Vernakalant Hydrochloride

Vernakalant Hydrochloride（CAS 号 748810-28-8）是心房选择性抗心律失常药物，核心生物活性为快速转复心房颤动（AF）至窦性心律，作用靶点包括心房特异性离子通道（IK、Ito、IKr、IKACh）、钠通道（INa，频率 / 电压 / 浓度依赖性阻断）及 Kv1.5、Kv4.3、hERG、Nav1.5 通道，通过延长心房不应期、抑制心房电重构发挥作用，对心室影响微弱；IC50 方面，母药对上述离子通道为 5~45 μM，代谢产物 RSD1385、RSD1390 为 15~80 μM，对 hKCa2.2/2.3 通道无显著抑制（IC50 远高于治疗浓度），PK/PD 模型中 QTcF 相关 EC50 为 2276 ng/ml（未转复 AF）和 4222 ng/ml（转复 AF），收缩压（SBP）相关 EC50 为 1141 ng/ml；常用应用浓度：体外细胞实验（HEK293 表达离子通道）测试浓度 0.1~300 μM，动物实验（狗 AF 模型）可选择性延长心房不应期并终止 AF，临床浓度为静脉输注方案（首次 3 mg/kg，10 分钟输注，未转复则 15 分钟后追加 2 mg/kg，10 分钟输注），单剂量 3 mg/kg 血浆峰浓度约 3.9 μg/ml，两剂量后约 4.3 μg/ml，有效治疗对应的游离血浆浓度为 1000~10000 nmol/L，短 Duration AF（3 小时～7 天）转复率达 51.7%，中位转复时间 8~12 分钟，耐受性良好，常见短暂不良反应为味觉障碍、打喷嚏，无明确 torsade de pointes 风险。

参考文献：

[1] Roy D, Pratt CM, Torp-Pedersen C, Wyse DG, Toft E, Juul-Moller S, Nielsen T, Rasmussen SL, Stiell IG, Coutu B, Ip JH, Pritchett EL, Camm AJ; Atrial Arrhythmia Conversion Trial Investigators. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation. 2008 Mar 25;117(12):1518-25. doi: 10.1161/CIRCULATIONAHA.107.723866. Epub 2008 Mar 10. PMID: 18332267.

[2] Mao ZL, Wheeler JJ, Clohs L, Beatch GN, Keirns J. Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors. J Clin Pharmacol. 2009 Jan;49(1):17-29. doi: 10.1177/0091270008325148. Epub 2008 Oct 16. PMID: 18927241.

[3] Stiell IG, Dickinson G, Butterfield NN, Clement CM, Perry JJ, Vaillancourt C, Calder LA. Vernakalant hydrochloride: A novel atrial-selective agent for the cardioversion of recent-onset atrial fibrillation in the emergency department. Acad Emerg Med. 2010 Nov;17(11):1175-82. doi: 10.1111/j.1553-2712.2010.00915.x. Erratum in: Acad Emerg Med. 2011 Feb;18(2):224. PMID: 21175515.

[4] Pratt CM, Roy D, Torp-Pedersen C, Wyse DG, Toft E, Juul-Moller S, Retyk E, Drenning DH; Atrial Arrhythmia Conversion Trial (ACT-III) Investigators. Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol. 2010 Nov 1;106(9):1277-83. doi: 10.1016/j.amjcard.2010.06.054. PMID: 21029824.

[5] Mao Z, Wheeler JJ, Townsend R, Gao Y, Kshirsagar S, Keirns JJ. Population pharmacokinetic-pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter. J Pharmacokinet Pharmacodyn. 2011 Oct;38(5):541-62. doi: 10.1007/s10928-011-9207-3. Epub 2011 Jul 24. PMID: 21786177.

[6] Simó-Vicens R, Sauter DRP, Grunnet M, Diness JG, Bentzen BH. Effect of antiarrhythmic drugs on small conductance calcium - activated potassium channels. Eur J Pharmacol. 2017 May 15;803:118-123. doi: 10.1016/j.ejphar.2017.03.039. Epub 2017 Mar 18. PMID: 28322838.