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Leif Carlsson - One of the best experts on this subject based on the ideXlab platform.
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electrophysiological characterization and Antiarrhythmic efficacy of the mixed potassium channel blocking Antiarrhythmic Agent az13395438 in vitro and in vivo
Journal of Cardiovascular Pharmacology and Therapeutics, 2013Co-Authors: Ingemar Jacobson, Göran Duker, Gunilla Linhardt, Malin Florentzson, Emma Lindhardt, Annkristin Nordkam, Annika Astrand, Leif CarlssonAbstract:Objective:To examine the electrophysiological, hemodynamic, and Antiarrhythmic effects of the novel Antiarrhythmic Agent AZ13395438.Methods:The ion channel-blocking potency of AZ13395438 was assessed in Chinese hamster ovary cells stably expressing various human cardiac ion channels and in human atrial myocytes. The in vivo electrophysiological, hemodynamic, and Antiarrhythmic effects of intravenously administered AZ13395438 were examined in anesthetized rabbits, in anesthetized naive dogs, and in dogs subjected to rapid atrial pacing (RAP) for 8 weeks. Pharmacokinetic/pharmacodynamic (PKPD) modeling was applied to predict the potency of AZ13395438 in increasing atrial and ventricular refractoriness.Results:AZ13395438 potently and predominantly blocked the atrial repolarizing potassium currents IKur, IAch, and Ito in vitro. In vivo, AZ13395438 caused a concentration-dependent and selective increase in atrial refractoriness with no or small effects on ventricular refractoriness and repolarization and on he...
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assessment of the ion channel blocking profile of the novel combined ion channel blocker azd1305 and its proarrhythmic potential versus dofetilide in the methoxamine sensitized rabbit in vivo
Journal of Cardiovascular Pharmacology, 2009Co-Authors: Leif Carlsson, Birgit Andersson, Gunilla Linhardt, Lena LofbergAbstract:Abstract:AZD1305 is a novel Antiarrhythmic Agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in co
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characterization of the in vivo and in vitro electrophysiological effects of the novel Antiarrhythmic Agent azd7009 in atrial and ventricular tissue of the dog
Journal of Cardiovascular Pharmacology, 2006Co-Authors: Leif Carlsson, Denis Chartier, Stanley NattelAbstract:This study evaluated the effects of the novel Antiarrhythmic Agent AZD7009 on atrial and ventricular repolarization and on the Na+-current system, using Vmax as an index. Anesthetized dogs were infused with AZD7009 or azimilide to produce three pseudo steady-state plasma concentrations in vivo. Microelectrode techniques were used to record action potentials and effective refractory period (ERP) in vitro. Whereas AZD7009 concentration-dependently increased atrial ERP (AERP, by 48 +/- 7 milliseconds maximum, P < 0.001 versus vehicle), the increases in ventricular ERP (VERP, 8 +/- 4 milliseconds) and QT interval (2 +/- 5.5 milliseconds) were small and not concentration-dependent. For azimilide, the AERP increase was less, whereas VERP and QT increases were substantially larger than with AZD7009. In vitro, AZD7009 concentration-dependently reduced Vmax and increased action potential duration (APD). ERP was increased through APD lengthening and post-repolarization refractoriness. The suppression of Vmax, but not APD prolongation, showed frequency-dependence. APD and ERP increases were more pronounced in atrial than ventricular tissue: in atria, 2 microM AZD7009 increased APD90 and ERP from 224 +/- 7 to 318 +/- 7 milliseconds and 241 +/- 7 milliseconds to 378 +/- 17 milliseconds; versus 257 +/- 5 to 283 +/- 7 milliseconds and 253 +/- 12 to 300 +/- 11 milliseconds respectively in ventricles. Thus, AZD7009 potently and predominantly increases atrial refractoriness in the dog, with actions mediated by combined effects on repolarization and the Na+-current system.
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Assessment of the Proarrhythmic Potential of the Novel Antiarrhythmic Agent AZD7009 and Dofetilide in Experimental Models of Torsades De Pointes
Journal of cardiovascular electrophysiology, 2005Co-Authors: Leif Carlsson, Tengxian Liu, Peter R. Kowey, Gan-xin YanAbstract:Proarrhythmic Potential of the Novel Antiarrhythmic Agent AZD7009 and Dofetilide. Background: This study examined the proarrhythmic potential of the novel Antiarrhythmic Agent AZD7009 and dofetilide. Methods and Results: The electrophysiological and proarrhythmic effects of AZD7009 and dofetilide were assessed in the arterially perfused canine and rabbit left ventricular wedge preparation. The proarrhythmic potential of AZD7009, dofetilide, and azimilide was further assessed in the methoxamine-sensitized rabbit model of torsades de pointes (TdP) in vivo. AZD7009 lengthened the action potential duration (APD) and the QT interval in a bell-shaped manner (15.9 ± 1.3% in canine wedge and 46.1 ± 2.9% in rabbit wedge) occurring at 3 and 1 µM. In contrast, dofetilide did not show the bell-shaped concentration response and the QT interval was lengthened more extensively (27.7 ± 1.6% and 100.8 ± 10.0%). Furthermore, whereas dofetilide prolonged the midmyocardial and endocardial APD predominantly, resulting in an increased transmural dispersion of repolarization (TDR), AZD7009 prolonged the APD more homogenously in all cell layers. At 1 µM, AZD7009 produced phase 2 early afterdepolarizations (EADs) in 1/4 rabbit preparations but without ventricular R-on-T extrasystoles or TdP. In contrast, starting at 0.03 µM, dofetilide-induced EADs, R-on-T extrasystoles and TdP in 6/6, 5/6, and 4/6 preparations. Following intravenous infusion of AZD7009 (210 nmol/kg/minute), dofetilide (2 nmol/kg/minute) or azimilide (3.33 µmol/kg/minute), TdP was induced in 0/8, 5/8, and 5/8 rabbits (P = 0.026 vs AZD7009), respectively. In 5/5 rabbits, AZD7009 promptly suppressed TdP induced by dofetilide. Conclusions: In animal models of TdP, AZD7009 delays ventricular repolarization in a self-limited way associated with a low risk of repolarization-related proarrhythmia. (J Cardiovasc Electrophysiol, Vol. 16,
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electrophysiological and inotropic characterization of a novel class iii Antiarrhythmic Agent glg v 13 in the mammalian heart
Journal of Cardiovascular Pharmacology, 1996Co-Authors: Tamas Fazekas, Leif Carlsson, Kenneth Berlin, Benjamin J Scherlag, P Mabo, Herve Poty, Mattias Palmer, Eugene Patterson, G L GarrisonAbstract:GLG-V-13, a novel 3,7-diheterabicyclo(3.3.1)nonane, was examined both in vivo and in vitro to characterize its electrophysiological, hemodynamic, and inotropic properties. In anesthetized guinea pigs, GLG-V-13 [0.5-500 micrograms/kg intravenously (i.v.), n = 6] lengthened the epicardial monophasic action potential (MAP) duration, the atrioventricular (AV) conduction time and the RR interval in a dose-dependent manner. At the highest dose, these variables were increased by 30, 13, and 23%, respectively. No significant effects were noted on QRS duration or blood pressure (BP). In rabbit atrial and papillary muscle preparations, GLG-V-13 (0.32-3.2 mg/L) did not exert a negative inotropic action and in isolated rabbit cardiomyocytes the Agent blocked the rapidly activating delayed rectifier K+ current (IKr, EC50 = 48 micrograms/L). In 10 intact anesthetized mongrel dogs, the left ventricular (LV) endocardial MAP was measured during atrial pacing before and after administration of GLG-V-13 (3 and 6 mg/kg i.v.). As compared with the drug-free state, the Agent induced a significant prolongation of the MAP at all pacing frequencies (2.0-4.5 Hz). In 15 anesthetized dogs studied 1-4 days after two-stage ligation of the left anterior descending coronary artery (LAD), the Antiarrhythmic/proarrhythmic potential of GLG-V-13 was compared with that of lidocaine. ECG, His bundle, LV (IZepi), and composite and normal zone composite electrograms were recorded. Programmed electrical stimulation (PES) and burst pacing (4.0-7.0 Hz) were delivered to the right ventricular outflow tract. In the drug-free state, sustained monomorphic ventricular tachycardia (SMVT) was inducible in 6 dogs (6 of 15). After lidocaine, SMVT was induced in 7 other dogs (13 of 15). GLG-V-13 prevented induction of SMVT in 5 of 6 dogs; a proarrhythmic action was noted in 1 dog only. GLG-V-13 slowed the heart rate (HR), increased the AH and the HV intervals, prolonged the paced (2.5 Hz) QT interval, and increased the ventricular effective refractory period (VERP). These effects were associated with 2:1 block of late potentials in the IZepi electrograms, a phenomenon also observed during rapid atrial pacing (2.5-3.5 Hz), suggestive of a marked prolongation of refractoriness in the ischemically damaged myocardium. In light of the recent Cardiac Arrhythmia Suppression Trial (CAST) study, the Antiarrhythmic efficacy, together with the low proarrhythmic potential and lack of cardiodepressant properties of GLG-V-13, may merit further investigation of this novel class III Antiarrhythmic Agent.
Jules C Hancox - One of the best experts on this subject based on the ideXlab platform.
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effects of the class iii Antiarrhythmic Agent dofetilide uk 68 798 on l type calcium current from rabbit ventricular myocytes
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Ashok A Paul, Derek J Leishman, Harry J Witchel, Jules C HancoxAbstract:The methanesulphonanilide Agent dofetilide (UK-68,798) exerts Class III Antiarrhythmic effects by inhibiting the cardiac rapid delayed rectifier potassium current (I(Kr)) encoded by HERG. The aim of the present study was to determine whether dofetilide also exhibits Class IV (L-type calcium-channel blocking) effects. L-type calcium current (I(Ca,L)) was measured from rabbit isolated ventricular myocytes, using the whole-cell patch-clamp technique under selective recording conditions. Positive control experiments demonstrated inhibition of I(Ca,L) elicited by pulses to + 10 mV by both nifedipine and externally applied Ni2+ ions. Three concentrations of dofetilide were tested: 100 nM, 1 microM and 10 microM. I(Ca,L) magnitude was not significantly reduced by any of the concentrations tested (P > 0.05; n = minimum of seven cells per drug concentration). The inactivation time-course of I(Ca,L) was also unaffected by 10 microM dofetilide. Heterologously expressed HERG current (I(HERG)) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 microM dofetilide, with inhibition at 1 microM not significantly different from 100% (P > 0.1). It is concluded that dofetilide produced no I(Ca,L) blocking effects at concentrations up to and exceeding that required for maximal I(HERG) inhibition. The findings support the notion that dofetilide is a highly selective Class III Antiarrhythmic Agent, devoid of Class IV Antiarrhythmic activity.
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high affinity herg k channel blockade by the Antiarrhythmic Agent dronedarone resistance to mutations of the s6 residues y652 and f656
Biochemical and Biophysical Research Communications, 2004Co-Authors: J M Ridley, Harry J Witchel, James T Milnes, Jules C HancoxAbstract:Abstract Pharmacological inhibition of human-ether-a-go-go-related gene (HERG) K + channels by structurally and therapeutically diverse drugs is associated with the ‘acquired’ form of long QT syndrome and with potentially lethal cardiac arrhythmias. Two aromatic amino-acid residues (Y652 and F656) on the inner (S6) helices are considered to be key constituents of a high affinity drug binding site within the HERG channel pore cavity. Using wild-type (WT) and mutant HERG channels expressed in mammalian cell lines, we have investigated HERG channel current ( I HERG ) blockade at 37 ± 1 °C by dronedarone (DRONED), a non-iodinated analogue of the Class III Antiarrhythmic Agent amiodarone (AMIOD). Under our conditions WT I HERG tails, measured at −40 mV following activating pulses to +30 mV, were blocked with IC 50 values of ∼59 and 70 nM for DRONED and AMIOD, respectively. I HERG inhibition by DRONED was contingent upon channel gating, with block developing rapidly on membrane depolarization, but with no preference for activated over inactivated channels. High external [K + ] (94 mM) reduced the potency of I HERG inhibition by both DRONED and AMIOD. Strikingly, mutagenesis to alanine of the S6 residue F656 (F656A) failed to eliminate blockade by both DRONED and AMIOD, whilst Y652A had comparatively little effect on DRONED but some effect on AMIOD. These findings demonstrate that high affinity drug blockade of I HERG can occur without a strong dependence on the Y652 and F656 aromatic amino-acid residues.
Rodney H Falk - One of the best experts on this subject based on the ideXlab platform.
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dofetilide a new pure class iii Antiarrhythmic Agent
American Heart Journal, 2000Co-Authors: Rodney H Falk, Jeanne M DecaraAbstract:Abstract Background Although there are a variety of Antiarrhythmic Agents used for the treatment of atrial fibrillation of flutter, each drug has drawbacks, and room exists for new pharmacologic Agents. Dofetilide, a pure class III Agent, has recently been approved by the Food and Drug Administration for therapy of these arrhythmias and is reviewed. Methods Data for dofetilide, published in full or in abstract form, were reviewed, concentrating on the properties related to its efficacy for the therapy of supraventricular arrhythmias. Results Results from animal and human studies indicate that dofetilide, a renally excreted drug, has pure class III properties related to blockade of the delayed rectifier potassium current. It is effective for the therapy of atrial arrhythmias, particularly atrial fibrillation and flutter, and has no demonstrable negative inotropic effect. Despite an incidence of torsades de pointes of approximately 2% in patients with impaired ventricular function, dofetilide exhibited no association with an increased mortality rate when studied in a large series of patients with a reduced ejection fraction. Conclusions Dofetilide's electrophysiologic and clinical profiles suggest that it will be safe and clinically useful for the termination and prevention of atrial fibrillation or flutter, even in patients with impaired ventricular function. (Am Heart J 2000;140:697-706.)
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intravenous dofetilide a class iii Antiarrhythmic Agent for the termination of sustained atrial fibrillation or flutter
Journal of the American College of Cardiology, 1997Co-Authors: Rodney H Falk, Arthur Pollak, Steven N Singh, Tilman FriedrichAbstract:Abstract Objectives. This study sought to determine the safety and efficacy of a single bolus of intravenous dofetilide, a pure class III Antiarrhythmic Agent, for the termination of sustained atrial fibrillation or flutter. Background. Dofetilide is a highly selective blocker of the rapid component of the delayed rectifier current causing action potential prolongation. These effects, and preliminary clinical data, suggest that it may be effective in the treatment of atrial fibrillation and flutter. Methods. Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) were entered into a double-blind, randomized multicenter study of one of two doses of dofetilide (4 or 8 μg/kg body weight) or placebo. Results. Dofetilide effectively terminated the arrhythmia in 31% of patients receiving 8 μg/kg, a statistically significant difference from those receiving 4 μg/kg (conversion rate 12.5%, p Conclusions. Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm. However, its efficacy is greater in flutter—a response that contrasts with the poorer response seen with class I Agents. This finding potentially represents an important advance in the pharmacologic termination of atrial flutter. (J Am Coll Cardiol 1997;29:385–90)
H S Rasmussen - One of the best experts on this subject based on the ideXlab platform.
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dofetilide a novel class iii Antiarrhythmic Agent
Journal of Cardiovascular Pharmacology, 1992Co-Authors: H S Rasmussen, M J Allen, K J Blackburn, Ghazwan Butrous, H W DalrympleAbstract:Dofetilide is a potent and selective class III Antiarrhythmic Agent that is under development for the treatment of re-entrant tachyarrhythmias (ventricular tachycardia/ventricular fibrillation, atrial fibrillation/atrial flutter, and paraoxysmal supraventricular tachycardia). In animal studies, dofetilide selectively inhibits the rapid component of the time-dependent outward potassium current (IKr) and therefore increases the effective refractory period and action potential duration without affecting the fast inward sodium current. Studies in dogs have shown that dofetilide (a) prolongs the effective refractory period in a dose-dependent manner, (b) elevates ventricular fibrillation threshold, (c) facilitates conversion of electrically induced ventricular fibrillation or fibrilloflutter to sinus rhythm, (d) does not influence conduction within the His-Purkinje system or within the myocardium, (e) does not impair cardiac contractility, and (f) reduces dispersion of ventricular repolarization. Dofetilide has been administered to healthy volunteers as well as to patients with ischemic heart disease or with supraventricular arrhythmias; the compound has generally been well tolerated. Side effects have occasionally been reported, but have generally been transient and mild and occur in placebo-treated subjects as well. No clinically significant changes in laboratory safety tests have been detected. The pharmacokinetic profile of dofetilide both in healthy volunteers and patients includes a linear dose-plasma concentration relationship and also a linear plasma concentration-QTc relationship. The terminal plasma elimination half-life is approximately 9-10 h and systemic bioavailability in the region of 100%. The elimination pattern is balanced, with 50% being excreted unchanged via the kidney, the remaining 50% being metabolized in the liver to inactive metabolites, with greater than 90% of circulating drug-related material being unchanged dofetilide. After intravenous administration of the compound, a slight hysteresis in the plasma drug level-QTc relationship has been detected. Pharmacodynamic data demonstrate dose- and concentration-dependent effects on myocardial repolarization as evidenced by prolongations of the QTc interval. This is reflected in significant prolongations in the effective and functional refractory periods and monophasic action potential duration throughout the myocardium. No effects on sinus node function, conduction parameters, or cardiac contractility have been detected in any of the clinical studies, supporting the contention that dofetilide is a highly selective class III Antiarrhythmic Agent.
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pharmacokinetic and pharmacodynamic effects of uk 68 798 a new potential class iii Antiarrhythmic drug
British Journal of Clinical Pharmacology, 1991Co-Authors: M Sedgwick, H S Rasmussen, D Walker, S M CobbeAbstract:1. The pharmacokinetic and pharmacodynamic properties of UK-68,798, a novel selective potential class III Antiarrhythmic Agent, were studied in 18 patients with coronary artery disease. Three groups of four patients received intravenous doses of 1.5, 3.0 and 4.5 micrograms kg-1 respectively over 10 min. 2. UK-68,798 caused a mean increase in electrocardiographic QTc interval of 41, 40 and 81 ms, and in uncorrected QT interval of 36, 52 and 83 ms at the three dose levels. There were no significant effects on heart rate, blood pressure, PR interval and QRS duration. UK-68,798 was well tolerated with no significant adverse effects. 3. A dosing regimen using a loading infusion of two thirds of the total dose over 15 min with the remainder given over the following 45 min in six patients produced stable plasma concentrations and lengthening in QTc during the maintenance infusion. 4. There was a linear correlation between plasma concentration and change in QTc. The drug exhibited first-order kinetics with a mean clearance of 4.7 +/- 1.2 ml min-1 kg-1 and a mean terminal plasma half-life of 9.7 h. 5. UK-68,798 warrants further study as a selective potential Class III Antiarrhythmic Agent.
Joseph J Lynch - One of the best experts on this subject based on the ideXlab platform.
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use dependent effects of the class iii Antiarrhythmic Agent ne 10064 azimilide on cardiac repolarization block of delayed rectifier potassium and l type calcium currents
Journal of Cardiovascular Pharmacology, 1995Co-Authors: Bernard Fermini, Joseph J Lynch, Nancy K Jurkiewicz, Brian Jow, Peter J Guinosso, Elizabeth P Baskin, Joseph J SalataAbstract:We studied the effects of NE-10064 (azimilide), a new Antiarrhythmic Agent reported to be a selective blocker of the slowly activating component of the delayed rectifier, IKs. In ferret papillary muscles, NE-10064 increased effective refractory period (ERP) and decreased isometric twitch tension in a concentration-dependent manner (0.3-30 microM). Increases in ERP showed reverse use-dependence, and were greater at 1 than at 3 Hz. In contrast, changes in tension were use dependent, with larger decreases observed at 3 than at 1 Hz. In guinea pig ventricular myocytes, NE-10064 (0.3-3 microM) significantly prolonged action potential duration (APD) at 1 Hz. At 3 Hz, NE-10064 (0.3-1 microM) increased APD only slightly, and at 10 microM decreased APD and the plateau potential. NE-10064 potently blocked the rapidly activating component of the delayed rectifier, IKr (IC50 0.4 microM), and inhibited IKs (IC50 3 microM) with nearly 10-fold less potency. NE-10064 (10 microM) did not block the inward rectifier potassium current (IKl). NE-10064 (10 microM) blocked the L-type calcium current (ICa) in a use-dependent manner; block was greater at 3 than at 1 Hz. We conclude that (a) NE-10064's block of potassium currents is relatively selective for IKr over IKs, (b) NE-10064 inhibits ICa in a use-dependent fashion, and (c) NE-10064's effects on ERP and tension in papillary muscle as well as APD and action potential plateau level in myocytes may be explained by its potassium and calcium channel blocking properties.
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demonstration of proarrhythmic activity with the class ic Antiarrhythmic Agent encainide in a canine model of previous myocardial infarction
Journal of Cardiovascular Pharmacology, 1993Co-Authors: Audrey A Wallace, Theresa Kothstein, John R Gehret, Raymond F Stupienski, Joseph J LynchAbstract:: The Antiarrhythmic efficacy and proarrhythmic potential of the class IC Antiarrhythmic Agent encainide were assessed in subacute and chronic postinfarction canine models, respectively. In conscious dogs with spontaneous premature ventricular complexes (PVCs) at 48 h after anterior myocardial infarction (MI), cumulative intravenous (i.v.) administration of 1.0 and 3 mg/kg encainide significantly reduced PVC frequency. However, in anesthetized dogs studied more chronically after anterior MI (range 8-44 days), i.v. administration of 0.3-3 mg/kg encainide resulted in induction of new ventricular tachyarrhythmias by programmed ventricular stimulation in 6 of 10 dogs with no inducible arrhythmias prior to encainide. Newly induced arrhythmias after encainide administration included unimorphic and polymorphic ventricular tachycardia (VT) as well as VT degenerating rapidly into ventricular fibrillation (VF). The incidences of new arrhythmia induction after cumulative i.v. administration of encainide were 3 of 9 after 0.3 mg/kg i.v. encainide, 4 of 9 after 1.0 mg/kg i.v. encainide, and 5 of 10 after 3.0 mg/kg i.v. encainide. Time elapsed between MI and electrophysiologic testing tended to predict proarrhythmic response to encainide, with the six preparations with newly induced arrhythmias tested earlier than the four preparations that remained nonresponsive to postencainide programmed stimulation (13.2 +/- 3.1 vs. 26.5 +/- 6.5 days postinfarction, respectively, p = 0.07). There was also a trend toward larger underlying anterior MIs in the six preparations with newly induced arrhythmias as compared with the four preparations that remained nonresponsive to postencainide programmed stimulation (13.2 +/- 2.9 vs. 7.5 +/- 2.1% of left ventricle, respectively, p = 0.19).(ABSTRACT TRUNCATED AT 250 WORDS)