observe the effect of amiodarone on heart function and ventricular rate.MethodsIn people's hospital of Anji county from June 2013 to June 2016 a total of 80 patients with atrial fibrillation and heart failure were enrolled in this study.The patients were randomly divided into control group and treatment group, 40 cases.(Ventricular rate, resting ventricular rate), cardiac function (ejection fraction-EF, stroke volume-SV, cardiac output-CO and left ventricular function) were measured before treatment and 6 months after treatment Ventricular end-diastolic early/late peak velocity ratio-VA/VE).The clinical efficacy and side effects during the treatment were statistically analyzed.ResultsThe ventricular rate and resting ventricular rate after exercise were significantly lower than those before treatment, but the ventricular rate and resting ventricular rate were significantly lower in the treatment group than those in the control group after 6 months of treatment (P<0.05).The VA/VE was significantly lower than that of the control group at 6 months after treatment, and the values of EF, SV and CO were significantly higher than those of the control group at 6 months after the treatment, SV, CO were significantly higher than the control group(P<0.05).Treatment group, the total effective rate was 92.5%, significantly higher than the control group 72.5%(χ2=7.77, P=0.02).No significant adverse reactions during treatment.ConclusionRapid ventricular rate of atrial fibrillation with congestive heart failure were treated with amiodarone combined with metoprolol succinate sustained release tablets can conducive to the ventricular rate and heart function of patients, and the effect is remarkable, safe, so it can be recommended as the drug of choice for clinical treatment of patients.

Effect of amiodarone hydrochloride treatment time on treatment success rate of ventricular premature beats after radiofrequency ablation / 中国生化药物杂志

Objective To investigate the effect of treatment time with amiodarone hydrochloride on treatment success rate of ventricular premature beats after radiofrequency ablation. Methods 46 cases of patients with frequent premature ventricular arrhythmia who received RFCA for the first time in department of gardiology,huangyan hospital of wenzhou medical university from February 2013 to February 2015 were selected,and randomly divided into two groups,the control group were treated with amiodarone hydrochloride for one months,the study group were treated with amiodarone hydrochloride for six months.Left ventricular function and structural parameters,heart rate variability were measured in two groups,the main clinical symptom scores,success rate,efficacy and safety were compared. Results Compared with before treatment,two groups of LVESD,LVEDD and PVC decreased (P<0.05),LVEF increased (P<0.05),SDNN,rMSSD,PNN50,LF and HF increased (P<0.05),scores of palpitation,shortness of breath,chest tightness and main symptom score decreased (P<0.05).Compared with the control group,level of PVC in the study group was lower (P<0.05),LVEF was higher(P<0.05),LVESD and LVEDD were had no significant differences,levels of SDNN,rMSSD,PNN50,LF,HF were higher (P<0.05),scores of palpitations,shortness of breath,chest tightness main symptom score were lower (P<0.05).There were no significant differences in the success rate, clinical efficacy and adverse reaction rate between the two groups. Conclusion The time of taking amiodarone after radiofrequency catheter ablation in patients with PVCs,but taking six months and medication compared to one month,can reduce heart palpitations,chest tightness and other symptoms,and improve left ventricular function,with high security.

Nursing of prevention of phlebitis caused by vein medication Amiodarone Hydrochloride / 中国生化药物杂志

Objective To research and analyze nursing measures of phlebitis caused by vein medication Amiodarone Hydrochloride. Methods 150 arrhythmias patients in the Traditional Chinese. Medicine Hospital of Wenling were selected as the subjects. The control group was given routine transfusion nursing, the experimental group was given comprehensive nursing intervention on the basis of the control group, saline irrigation before and after transfusion, observed the local reaction of patients, and controlled the concentration and external application of potato chips. Results After the corresponding nursing measures, in the control group, accounting for 46.7%. 35 cases of phlebitis occurred in the experimental group. The incidence of phlebitis in the experimental group was 16.0%, which was significantly lower than that (46.7%) in the control group, which was statistically significant (P<0.05). In the experimental group, the number of patients with I degree phlebitis was 8, and the proportion was 66.67%. In the control group, there were 7 cases of I degree phlebitis, accounting for 20%, which was statistically significant (P<0.05). In the experimental group, there were 4 cases of II degree phlebitis, the proportion was 33.33%, significantly lower than that (54.28%) of the control group (19 cases of II degree phlebitis) with statistical significance (P<0.05). Conclusion The application of comprehensive nursing measures in arrhythmia patients treated with Amiodarone Hydrochloride vein medication, could significantly reduce the occurrence of phlebitis and improve the curative effect with high safety and clinical significance.

Nursing of prevention of phlebitis caused by vein medication Amiodarone Hydrochloride / 中国生化药物杂志

Objective To research and analyze nursing measures of phlebitis caused by vein medication Amiodarone Hydrochloride. Methods 150 arrhythmias patients in the Traditional Chinese. Medicine Hospital of Wenling were selected as the subjects. The control group was given routine transfusion nursing, the experimental group was given comprehensive nursing intervention on the basis of the control group, saline irrigation before and after transfusion, observed the local reaction of patients, and controlled the concentration and external application of potato chips. Results After the corresponding nursing measures, in the control group, accounting for 46.7%. 35 cases of phlebitis occurred in the experimental group. The incidence of phlebitis in the experimental group was 16.0%, which was significantly lower than that (46.7%) in the control group, which was statistically significant (P<0.05). In the experimental group, the number of patients with I degree phlebitis was 8, and the proportion was 66.67%. In the control group, there were 7 cases of I degree phlebitis, accounting for 20%, which was statistically significant (P<0.05). In the experimental group, there were 4 cases of II degree phlebitis, the proportion was 33.33%, significantly lower than that (54.28%) of the control group (19 cases of II degree phlebitis) with statistical significance (P<0.05). Conclusion The application of comprehensive nursing measures in arrhythmia patients treated with Amiodarone Hydrochloride vein medication, could significantly reduce the occurrence of phlebitis and improve the curative effect with high safety and clinical significance.

Preparation of liposomal amiodarone and investigation of its cardiomyocyte-targeting ability in cardiac radiofrequency ablation rat model.

The objective of this study was to develop an amiodarone hydrochloride (ADHC)-loaded liposome (ADHC-L) formulation and investigate its potential for cardiomyocyte targeting after cardiac radiofrequency ablation (CA) in vivo. The ADHC-L was prepared by thin-film method combined with ultrasonication and extrusion. The preparation process was optimized by Box-Behnken design with encapsulation efficiency as the main evaluation index. The optimum formulation was quantitatively obtained with a diameter of 99.9±0.4 nm, a zeta potential of 35.1±10.9 mV, and an encapsulation efficiency of 99.5%±13.3%. Transmission electron microscopy showed that the liposomes were spherical particles with integrated bilayers and well dispersed with high colloidal stability. Pharmacokinetic studies were investigated in rats after intravenous administration, which revealed that compared with free ADHC treatment, ADHC-L treatment showed a 5.1-fold increase in the area under the plasma drug concentration-time curve over a period of 24 hours (AUC0-24 h) and an 8.5-fold increase in mean residence time, suggesting that ADHC-L could facilitate drug release in a more stable and sustained manner while increasing the circulation time of ADHC, especially in the blood. Biodistribution studies of ADHC-L demonstrated that ADHC concentration in the heart was 4.1 times higher after ADHC-L treatment in CA rat model compared with ADHC-L sham-operated treatment at 20 minutes postinjection. Fluorescence imaging studies further proved that the heart-targeting ability of ADHC-L was mainly due to the CA in rats. These results strongly support that ADHC-L could be exploited as a potential heart-targeting drug delivery system with enhanced bioavailability and reduced side effects for arrhythmia treatment after CA.

Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking.

The antiarrhythmic drug amiodarone delays cardiac repolarisation through inhibition of hERG-encoded potassium channels responsible for the rapid delayed rectifier potassium current (IKr). This study aimed to elucidate molecular determinants of amiodarone binding to the hERG channel. Whole-cell patch-clamp recordings were made at 37°C of ionic current (IhERG) carried by wild-type (WT) or mutant hERG channels expressed in HEK293 cells. Alanine mutagenesis and ligand docking were used to investigate the roles of pore cavity amino-acid residues in amiodarone binding. Amiodarone inhibited WT outward IhERG tails with a half-maximal inhibitory concentration (IC50) of ∼45nM, whilst inward IhERG tails in a high K(+) external solution ([K(+)]e) of 94mM were blocked with an IC50 of 117.8nM. Amiodarone's inhibitory action was contingent upon channel gating. Alanine-mutagenesis identified multiple residues directly or indirectly involved in amiodarone binding. The IC50 for the S6 aromatic Y652A mutation was increased to ∼20-fold that of WT IhERG, similar to the pore helical mutant S624A (∼22-fold WT control). The IC50 for F656A mutant IhERG was ∼17-fold its corresponding WT control. Computational docking using a MthK-based hERG model differentiated residues likely to interact directly with drug and those whose Ala mutation may affect drug block allosterically. The requirements for amiodarone block of aromatic residues F656 and Y652 within the hERG pore cavity are smaller than for other high affinity IhERG inhibitors, with relative importance to amiodarone binding of the residues investigated being S624A∼Y652A>F656A>V659A>G648A>T623A.

Multiple modes of inhibition of human cytochrome P450 2J2 by dronedarone, amiodarone and their active metabolites.

Dronedarone, a multiple ion channel blocker is prescribed for the treatment of paroxysmal and persistent atrial fibrillation. While dronedarone does not precipitate toxicities like its predecessor amiodarone, its clinical use has been associated with idiosyncratic hepatic and cardiac adverse effects and drug-drug interactions (DDIs). As dronedarone is a potent mechanism-based inactivator of CYP3A4 and CYP3A5, a question arose if it exerts a similar inhibitory effect on CYP2J2, a prominent cardiac CYP450 enzyme. In this study, we demonstrated that CYP2J2 is reversibly inhibited by dronedarone (Ki=0.034 µM), amiodarone (Ki=4.8µM) and their respective pharmacologically active metabolites namely N-desbutyldronedarone (NDBD) (Ki=0.55 µM) and N-desethylamiodarone (NDEA) (Ki=7.4 µM). Moreover, time-, concentration- and NADPH-dependent irreversible inactivation of CYP2J2 was investigated where inactivation kinetic parameters (KI, kinact) and partition ratio (r) of dronedarone (0.05 µM, 0.034 min(-1), 3.3), amiodarone (0.21 µM, 0.015 min(-1), 20.7) and NDBD (0.48 µM, 0.024 min(-1), 21.7) were observed except for NDEA. The absence of the characteristic Soret peak, lack of recovery of CYP2J2 activity upon dialysis, and biotransformation of dronedarone and NDBD to quinone-oxime reactive metabolites further confirmed the irreversible inactivation of CYP2J2 by dronedarone and NDBD is via the covalent adduction of CYP2J2. Our novel findings illuminate the possible mechanisms of DDIs and cardiac adverse effects due to both reversible inhibition and irreversible inactivation of CYP2J2 by dronedarone, amiodarone and their active metabolites.