ABSTRACT
Xin Su Ning (XSN) is a patented multicomponent medicine, which was certified in 2005 by the China State Food and Drug Administration to be produced pharmaceutically and to be used clinically. The XSN capsule was developed from an effective formula composed by Prof. Shuwen Ding of Shandong University of Traditional Chinese Medicine. Through more than 30 years of clinical observation, Prof. Ding concluded that XSN has a significant effect on arrhythmia with phlegm-heat heart-disturbed syndrome according to the traditional Chinese medicine (TCM) diagnosis. XSN, derived from a classical TCM formula Huanglian Wen Dan Decoction, is formulated with 11 Chinese herbal medicines to treat cardiac ventricular arrhythmia. Clinical evidence suggests that it is particularly efficacious for the arrhythmias induced by cardiac ischemia and viral myocarditis without obvious adverse reactions being reported. Cellular electrophysiological studies in ventricular myocytes revealed that XSN prolongs the duration and suppresses the amplitude of the action potential (AP), which is supported by the blockage of sodium and potassium channels indicating the characteristics of class I and III antiarrhythmic drugs. A recently reported double-blind, placebo-controlled, multicenter clinical trial of XSN enrolled 861 patients (ChiCTR-TRC-14004180) and showed that XSN significantly inhibited premature ventricular contraction (PVC). The cellular electrophysiological discoveries provided the mechanistic evidence for the clinical efficacy on inhibition of PVC by XSN as demonstrated in the clinical trial. These studies, for the first time, provided exclusive evidence that multicomponent TCM antiarrhythmic medicine can be evaluated using conventional research methods that have been used for antiarrhythmic drug discoveries for decades. We aimed to give a comprehensive review on XSN including its origin with the support of TCM theory, its pre-licensing clinical use and development, and its pharmacological and clinical study discoveries. The review will be summarized with the discoveries reported in a novel network pharmacological study that introduced a weight coefficient, which made it possible to evaluate the pharmacological properties of the TCM formula with regard to its formation based on TCM theory. Limitations regarding XSN's basic and clinical research and possible future studies are listed. We hope that the advances in how XSN was studied may offer useful guidance on how other TCM could be studied with respect to the integrity of the TCM formulas.
ABSTRACT
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.
ABSTRACT
Xin Su Ning (XSN) is a China patented and certified traditional Chinese herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. XSN is formulated with 11 herbs, designed to treat arrhythmia with phlegm-heat heart-disturbed syndrome (PHHD) according to Chinese medicine theory. The rational compatibility of the 11 herbs decides the therapeutic outcome of XSN. Due to the multicomponent nature of traditional Chinese medicine, it is difficult to use conventional pharmacology to interpret the therapeutic mechanism of XSN in terms of clear-cut drug molecule and target interactions. Network pharmacology/systematic pharmacology usually consider all the components in a formula with the same weight; therefore, the proportion of the weight of the components has been ignored. In the present study, we introduced a novel coefficient to mimic the relative amount of all the components in relation with the weight of the corresponding herb in the formula. The coefficient is also used to weigh the pharmacological effect of XSN on all relative biological pathways. We also used the cellular electrophysiological data generated in our lab, such as the effect of liensinine and isoliquiritigenin on NaV1.5 channels; we therefore set sodium channel as one of the targets of these two components, which would support the clinical efficacy of XSN in treating tachyarrhythmia. Combining the collected data and our discovery, a panoramagram of the pharmacological mechanism of XSN was established. Pathway enrichment and analysis showed that XSN treated PHHD arrhythmia through multiple ion channels regulation, protecting the heart from I/R injury, inhibiting the apoptosis of cardiomyocyte, and improving glucose and lipid metabolism.
ABSTRACT
[This corrects the article DOI: 10.3389/fphar.2019.00070.].
ABSTRACT
Xin Su Ning (XSN) is a China patented and certified herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. A recent completed clinical trial of 861 patients showed that XSN had similar PVC inhibition rate to the class I antiarrhythmic drug mexiletine, at 65.85% for XSN and 63.10% for mexiletine. We have previously reported that XSN prolongs action potential duration (APD) and suppresses action potential amplitude (APA) of the cardiac ventricular myocytes. In this report we aim to reveal the effect of XSN on the ionic channels that govern APD and APA, which would help to explain the cellular electrophysiological mechanism of XSN. Our main findings are: (1) On ECG recorded in isolated rat, in the presence of XSN the amplitude of R wave was significantly decreased and the amplitude of T wave was increased significantly; (2) XSN blocked hNaV1.5 channel stably transfected cell line in a dose-dependent manner with an IC50 of 0.18 ± 0.02 g/L; and (3) XSN suppresses hERG channels in a dose-dependent manner with an IC50 of 0.34 ± 0.01 g/L. In conclusion, the clinical antiarrhythmic efficacy of XSN is based on its class I and Class III antiarrhythmic properties by suppression hNaV1.5 channel and hERG channels, which are directly responsible for XSN's effect on APA suppression and APD prolongation.