Propafenone is a currently used medicine to treat atrial fibrillation and is a mixture of two compounds, (R)-propafenone and (S)-propafenone. In this study, the investigators will randomize participants to (R)-propafenone, (S)-propafenone, or placebo.

开始日期2016-10-31

申办/合作机构

Vanderbilt University

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100 项与 (R)-Propafenone(Vanderbilt University) 相关的临床结果

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100 项与 (R)-Propafenone(Vanderbilt University) 相关的转化医学

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项与 (R)-Propafenone(Vanderbilt University) 相关的文献（医药）

2014-04-01·Circulation: Arrhythmia and Electrophysiology1区 · 医学

Suppression of Spontaneous Ca Elevations Prevents Atrial Fibrillation in Calsequestrin 2-Null Hearts

1区 · 医学

Article

作者: Venkataraman, Raghav ; Darbar, Dawood ; Savio-Galimberti, Eleonora ; Kannankeril, Prince J. ; Faggioni, Michela ; Knollmann, Björn C. ; Hwang, Hyun Seok

Background—Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy.Methods and Results— Compared with wild-type Casq2 +/+ mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2 −/− mice and in isolated Casq2 −/− hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein region. Ca and voltage mapping demonstrated diastolic subthreshold spontaneous Ca elevations (SCaEs) and delayed afterdepolarizations whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R-propafenone (3 μmol/L) significantly reduced frequency and amplitude of SCaEs and delayed afterdepolarizations in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaEs and delayed afterdepolarizations and failed to prevent AF. Conclusions—Loss of Casq2 increases risk of AF by promoting regional SCaEs and delayed afterdepolarizations in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF caused by leaky RyR2 Ca channels with R-propafenone may be a more mechanism-based approach to treating this common arrhythmia.

2012-07-01·Heart Rhythm1区 · 医学

Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles

1区 · 医学

Article

作者: Björn C. Knollmann ; Peng Sheng Chen ; Yu Cheng Hsieh ; Huiyong Yin ; Changyu Shen ; Chia Hsiang Hsueh ; Hyung Wook Park ; Shien Fong Lin ; Kyoung Suk Rhee ; Young Soo Lee ; Po Cheng Chang ; Hyun Seok Hwang ; Mitsunori Maruyama

BACKGROUNDNa channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs.OBJECTIVETo test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles.METHODSWe compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Ca(i)) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats.RESULTSSCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02-0.06] vs 0.23 arbitrary units [95% confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of I(Na).CONCLUSIONSBoth Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.

2011-11-01·Journal of Molecular and Cellular Cardiology2区 · 医学

Efficacy and potency of class I antiarrhythmic drugs for suppression of Ca2+ waves in permeabilized myocytes lacking calsequestrin

2区 · 医学

Article

作者: Eleonora Savio Galimberti ; Björn C. Knollmann

Ca(2+) waves can trigger ventricular arrhythmias such as catecholaminergic-polymorphic ventricular tachycardia (CPVT). Drugs that prevent Ca(2+) waves may have antiarrhythmic properties. Here, we use permeabilized ventricular myocytes from a CPVT mouse model lacking calsequestrin (casq2) to screen all clinically available class I antiarrhythmic drugs and selected other antiarrhythmic agents for activity against Ca(2+) waves. Casq2-/- myocytes were imaged in line-scan mode and the following Ca(2+) wave parameters analyzed: wave incidence, amplitude, frequency, and propagation speed. IC(50) (potency) and maximum inhibition (efficacy) were calculated for each drug. Drugs fell into 3 distinct categories. Category 1 drugs (flecainide and R-propafenone) suppressed wave parameters with the highest potency (IC(50)<10 μM) and efficacy (>50% maximum wave inhibition). Category 2 drugs (encainide, quinidine, lidocaine, and verapamil) had intermediate potency (IC(50) 20-40 μM) and efficacy (20-40% maximum wave inhibition). Category 3 drugs (procainamide, disopyramide, mexiletine, cibenzoline, and ranolazine) had no significant effects on Ca(2+) waves at the highest concentration tested (100 μM). Propafenone was stereoselective, with R-propafenone suppressing waves more potently than S-propafenone (IC(50): R-propafenone 2 ± 0.2 μM vs. S-propafenone 54 ± 18 μM). Both flecainide and R-propafenone decreased Ca(2+) spark mass and converted propagated Ca(2+) waves into non-propagated wavelets and frequent sparks, suggesting that reduction in spark mass, not spark frequency, was responsible for wave suppression. Among all class I antiarrhythmic drugs, flecainide and R-propafenone inhibit Ca(2+) waves with the highest potency and efficacy. Permeabilized casq2-/- myocytes are a simple in-vitro assay for finding drugs with activity against Ca(2+) waves. This article is part of a Special Issue entitled 'Possible Editorial'.

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适应症	最高研发状态	国家/地区	公司	日期
心房颤动	临床2期	美国	Vanderbilt University	2021-06-09

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02710669 (CTgov)	临床1/2期	心房颤动	193	(R)-propafenone ((R)-Propafenone)	膚憲願築壓遞繭網顧壓(淵夢願鹽壓鏇鑰顧夢鬱) = 淵鹽獵鑰餘淵獵願顧範願艱選鹽築網鑰鹹衊網 (鹹壓夢醖醖鹹蓋顧窪齋, 遞觸積壓窪鬱醖淵築觸 ~ 鬱獵壓淵憲夢選積艱觸) 更多	-	2021-05-14
				(S)-Propafenone ((S)-Propafenone)	膚憲願築壓遞繭網顧壓(淵夢願鹽壓鏇鑰顧夢鬱) = 遞鏇鹽蓋醖糧膚觸窪鏇願艱選鹽築網鑰鹹衊網 (鹹壓夢醖醖鹹蓋顧窪齋, 蓋顧製構艱夢膚醖鑰網 ~ 製襯鹽窪襯廠餘齋構鏇) 更多