预约演示
更新于：2025-11-29
(R)-Propafenone(Vanderbilt University)
更新于：2025-11-29
概要
基本信息
药物类型 小分子化药 |
别名- |
作用方式 阻滞剂 |
作用机制 钠通道阻滞剂 |
治疗领域 |
在研适应症- |
非在研适应症 |
在研机构- |
权益机构- |
最高研发阶段终止临床1/2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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关联
1
项与 (R)-Propafenone(Vanderbilt University) 相关的临床试验NCT02710669
Comparison of (R) and (S) Propafenone for Prevention of Atrial Fibrillation Induction
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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100 项与 (R)-Propafenone(Vanderbilt University) 相关的专利（医药）
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17
项与 (R)-Propafenone(Vanderbilt University) 相关的文献（医药）2022-10-01Circulation. Arrhythmia and electrophysiology
A Mechanistic Clinical Trial Using (
R
)- Versus
(S
)-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the Prevention of Atrial Fibrillation Induction
Article
作者: Montgomery, Jay A. ; Saavedra, Pablo ; Crossley, George ; Richardson, Travis ; Michaud, Gregory F. ; Kanagasundram, Arvindh ; Phillips, Sharon ; Knollmann, Bjorn C. ; Shen, Sharon T. ; Akers, Wendell S. ; Estrada, Juan C. ; Crawford, Diane M. ; Shyr, Yu ; Shoemaker, M. Benjamin ; Yoneda, Zachary T. ; Ellis, Christopher R.
Background::
Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however,
(R
)-propafenone is an ryanodine receptor inhibitor whereas
(S
)-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with
(R
)-propafenone prevents induction of AF compared to
(S
)-propafenone or placebo in patients referred for AF ablation.
Methods::
Participants were randomized 4:4:1 to a one-time intravenous dose of
(R
)-propafenone,
(S
)-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter.
Results::
A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving
(R
)-propafenone, 60 (80.0%) receiving
(S
)-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the
(R
)-propafenone (N=23, 32.4%) and
(S
)-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%,
P
=0.029). There was no significant difference between
(R
)-propafenone and
(S
)-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable (
P
=0.522) or multivariable analysis (
P
=0.199, adjusted for age and serum drug level).
Conclusions::
There is no difference in AF inducibility between
(R
)-propafenone and
(S
)-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade.
Registration::
https://clinicaltrials.gov
; Unique Identifier: NCT02710669.
2014-04-01Circulation. 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 ; Hwang, Hyun Seok ; Darbar, Dawood ; Faggioni, Michela ; Savio-Galimberti, Eleonora ; Knollmann, Björn C. ; Kannankeril, Prince J.
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.
2012-07-01Heart 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: Hyung Wook Park ; Björn C. Knollmann ; Po Cheng Chang ; Mitsunori Maruyama ; Yu Cheng Hsieh ; Changyu Shen ; Chia Hsiang Hsueh ; Shien Fong Lin ; Huiyong Yin ; Hyun Seok Hwang ; Young Soo Lee ; Kyoung Suk Rhee ; Peng Sheng Chen
BACKGROUND:
Na 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.
OBJECTIVE:
To 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.
METHODS:
We 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.
RESULTS:
SCaEs 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).
CONCLUSIONS:
Both 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.
100 项与 (R)-Propafenone(Vanderbilt University) 相关的药物交易
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研发状态
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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 | 2016-10-01 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床1/2期 | 心房颤动 ryanodine receptor | 193 | 鏇遞衊鑰範艱糧鏇鏇願(壓襯遞範淵鹹艱顧遞餘) = 網鏇淵繭夢鬱顧醖壓顧 築遞淵鑰遞膚遞膚糧鹹 (鬱淵鏇壓鹽積簾憲鏇淵 ) 更多 | 不佳 | 2022-10-01 | ||
鏇遞衊鑰範艱糧鏇鏇願(壓襯遞範淵鹹艱顧遞餘) = 鏇壓鹹艱顧襯繭鹹衊糧 築遞淵鑰遞膚遞膚糧鹹 (鬱淵鏇壓鹽積簾憲鏇淵 ) 更多 | |||||||
临床1/2期 | 193 | ((R)-Propafenone) | 艱糧齋淵餘遞壓壓膚廠 = 積積鏇襯齋積構餘積鬱 糧鏇鏇顧壓構範選築艱 (願顧構襯繭積艱鬱鏇壓, 餘糧鏇製醖鏇蓋齋襯餘 ~ 鹽築襯鹽構鏇膚獵蓋壓) 更多 | - | 2021-05-14 | ||
((S)-Propafenone) | 艱糧齋淵餘遞壓壓膚廠 = 構簾範製積積構襯夢選 糧鏇鏇顧壓構範選築艱 (願顧構襯繭積艱鬱鏇壓, 積遞鹽觸觸鹹壓築膚製 ~ 鑰觸遞積衊製鹽構糧願) 更多 |
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