Ma Yu-Ling, Hu Rou-Mu, Yang Xinchun, Wang Taiyi, Noble Penelope J, Wilkins Robert, Ellory Clive, Carr Carolyn, Noble Denis, Yang Jiefu, Lu Weixing, Zhang Junhua, Hu Hongde, Guo Xiaomei, Chen Min, Wu Yang, Wei Meng, Mao Jingyuan, Ma Xiaochang, Qin Ling, Wu Huanlin, Lu Feng, Cao Ying, Gao Sheng, Gu Wanli
Oxford Chinese Medicine Research Centre & Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Heart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Front Pharmacol. 2020 May 6;11:600. doi: 10.3389/fphar.2020.00600. eCollection 2020.
Xin Su Ning (XSN), a China patented and certified multi-herbal medicine, has been available in China since 2005 for treating cardiac ventricular arrhythmia including arrhythmia induced by ischemic heart diseases and viral myocarditis, without adverse reactions being reported. It is vitally important to discover pharmacologically how XSN as a multicomponent medicine exerts its clinical efficacy, and whether the therapeutic effect of XSN can be verified by standard clinical trial studies. In this paper we report our discoveries in a cellular electrophysiological study and in a three-armed, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Conventional electrophysiological techniques were used to study the cellular antiarrhythmic mechanism of XSN. Data was then modeled with computational simulation of human action potential (AP) of the cardiac ventricular myocytes. The clinical trial was conducted with a total of 861 eligible participants randomly assigned in a ratio of 2:2:1 to receive XSN, mexiletine, or the placebo for 4 weeks. The primary and secondary endpoint was the change of premature ventricular contraction (PVC) counts and PVC-related symptoms, respectively. This trial was registered in the Chinese Clinical Trial Register Center (ChiCTR-TRC-14004180). We found that XSN prolonged AP duration of the ventricular myocytes in a dose-dependent, reversible manner and blocked potassium channels. Patients in XSN group exhibited significant total effective responses in the reduction of PVCs compared to those in the placebo group (65.85% vs. 27.27%, P < 0.0001). No severe adverse effects attributable to XSN were observed. In conclusion, XSN is an effective multicomponent antiarrhythmic medicine to treat PVC without adverse effect in patients, which is convincingly supported by its class I & III pharmacological antiarrhythmic mechanism of blocking hERG potassium channels and hNaV1.5 sodium channel reported in our earlier publication and prolongs AP duration both in ventricular myocytes and with computational simulation of human AP presented in this report.
心速宁（XSN）是一种获得中国专利并通过认证的多草药复方制剂，自2005年起在中国用于治疗室性心律失常，包括由缺血性心脏病和病毒性心肌炎引起的心律失常，且未报告有不良反应。从药理学角度探究XSN这种多成分药物如何发挥其临床疗效，以及其治疗效果能否通过标准的临床试验研究得到验证，这至关重要。在本文中，我们报告了在细胞电生理研究以及一项三臂、随机、双盲、安慰剂对照、平行组、多中心试验中的发现。采用传统电生理技术研究XSN的细胞抗心律失常机制。然后用计算模拟心室肌细胞的人类动作电位（AP）对数据进行建模。临床试验共纳入861名符合条件的参与者，按2:2:1的比例随机分配，分别接受XSN、美西律或安慰剂治疗4周。主要终点和次要终点分别是室性早搏（PVC）计数的变化和与PVC相关的症状。该试验已在中国临床试验注册中心注册（ChiCTR - TRC - 14004180）。我们发现XSN以剂量依赖性、可逆的方式延长心室肌细胞的AP持续时间，并阻断钾通道。与安慰剂组相比，XSN组患者在减少PVC方面表现出显著的总有效反应（65.85%对27.27%，P < 0.0001）。未观察到归因于XSN的严重不良反应。总之，XSN是一种有效的多成分抗心律失常药物，可治疗PVC且对患者无不良影响，这在我们早期发表的报告中所报道的其通过阻断hERG钾通道和hNaV1.5钠通道的I类和III类药理学抗心律失常机制以及本报告中在心室肌细胞和人类AP计算模拟中延长AP持续时间方面均得到了令人信服的支持。
