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Stanley Nattel - One of the best experts on this subject based on the ideXlab platform.
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Modulation of Flecainide's cardiac sodium channel blocking actions by extracellular sodium: a possible cellular mechanism for the action of sodium salts in Flecainide cardiotoxicity.
The Journal of pharmacology and experimental therapeutics, 1993Co-Authors: Suzanne Ranger, R Sheldon, B. Fermini, Stanley NattelAbstract:Sodium salts reverse the clinical cardiotoxicity of class 1c antiarrhythmic agents, but the underlying mechanisms are unknown. We studied the modulation of Flecainide's action by changes in extracellular sodium concentration ([Na+]e) produced by isotonic substitution of choline for sodium. Increasing [Na+]e by 25 mM attenuated the depressant effects of 3.2 microM Flecainide of Vmax in canine cardiac Purkinje fibers, whereas decreasing [Na+]e enhanced drug action. The voltage dependence of Vmax was shifted by Flecainide (activation potential for 50% decrease in Vmax, V50: -77.4 +/- 3.5 mV at 3.2 microM Flecainide) compared to control (V50: -73.7 +/- 2.8 mV, mean +/- S.D., P < .05). Increasing [Na+]e in the presence of Flecainide returned V50 toward control (-75.8 +/- 3.1 mV, P < .05 vs. Flecainide at normal [Na+]e). Increased [Na+]e shifted the Flecainide concentration-response curve to the right (EC50 19.0 microM) compared to normal (EC50 14.6 microM) and low (EC50 10.8 microM) [Na+]e. [Na+]e modulated the concentration-dependent displacement by Flecainide of [3H]batrachotoxin-A-benzoate, with increased [Na+]e shifting the binding curve to the right and decreased [Na+]e shifting it to the left compared to normal [Na+]e. There was a strong linear correlation (r = 0.99) between Flecainide's EC50 for Vmax depression and its IC50 for [3H]batrachotoxin-A-benzoate displacement at various [Na+]e. We conclude that [Na+]e modulates Flecainide's interaction with the sodium channel. Sodium's ability to displace blocking drug from the sodium channel may underlie the efficacy of sodium salts in treating Flecainide toxicity, and could play a similar role in antagonizing cardiotoxicity of other class 1 compounds.
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mechanism of Flecainide s antiarrhythmic action in experimental atrial fibrillation
Circulation Research, 1992Co-Authors: Zhiguo Wang, Pierre Page, Stanley NattelAbstract:Class Ic antiarrhythmic drugs are effective in the treatment of atrial fibrillation, but their mechanism of action is unknown. In previous work, we have found that Flecainide causes tachycardia-dependent increases in atrial action potential duration (APD) and effective refractory period (ERP) by reducing APD accommodation to heart rate. The present study was designed to evaluate the efficacy and mechanisms of action of Flecainide in an experimental model of sustained atrial fibrillation (AF). AF was produced by a brief burst of atrial pacing in the presence of vagal stimulation and persisted spontaneously until vagal stimulation was stopped. The actions of Flecainide at two dose levels were compared with those of isotonic glucose placebo in each dog, with a randomized order of blinded drug administration. Flecainide terminated AF in all 16 dogs, while glucose was effective in none (p less than 0.0001). Flecainide increased atrial ERP and reduced conduction velocity in a tachycardia-dependent manner. Doses of Flecainide that converted AF resulted in larger changes in ERP than in conduction velocity, increasing the minimum path-length capable of supporting reentry (wavelength). In addition, Flecainide reduced regional heterogeneity in ERP and wavelength, an action opposite that of vagal stimulation. Atrial epicardial mapping with a 112-electrode atrial array was used to study the mechanism of Flecainide action on AF. Under control conditions, multiple small zones of reentry coexisted. Flecainide progressively increased the size of reentry circuits, decreased their number, and slowed the frequency of atrial activation until the arrhythmia finally terminated; all changes were compatible with an increase in wavelength. We conclude that Flecainide terminates atrial fibrillation in this experimental model by causing tachycardia-dependent increases in atrial ERP, which increase the wavelength at the rapid rates characteristic of AF to the point that the arrhythmia can no longer sustain itself.
Masato Homma - One of the best experts on this subject based on the ideXlab platform.
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Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide.
Biological & pharmaceutical bulletin, 2019Co-Authors: Kosuke Doki, Sándor Apáti, Takeshi Sakata, Masato HommaAbstract:Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of Flecainide remains unclear except that Flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of Flecainide, we conducted in vitro interaction studies of Flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that Flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2- and hMATE2-K-mediated transport. For investigating Flecainide as a substrate of hMATE1, the accumulation of Flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that Flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 ± 23.9 vs. 11.8 ± 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that Flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug-drug interaction for renal excretion of Flecainide. However, in vivo drug-drug interaction studies of Flecainide with substrates of hMATE1 may be needed because Flecainide has the potential to inhibit hMATE1.
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effects of cyp2d6 genotypes on age related change of Flecainide metabolism involvement of cyp1a2 mediated metabolism
British Journal of Clinical Pharmacology, 2009Co-Authors: Kosuke Doki, Masato Homma, Keisuke Kuga, Kazutaka Aonuma, Yukinao KohdaAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2D6 is a main enzyme for Flecainide metabolism in terms of the conversion of Flecainide to m-O-dealkylated Flecainide (MODF). • Age-related reduction of Flecainide metabolism cannot be explained by CYP2D6 alone, the activity of which is known to be practically unchanged by ageing. • Flecainide metabolites including MODF have been found in plasma obtained from CYP2D6 poor metabolizers, suggesting that other CYPs may be involved in Flecainide metabolism. WHAT THIS STUDY ADDS • Age-related reduction in metabolic clearance of Flecainide was remarkable in patients carrying CYP2D6 mutant alleles. • An in vitro study using human liver microsomes revealed that CYP1A2 was involved in MODF formation in addition to CYP2D6. • It is suggested that CYP1A2 plays an important role in Flecainide metabolism in patients with poor CYP2D6-mediated metabolism. AIMS The aim of this study was to clarify the effects of CYP2D6 genotype on age-related change in Flecainide metabolism in patients with supraventricular tachyarrhythmias. An in vitro study using microsomes was performed to identify other CYPs responsible for age-related change in Flecainide metabolism. METHODS The study population comprised 111 genotyped patients: CYP2D6-homozygous extensive metabolizers (hom-EMs, n= 34), heterozygous EMs (het-EMs, n= 56), and intermediate and poor metabolizers (IMs/PMs, n= 21). Serum concentrations of Flecainide and its metabolites [m-O-dealkylated Flecainide (MODF) and m-O-dealkylated lactam of Flecainide] were determined by use of a high-performance liquid chromatography. Metabolic ratio (MR) was expressed as serum concentrations of Flecainide to its metabolites. In vitro formation of MODF was examined in human liver microsomes and cDNA-expressed CYP isoforms. RESULTS MR was higher in elderly patients (≥70 years) than in middle-aged patients (<70 years). The increase of MR in elderly patients differed among CYP2D6 genotypes: 1.6-fold in het-EMs [4.3, 95% confidence interval (CI) 2.8, 5.7 vs. 2.7, 95% CI 2.3, 3.1, P < 0.05], 1.5-fold in IMs/PMs (6.0, 95% CI 4.5, 7.6 vs. 4.1, 95% CI 2.9, 5.4, P < 0.05), and no change in hom-EMs. The in vitro study using microsomes revealed that both CYP2D6 and CYP1A2 were involved in the formation of MODF. MODF formation in CYP2D6 PM microsomes increased as CYP1A2 activity increased. CONCLUSIONS The results suggest that patients with poor CYP2D6-mediated metabolism (het-EMs and IMs/PMs) showed age-related reduction in Flecainide metabolism because metabolism was taken over by CYP1A2, whose activity decreases with age.
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Assessment of serum Flecainide trough levels in patients with tachyarrhythmia.
The Journal of pharmacy and pharmacology, 2005Co-Authors: Masato Homma, Kosuke Doki, Kumi Katori, Keisuke Kuga, Iwao Yamaguchi, Kenji Sugibayashi, Yukinao KohdaAbstract:The reported therapeutic range for trough Flecainide concentration is 200-1000 ng mL - 1 . Severe adverse events, such as ventricular arrhythmias, have occurred occasionally in patients whose serum Flecainide exceeded 1000ng mL - 1 . However, the lower limit remains controversial. We have evaluated blood Flecainide concentrations in patients with tachyarrhythmia who received the drug to control palpitation. We measured the Flecainide trough levels and incidence and frequency of palpitation of 44 outpatients receiving oral Flecainide (150-300 mg daily). Mean serum Flecainide trough concentrations differed significantly between patients with (n=14) and without (n=30) palpitation (259.5 ′ 85.2 vs 462.2 ′ 197.7 ng mL - 1 , P
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Liquid chromatographic determination of unbound Flecainide in therapeutic drug monitoring
Journal of pharmaceutical and biomedical analysis, 2003Co-Authors: Kumi Katori, Masato Homma, Keisuke Kuga, Iwao Yamaguchi, Kenji Sugibayashi, Yukinao KohdaAbstract:Abstract An assay method was developed for determining unbound Flecainide in serum by reversed phase-high performance liquid chromatography (HPLC). Serum water including unbound Flecainide was separated by ultrafiltration of the serum sample and subjected to C 18 -cartridge extraction followed by HPLC analysis. The recovery of Flecainide from serum water was greater than 93%. The coefficient variations for intra- and inter-day assay of Flecainide were smaller than 2.4 and 3.7%, respectively. We applied the method to determining unbound Flecainide in serum samples collected from 20 patients receiving oral Flecainide (150–300 mg/day) for tachyarrhythmia. Total and unbound concentrations for serum Flecainide were 403.5±200.8 ng/ml and 180.2±95.0 ng/ml, respectively. Linear relationship was observed between total and unbound concentrations ( r =0.978, P 1 -acid glycoprotein (
Bjorn C. Knollmann - One of the best experts on this subject based on the ideXlab platform.
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Calmodulin Potentiates RyR2 Block and Ca Wave Suppression by Flecainide
Biophysical Journal, 2015Co-Authors: Nieves Gomez-hurtado, Derek R. Laver, Bjorn C. KnollmannAbstract:Flecainide, a dual sodium channel and RyR2 Ca release channel blocker classified as a class Ic antiarrhythmic agent, has been used to suppress ventricular arrhythmias caused by spontaneous Ca release from the sarcoplasmic reticulum in animal models and humans. Since Flecainide exhibits much lower antiarrhythmic potency in isolated cells and single RyR2 in vitro than in vivo, whether RyR2 block contributes to its antiarrhythmic mechanism of action has remained controversial. Here we test the hypothesis that loss of Calmodulin (CaM), a physiological binding partner of RyR2 Ca release channels, is responsible for the discrepancy of in vivo and in vitro results.Using single channels isolated from sheep hearts and incorporated into lipid bilayers, we constructed concentration-response curves of Flecainide in the presence and absence of physiological CaM concentrations (100nM). Presence of CaM potentiated the action of Flecainide on single RyR2 channels, with 3-fold increase in potency (IC50 Flecainide= 8.6 µM vs. IC50 Flecainide + CaM= 2.8 µM) and a modest increase in Emax. We next tested Flecainide in permeabilized ventricular myocytes isolated from calsequestrin knockout mice, an established genetic model of Ca-release triggered ventricular arrhythmia, and from C57Bl6 wild-type mice. Addition of 100 nM CaM doubled both the potency (from 3 µM to 1.4 µM) and efficacy (from 40% to 80% inhibition) of Ca wave suppression by Flecainide in calsequestrin KO cells. Moreover, in wild type cells, Flecainide had no effect in absence of CaM, whereas in the presence of CaM, Flecainide exhibited a modest effect in waves suppression with 25% inhibition of Ca waves and IC50 = 1 µM. Thus, the presence of physiological concentrations of Calmodulin is critical for Flecainide's block of RyR2 channels and therefore its antiarrhythmic effect.
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Mechanism of Antiarrhythmic Effects of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia
Circulation research, 2011Co-Authors: Hiroshi Watanabe, Derek S Steele, Bjorn C. KnollmannAbstract:To The Editor: We read with interest the recent article by Liu et al, in Circulation Research , on the mechanism underlying the antiarrhythmic effects of Flecainide in catecholaminergic polymorphic ventricular tachycardia (CPVT).1 They conclude that Na+ channel block but not inhibition of the cardiac ryanodine receptor (RyR2) has a key role in the antiarrhythmic effects of Flecainide in CPVT, because they found Flecainide suppresses triggered activity without a reduction of Ca2+ waves in RyR2R4496C+/− mice. However, we have previously reported that Flecainide directly inhibits RYR2 and thereby prevents CPVT.2 Evidence that Flecainide reduces the frequency of triggered beats to a greater extent than that of spontaneous Ca2+ waves in cardiac calsequestrin Casq2 null (Casq2−/−) mice, another model of CPVT, led us to propose a dual mode of Flecainide action in CPVT: suppression of …
Edward L.c. Pritchett - One of the best experts on this subject based on the ideXlab platform.
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Flecainide acetate prevents recurrence of symptomatic paroxysmal supraventricular tachycardia. The Flecainide Supraventricular Tachycardia Study Group.
Circulation, 1991Co-Authors: Richard W. Henthorn, Albert L. Waldo, Jeffrey L. Anderson, Edward M. Gilbert, Barry L. Alpert, Anil K. Bhandari, Ronald W. Hawkinson, Edward L.c. PritchettAbstract:Oral Flecainide acetate was administered to 34 patients with documented symptomatic paroxysmal supraventricular tachycardia (PSVT) with a double-blind, placebo-controlled, 8-week crossover trial design. PSVT was defined as a regular tachycardia of at least 120 beats/min without evidence of atrioventricular dissociation. The study required considerable patient cooperation. Patients first entered a 4-week qualifying phase followed by a 3-week, open label, Flecainide dose-ranging phase. They were then randomized in a blind fashion to receive either placebo or tolerated Flecainide dose for an 8-week treatment period and then crossed over after four symptomatic documented episodes of PSVT or at the end of the treatment period. By all efficacy parameters analyzed, Flecainide was superior to placebo. Flecainide was associated with an actuarial 79% freedom from symptomatic PSVT events compared with only 15% on placebo at 60 days (p less than 0.001). Of the 34 patients, 29 had recurrence of symptomatic PSVT at least once during the placebo phase; only eight patients had a recurrence during the Flecainide phase (p less than 0.001). The median time to the first symptomatic PSVT event was 11 days in the placebo group and greater than 55 days in the Flecainide group (p less than 0.001). Likewise, the interval between attacks was a median of 12 days on placebo compared with more than 55 days on Flecainide (p less than 0.001). Finally, the Flecainide slowed symptomatic PSVT heart rates to 143 +/- 12 beats/min from 178 +/- 12 on placebo (p less than 0.02) in the seven patients who had events in the placebo and Flecainide treatment phases.(ABSTRACT TRUNCATED AT 250 WORDS)
Mark L Bannister - One of the best experts on this subject based on the ideXlab platform.
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effect of Flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor
British Journal of Pharmacology, 2016Co-Authors: Mark L Bannister, Lowri N Thomas, Anita Alvarezlaviada, Sammy A Mason, Sharon Louise Coleman, Christo L Du Plessis, Abbygail T Moran, David Neillhall, Hasnah Osman, Mark C BagleyAbstract:Background and Purpose Flecainide is a use-dependent blocker of cardiac Na+ channels. Mechanistic analysis of this block showed that the cationic form of Flecainide enters the cytosolic vestibule of the open Na+ channel. Flecainide is also effective in the treatment of catecholaminergic polymorphic ventricular tachycardia but, in this condition, its mechanism of action is contentious. We investigated how Flecainide derivatives influence Ca2+-release from the sarcoplasmic reticulum through the ryanodine receptor channel (RyR2) and whether this correlates with their effectiveness as blockers of Na+ and/or RyR2 channels. Experimental Approach We compared the ability of fully charged (QX-FL) and neutral (NU-FL) derivatives of Flecainide to block individual recombinant human RyR2 channels incorporated into planar phospholipid bilayers, and their effects on the properties of Ca2+ sparks in intact adult rat cardiac myocytes. Key Results Both QX-FL and NU-FL were partial blockers of the non-physiological cytosolic to luminal flux of cations through RyR2 channels but were significantly less effective than Flecainide. None of the compounds influenced the physiologically relevant luminal to cytosol cation flux through RyR2 channels. Intracellular Flecainide or QX-FL, but not NU-FL, reduced Ca2+ spark frequency. Conclusions and Implications Given its inability to block physiologically relevant cation flux through RyR2 channels, and its lack of efficacy in blocking the cytosolic-to-luminal current, the effect of QX-FL on Ca2+ sparks is likely, by analogy with Flecainide, to result from Na+ channel block. Our data reveal important differences in the interaction of Flecainide with sites in the cytosolic vestibules of Na+ and RyR2 channels.
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the mechanism of Flecainide action in cpvt does not involve a direct effect on ryr2
Circulation Research, 2015Co-Authors: Mark L Bannister, Lowri N Thomas, Markus B Sikkel, Saptarshi Mukherjee, Chloe Maxwell, Kenneth T Macleod, Christopher H George, Alan J WilliamsAbstract:Rationale: Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of Flecainide in CPVT is because of the combined actions of direct blockade of ryanodine receptors (RyR2) and Na+ channel inhibition. However, there is presently no direct evidence to support the notion that Flecainide blocks RyR2 Ca2+ flux in the physiologically relevant (luminal-to-cytoplasmic) direction. The mechanism of Flecainide action remains controversial. Objective: To examine, in detail, the effect of Flecainide on the human RyR2 channel and to establish whether the direct blockade of physiologically relevant RyR2 ion flow by the drug contributes to its therapeutic efficacy in the clinical management of CPVT. Methods and Results: Using single-channel analysis, we show that, even at supraphysiological concentrations, Flecainide did not inhibit the physiologically relevant, luminal-to-cytosolic flux of cations through the channel. Moreover, Flecainide did not alter RyR2 channel gating and had negligible effect on the mechanisms responsible for the sarcoplasmic reticulum charge-compensating counter current. Using permeabilized cardiac myocytes to eliminate any contribution of plasmalemmal Na+ channels to the observed actions of the drug at the cellular level, Flecainide did not inhibit RyR2-dependent sarcoplasmic reticulum Ca2+ release. Conclusions: The principal action of Flecainide in CPVT is not via a direct interaction with RyR2. Our data support a model of Flecainide action in which Na+-dependent modulation of intracellular Ca2+ handling attenuates RyR2 dysfunction in CPVT.