Clinical effects and mechanisms of a Chinese patent medicine, Tongxinluo capsule, as an adjuvant treatment in coronary heart disease.

Coronary heart disease (CHD) is the leading cause of death globally, posing a serious threat to human health. However, the current treatment approaches available for CHD fall short of the ideal results. Tongxinluo (TXL) is a traditional Chinese medicine (TCM) that has been employed in the clinical treatment of cardiovascular and cerebrovascular diseases (such as angina pectoris, stroke, etc.) in China for many years and holds great potential as a prospective treatment. TXL either as a standalone treatment or in combination with interventions recommended in CHD guidelines has been shown to be effective and well tolerated in clinical trials for CHD. Drawing on the evidence from clinical trials and experimental studies, this review will focus on the cardiovascular protective properties and related mechanisms of TXL. By searching 8 Chinese and English databases, more than 4000 articles were retrieved. These articles were categorized, then read, and finally written into this review. In this review, the pharmacological properties of TXL include regulation of blood lipids, improvement of endothelial function, anti-inflammatory, antioxidant, inhibition of apoptosis and regulation of autophagy, anti-fibrosis, promotion of angiogenesis, and modulation of exosome communication. The information provided in this review will help the reader to comprehend better the insights that TCM has developed over time in practice and provide new perspectives for the treatment of CHD.

Efficacy and safety of tongxinluo capsule for angina pectoris of coronary heart disease: an overview of systematic reviews and meta-analysis.

Background: Tongxinluo capsule (TXLC) is a common drug for treating angina pectoris of coronary heart disease (CHD). In recent years, many systematic reviews (SRs) and meta-analyses (MAs) have reported the efficacy and safety of TXLC for improving angina symptoms in patients with CHD. We aimed to comprehensively evaluate the existing SRs and MAs of TXLC in treating angina pectoris of CHD, summarize the evidence quality, and provide scientific evidence and recommendations. Methods: We searched seven databases for relevant SRs/MAs published up to 1 June 2023. Two reviewers independently completed the literature retrieval, screening, and data extraction. We used A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) to evaluate the methodological quality, the Risk of Bias in Systematic Reviews (ROBIS) to assess the risk of bias, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to determine the strength of the evidence. RevMan 5.3 was used to synthesize data. Results: We identified 15 SRs/MAs, including 329 RCTs and 33,417 patients. According to the evaluation results of AMSTAR-2, only one SR was of high methodological quality, the others were very low. ROBIS assessment showed that one SR (6.67%) had a low risk, 3 SRs (20%) had an unclear risk, and 11 SRs (73.33%) had a high risk. We assessed 42 outcomes by the GRADE, 10 (23.81%) for moderate-quality evidence, 17 (40.48%) for low-quality evidence, and 15 (35.71%) for very-low-quality evidence. Mate-analysis showed that TXLC combined with conventional western medications improved electrocardiogram efficacy (RR = 1.38, 95% CI: 1.23-1.43, P < 0.001) and angina efficacy (OR = 3.58, 95% CI: 3.02-4.24, P < 0.001), reduced angina attack frequency (SMD = -0.54, 95% CI: -0.64 to -0.44, P < 0.001) and angina duration (SMD = -0.42, 95% CI: -0.57 to -0.28, P < 0.001), with general heterogeneity. The pooled results showed that TXLC appears to have some efficacy in improving cardiac function and relieving angina symptoms, but there is limited evidence that it improves cardiovascular event rates, hemorheology, lipids, or hs-CRP. In the assessment of drug safety, TXLC was associated with different degrees of adverse drug reactions. Conclusion: Based on the evidence, TXLC may be effective as an adjuvant treatment for angina pectoris of CHD. However, the quality of the evidence is low, and the drug's safety must be carefully interpreted. In future studies, high-quality randomized controlled trials are needed to confirm the effectiveness and safety of TXLC. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022365372).

Inhibiting leukocyte-endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no-reflow after arterial recanalization in ischemic stroke.

AIMS: Despite successful vascular recanalization in stroke, one-fourth of patients have an unfavorable outcome due to no-reflow. The pathogenesis of no-reflow is fully unclear, and therapeutic strategies are lacking. Upon traditional Chinese medicine, Tongxinluo capsule (TXL) is a potential therapeutic agent for no-reflow. Thus, this study is aimed to investigate the pathogenesis of no-reflow in stroke, and whether TXL could alleviate no-reflow as well as its potential mechanisms of action. METHODS: Mice were orally administered with TXL (3.0 g/kg/d) after transient middle cerebral artery occlusion. We examined the following parameters: neurological function, no-reflow, leukocyte-endothelial cell interactions, HE staining, leukocyte subtypes, adhesion molecules, and chemokines. RESULTS: Our results showed stroke caused neurological deficits, neuron death, and no-reflow. Adherent and aggregated leukocytes obstructed microvessels as well as leukocyte infiltration in ischemic brain. Leukocyte subtypes changed after stroke mainly including neutrophils, lymphocytes, regulatory T cells, suppressor T cells, helper T type 1 (Th1) cells, Th2 cells, B cells, macrophages, natural killer cells, and dendritic cells. Stroke resulted in upregulated expression of adhesion molecules (P-selectin, E-selectin, and ICAM-1) and chemokines (CC-chemokine ligand (CCL)-2, CCL-3, CCL-4, CCL-5, and chemokine C-X-C ligand 1 (CXCL-1)). Notably, TXL improved neurological deficits, protected neurons, alleviated no-reflow and leukocyte-endothelial cell interactions, regulated multiple leukocyte subtypes, and inhibited the expression of various inflammatory mediators. CONCLUSION: Leukocyte-endothelial cell interactions mediated by multiple inflammatory factors are an important cause of no-reflow in stroke. Accordingly, TXL could alleviate no-reflow via suppressing the interactions through modulating various leukocyte subtypes and inhibiting the expression of multiple inflammatory mediators.

Intervention effect of Tongxinluo capsule on renal fibrosis in diabetic nephropathy rats / 中国药房

OBJECTIVE To explore the intervention effect and related mechanism of Tongxinluo capsule on renal fibrosis in rats with diabetic nephropathy （DN）. METHODS Eight rats were selected as control group （ordinary feed）， the remaining rats were given high-glucose and high-fat diet combined with ip injection of streptozotocin （35 mg/kg） to induce DN model. Model rats were randomly divided into model group （purified water）， irbesartan group （positive control， 14.12 mg/kg） and Tongxinluo capsule group （0.3 g/kg）， including 12 rats in the model group and 11 rats for each of the other two groups. All groups were given relevant medicine or water intragastrically， once a day， for 16 consecutive weeks. After the last medication， fasting blood glucose and 24 h urinary total protein （24 h UTP） were detected. Pathological changes in renal cortex of rats in each group were observed. Serum levels of tissue-type plasminogen activator （PA） and plasminogen activator inhibitor 1 （PAI-1） were measured. mRNA expressions of transforming growth factor-β（1 TGF-β1）， type Ⅳ collagen（COL-Ⅳ）， Wnt4 and β-catenin in renal cortex of rats were detected. The protein depositions or expressions of TGF-β1， COL-Ⅳ， focal adhesion kinase （FAK）， integrin-linked kinase （ILK）， E-cadherin， PA， PAI-1， Wnt4 and β-catenin in renal cortex of rats were observed or determined. RESULTS Compared with model group， 24 h UTP of rats in Tongxinluo capsule group were all significantly reduced （P＜0.05）； pathological damage and fibrosis of renal cortex were relieved； the expression of PA in serum and renal cortex was significantly increased， while PAI-1 level was significantly reduced （P＜0.05）； the depositions of COL-Ⅳ and TGF-β1 in renal cortex were all reduced， and corresponding mRNA expression was decreased significantly （P＜0.05）； the depositions of ILK and FAK were decreased， while the deposition of E-cadherin was increased； protein and mRNA expressions of Wnt4 and β-catenin were significantly reduced （P＜0.05）. CONCLUSIONS Tongxinluo capsule can relieve pathological damage to renal tissue and renal fibrosis of DN model rats， and reduce extracellular matrix deposition. The mechanism may be related to regulation of fibrinolytic system activity， the decrease of ILK and FAK expression， and inhibition of Wnt/β-catenin signaling pathway.

Efficacy and Safety of Different Courses of Tongxinluo Capsule as Adjuvant Therapy for Coronary Heart Disease after Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Tongxinluo capsule (TXLC) is a widely used traditional Chinese medicine for coronary heart disease (CHD). However, the efficacy and safety of different courses of TXLC for CHD after percutaneous coronary intervention (PCI) have not been systematically evaluated yet. The Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, Wanfang Database, and Chinese Scientific Journal Database were searched from the inception to 26 August 2021. A meta-analysis was performed using a fixed- or random-effects model. The risk of adverse cardiovascular events, mortality, or adverse effects was evaluated by risk ratio (RR) with 95% confidence interval (CI). Thirty-four studies involving 3652 patients were finally included. After the 6-month treatment, compared with conventional treatment alone, TXLC combined with conventional treatment achieved better efficacy in lowering the risk of angiographic restenosis (RR = 0.37, 95% CI = 0.28−0.48, p < 0.001), myocardial infarction (RR = 0.38, 95% CI = 0.25−0.60, p < 0.001), heart failure (RR = 0.32, 95% CI = 0.18−0.56, p < 0.001), angina (RR = 0.26, 95% CI = 0.17−0.38, p < 0.001), revascularization (RR = 0.20, 95% CI = 0.09−0.46, p < 0.001), all-cause mortality (RR = 0.24, 95% CI = 0.10−0.58, p = 0.001), and mortality due to any cardiovascular event (RR = 0.27, 95% CI = 0.09−0.80, p = 0.018). After the 12-month treatment, TXLC reduced the recurrence risk of angina (RR = 0.40, 95% CI = 0.20−0.80, p = 0.009). However, there was no difference in any outcomes after the 3-month treatment. Besides, no difference was found in the incidence of adverse effects after the 3-month and 6-month treatments (3 months: RR = 0.73, 95% CI = 0.35−1.56, p = 0.418; 6 months: RR = 1.71, 95% CI = 0.74−3.93, p = 0.209). The certainty of evidence ranged from very low to moderate due to the risk of bias, inconsistency, and imprecision. TXLC showed beneficial effects on reducing the adverse cardiovascular events without compromising safety for CHD patients after PCI on the 6-month course. However, due to the unavoidable risk of bias, more high-quality and long-term studies are still needed to further evaluate the efficacy and safety of TXLC in many countries, not only in China.

Tongxinluo capsule as supplementation and cardiovascular endpoint events in patients with coronary heart disease: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo Capsule(TXLC) is a well-known traditional Chinese medicine prescription with effects of tonifying Qi and activating blood based on the Chinese herbal medicine theory that has been recommended as routine adjuvant treatment in patients with coronary heart disease (CHD) in China. AIM OF THE STUDY: This meta-analysis aimed to evaluate the efficacy and safety of TXLC as supplementation in the prevention of adverse cardiovascular events in patients with CHD. MATERIALS AND METHODS: We performed a literature search in Pubmed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wan Fang Database, and Chinese Biomedical Database (CBM) from their inceptions to March 2020. Only randomized controlled trials (RCTs) that assessed supplementation with TXLC or placebo and with adverse cardiovascular outcomes, were included in this meta-analysis. Primary end points were myocardial infarction (MI), target vessel revascularization (TVR) or in-stent restenosis (ISR), and cardiovascular death. Secondary end points included cerebrovascular accidents, heart failure (HF), and unscheduled readmission for cardiovascular diseases (CVDs). Adverse drug events were also evaluated. Trial sequential analysis (TSA) was conducted to reduce random errors introduced by possible insufficient sample size. RESULTS: Eleven RCTs involving 1505 patients were analyzed. The mean(SD) age of included patients were 59.03(9.7) years. Treatment duration varied from 2 months to 12 months. Compared with placebo, TXLC supplementation showed significant effects on reducing the risk of MI (RR = 0.44, [95% CI, 0.24-0.80]), TVR or ISR (RR = 0.43, [95% CI, 0.31-0.58]), cerebrovascular accidents(RR = 0.17, [95% CI, 0.06-0.46]), HF (RR = 0.41, [95% CI, 0.21-0.79]), and unscheduled readmission for CVDs (RR = 0.72, [95% CI], P = 0.04), but did not have associations with incidence of cardiovascular death (RR = 0.53, [95% CI, 0.15-1.91]). Subgroups of trials with 2-month (MI: RR = 0.44, [95% CI, 0.13-1.53]; cardiovascular death: RR = 0.30, [95% CI, 0.01-7.67]; cerebrovascular accidents: RR = 0.04, [95% CI, 0.01-0.26]; unscheduled readmission for CVDs: RR = 0.43, [95% CI, 0.20-0.94]) and 12-month (MI: RR = 0.42, [95% CI, 0.20-0.89]; TVR or ISR: RR = 0.42, [95% CI, 0.31-0.58]; HF: RR = 0.34, [95% CI, 0.14-0.78]; unscheduled readmission for CVDs: RR = 0.85, [95% CI, 0.59-1.22]) intervention period were analyzed. The adverse drug reactions were mild with no significant difference between TXLC and placebo. CONCLUSIONS: This meta-analysis indicated that TXLC supplementation had beneficial effects on the prevention of cardiovascular adverse events, especially in TVR or ISR after coronary revascularization and may possibly lower the incidence of first or recurrent MI and HF within 12 months in patients with CHD, while insufficient sample size implied that these results lacked certain stability. And the effects of TXLC on cardiovascular mortality, cerebrovascular events, and unscheduled readmission for CVDs could not be confirmed due to insufficient cases. Clinical trials with large-sample sizes and extended follow-up time are of interest in the future researches.

Effect of Tongxinluo capsule on improvement of cardiac function and expression of myocardial enzyme spectrum in patients with coronary heart disease after percutaneous coronary intervention / 中国医师进修杂志

Objective:To investigate the effects of Tongxinluo capsule on the improvement of cardiac function and the expression of myocardial enzyme spectrum in patients with coronary heart disease after percutaneous coronary intervention (PCI).Methods:One hundred patients with coronary heart disease after PCI who received treatment in Hebei Xianghe County People′s Hospitalfrom April 2018 to April 2020 were enrolled and randomly divided into the observation group and the control group. The control group was given conventional treatment, while the observation group was treated with Tongxinluo capsule on the basis of the control group. Patients in both groups were treated for 3 months. The normal clinical remission after treatment was observed in the two groups. The improvement of cardiac function index left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF) and myocardial enzyme index aspartate aminotransferase (AST), creatine kinase (CK), creatine kinase isoenzyme - MB (CK - MB), lactate dehydrogenase (LDH), troponin T (TnT) were compared between the two groups before and after the treatment.Results:After treated for 3 months, the total effective rate in the observation group was higher than that in the control group: 92.0%(46/50) vs. 76.0%(38/50), the difference was statistically significant ( χ2 = 4.76, P<0.05). After treated for 3 months, the levels of LVEDV and LVESV in two groups were decreased, and the level of LVEF in two groups was increased, and the levels of LVEDV and LVESV in the observation group were lower than those in the control group: (153.39 ± 8.35) ml/m 2 vs. (155.57 ± 9.32) ml/m 2, (103.49 ± 9.25) ml/m 2 vs. (109.65 ± 10.46) ml/m 2; the levels of LVEF in the observation group was higher than that in the control group: (58.14 ± 7.41)% vs. (54.59 ± 6.92)%, the differences were statistically significant ( P<0.05). After treated for 3 months, the levels of AST, CK, CK-MB, LDH, TnT in two groups were decreased, and the levels of above index in the observation group were lower than those in the control group: (38.14 ± 7.28) U/L vs. (45.04 ± 8.12) U/L, (637.15 ± 75.25) U/L vs. (756.24 ± 85.24) U/L, (553.28 ± 53.14) U/L vs. (632.17 ± 62.81) U/L, (162.43 ± 15.41) U/L vs. (181.74 ± 19.25) U/L, (0.32 ± 0.15) μg/L vs. (0.39 ± 0.11) μg/L, the differences were statistically significant ( P<0.05). Conclusions:The application of Tongxinluo capsule in patients with coronary heart disease after PCI can effectively alleviate clinical symptoms, improve cardiac function, and regulate the enzyme activity of the body.

Efficacy and Safety of Tongxinluo Capsule as Adjunctive Treatment for Unstable Angina Pectoris: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Tongxinluo capsule (TXLC) is a commonly used Chinese medicine for unstable angina pectoris (UA). This article aimed to clarify the safety and efficacy of TXLC as an adjunctive treatment for UA. Two reviewers searched 7 databases from inception to August 2021, and performed literature screening and information extraction independently. The meta-analysis was implemented after evaluating the methodological quality of each randomized controlled trial (RCT) by the Cochrane Risk of Bias tool. Sensitivity analyses were conducted for testing the stability of the results, and the Begg and Egger tests were performed for any potential publication bias. After eligibility assessment, 42 RCTs with a total of 5,421 participants were included. Evidence showed that TXLC reduced the rate of cardiovascular events [RR = 0.29, 95% CI (0.19, 0.45), p < 0.00001, I 2 = 0%] {including cardiovascular mortality [RR = 0.16, 95% CI (0.03, 0.88), p = 0.03, I 2 = 20%], the incidence of acute myocardial infarction [RR = 0.27, 95% CI (0.13, 0.57), p = 0.0006, I 2 = 0%] and the occurrence of revascularization [RR = 0.28, 95% CI (0.15,0.54), p = 0.0001, I 2 = 0%]}, all-cause mortality [RR = 0.25, 95% CI (0.06, 0.99), p = 0.05, I 2 = 19%], recurrence of angina [RR = 0.25, 95% CI (0.11, 0.61), p = 0.002, I 2 = 0%], the number of ST-segment depression [MD = -0.45, 95% CI (-0.69, -0.20), p = 0.0005, I 2 = 0%], the summation of ST-segment depression [MD = -0.70, 95% CI (-1.08, -0.32), p = 0.0003, I 2 = 70%] and the hypersensitive C-reactive protein level [MD = -2.86, 95% CI (-3.73, -1.99), p < 0.00001, I 2 = 86%], increased the nitric oxide level [MD = 11.67, 95% CI (8.33, 15.02), p < 0.00001, I 2 = 33%], improved the electrocardiogram change [RR = 1.23, 95% CI (1.16, 1.30), p < 0.00001, I 2 = 0%] and the clinical efficacy in UA [RR = 1.26, 95% CI (1.21, 1.32), p < 0.00001, I 2 = 24%], and relieved the symptoms of angina pectoris {including chest pain or tightness [RR = 1.13, 95% CI (0.97, 1.32), p = 0.12, I 2 = 30%], palpitations [RR = 1.47, 95% CI (1.18, 1.84), p = 0.0007, I 2 = 0%], shortness of breath [RR = 1.53, 95% CI (1.24, 1.88), p < 0.0001, I 2 = 0%], and asthenia [RR = 1.69, 95% CI (0.83, 3.43), p = 0.15, I 2 = 90%]}. The most common adverse effect was gastrointestinal symptoms which could be relieved and eliminated through dose reduction, medication time adjustment and symptomatic remedy. Collectively, TXLC was effective and considerably safe for UA. However, due to the unavoidable risk of bias, these results must be interpreted with caution and further verified by large-scale and high-quality RCTs. Systematic Review Registration: www.crd.york.ac.uk/PROSPERO/, identifier CRD42021232771.

Chinese medicine Tongxinluo capsule protects against blood-brain barrier disruption after ischemic stroke by inhibiting the low-density lipoprotein receptor-related protein 1 pathway in mice.

BACKGROUND: Chinese medicine Tongxinluo capsule (TXL) has been extensively used to treat ischemic stroke in China, and one of its mechanisms is to protect against blood brain barrier (BBB) disruption after stroke. However, the underlying protective mechanisms are not fully illuminated. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP-1) is involved in BBB disruption after brain ischemia. In this study, we explored whether TXL could downregulate LRP-1 expression and subsequently protect against BBB disruption after stroke using permanent middle cerebral artery occlusion (pMCAO) in mice. METHODS: The animal model of ischemic stroke was induced by pMCAO in male adult C57BL/6J mice. The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 h after pMCAO. Meanwhile, the LRP-1 antagonist receptor associated protein (RAP) was intracerebroventricularly injected at 1 and 21 h after stroke. We measured the following parameters at 6 and 24 h: LRP-1 protein level, BBB leakage, and the expression of tight junction (TJ) proteins including occludin, claudin-5 and zonula occludens-1 (ZO-1). RESULTS: Our results showed that TXL downregulated LRP-1 level, upregulated these TJ proteins level, and reduced BBB leakage in peri-infarct regions after pMCAO. Further study found that the inhibitor RAP played the same role as did TXL in upregulating these TJ proteins level and reducing BBB leakage after stroke. CONCLUSION: Our study demonstrates that TXL protects against BBB disruption after stroke via inhibiting the LRP-1 pathway.

Protective Effect of Tongxinluo Capsule on Cerebral Ischemia-reperfusion Injury and Its Mechanism of Action / 中国实验方剂学杂志

Objective:To study the protective effect of Tongxinluo capsule on cerebral ischemia-reperfusion injury, and explore the mechanism of Tongxinluo capsule in treating cerebral ischemia through network pharmacology. Method:The C57BL/6 mouse middle cerebral artery occlusion(MCAO) model was established by improved suture method and divided into sham operation group, model group, low, medium and high-dose Tongxinluo groups (crude drug 1,2,4 g·kg-1, intragastric administration), Aspirin group (2.055 g·L-1, intraperitoneal injection). Then, neurological function score and 2,3,5-triphenyltetrazole chloride(TTC) staining method were used to determine the infarct size of mice at 24, 48, 72 h by cerebral ischemia-reperfusion. First, chemical constituents of Tongxinluo capsule were screened from the BATMAN-TCM database, and the targets were analyzed. Then, gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed, and traditional Chinese medicine(TCM)-active ingredient-target network was constructed. Finally, the multi-dimensional pharmacological mechanism of Tongxinluo capsule in the treatment of cerebral ischemia was predicted. Result:Longa score, HE staining and TTC staining all suggested that Tongxinluo capsule could alleviate brain injury in mice after cerebral ischemia and reperfusion, and the improvement degree of Tongxinluo capsule on brain injury was gradually enhanced with the increase of Tongxinluo capsule dose. A total of 132 active components and 240 intersection targets, including cyclic adenosine monophosphate(cAMP)-dependent protein kinase catalytic subunit alpha (PRKACA), adenylate cyclase 1(ADCY1), serine/threonine kinase 1 (Akt1), dopamine receptor D2 (DRD2) and discs large homolog 4 (DLG4) were screened from 12 TCM in Tongxinluo capsule. GO was enriched in cationic channel activity, ion gated channel activity, gate channel activity, neurotransmitter receptor activity, ion channel activity, etc. KEGG was enriched in cAMP signaling pathway, calcium signaling pathway, neuroactive ligand-receptor interaction, cyclic guanosine monophosphate(cGMP)/protein kinase G(PKG) signaling pathway and dopaminergic synaptic signaling pathway. Conclusion:Tongxinluo capsule can alleviate brain damage in mice with cerebral ischemia-reperfusion, and achieve brain protection through multiple targets and multiple links. Network pharmacology reveals effective components，targets and pathway of Tongxinluo capsule in the treatment of cerebral ischemia, which provides theoretical support for the mechanism of Tongxinluo capsule in the treatment of cerebral ischemia.

The sonic hedgehog pathway mediates Tongxinluo capsule-induced protection against blood-brain barrier disruption after ischaemic stroke in mice.

Tongxinluo capsule (TXL), a Chinese prescription, has been extensively used for treating ischaemic cerebrovascular diseases in China. Studies have demonstrated that TXL protects the blood-brain barrier (BBB) after cerebral ischaemia. However, the underlying protective mechanisms are not fully elucidated. Enlightened by the critical role of sonic hedgehog (Shh) pathway in promoting BBB integrity through up-regulating tight junction (TJ) proteins, we examined whether the Shh pathway could mediate TXL-induced up-regulation of TJ proteins and subsequent protection against BBB disruption after stroke. Ischaemic stroke was induced in adult male C57BL/6J mice by permanent middle cerebral artery occlusion (pMCAO). The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 hours after stroke. Meanwhile, cyclopamine, a specific Shh pathway inhibitor, was intraperitoneally injected at 1 and 21 hours after stroke. The following parameters were measured at 6 and 24 hours after pMCAO: BBB permeability; TJ proteins including occludin, claudin-5 and zonula occludens-1 (ZO-1); and Shh signalling molecules such as Shh, Patched, Smoothened (Smo) and Gli-1. Our results showed that TXL protected against BBB disruption at 6 and 24 hours after pMCAO, and cyclopamine partly reversed the protective effect of TXL on BBB. Meanwhile, cyclopamine blocked the effect of TXL-up-regulated expression of occludin, claudin-5 and ZO-1. Moreover, TXL up-regulated the expression of Shh derived from astrocytes, Patched, Smo and Gli-1, and thus activated the Shh pathway. And cyclopamine inhibited TXL-induced activation of the Shh pathway. Thus, our study demonstrates that the Shh pathway mediates TXL-induced protection against BBB disruption after ischaemic stroke.

Tongxinluo Capsule () for Cardiac Syndrome X: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of Tongxinluo Capsule (, TXL) for patients with cardiac syndrome X (CSX). METHODS: Randomized controlled trials (RCTs) regarding TXL in the treatment of CSX were searched in Chinese Biomedicine Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, PubMed, EMBASE, Cochrane Central Register of Controlled Trial, websites of the Chinese and International Clinical Trial Registry platform up to June 30, 2015. The intervention was either TXL alone or TXL combined with conventional treatment, while the control intervention was conventional treatment with or without placebo. Data extraction, methodological quality assessment and data analyses were performed according to the Cochrane criteria. The primary outcome was a composite event of death, acute myocardial infarction (AMI), angina requiring hospitalization, revascularization, and heart failure. The secondary outcome measures were angina symptom improvement, electrocardiograph (ECG) improvement, and serum endothelin-1 (ET-1) level. The adverse events were also recorded. RevMan 5.3 software was applied for data analyses. RESULTS: Twelve RCTs (696 patients) were included. Compared with conventional treatment, the addition of TXL to conventional treatment showed some benefits on relieving angina symptoms [risk ratio (RR): 1.46, 95% confidence interval (CI) (1.25, 1.71), P<0.01], and improving ECG [RR: 1.45, 95% CI (1.21, 1.74), P<0.01]. The pooled result did not support a benefit of TXL on reducing the incidence of primary outcome [RR: 0.20, 95% CI (0.02, 1.61), P=0.13]. In addition, TXL decreased serum ET-1 concentration of CSX patients [standardized mean number:-1.63, 95% CI (-2.29,-0.96), P<0.01]. No serious adverse events were reported. CONCLUSIONS: TXL documents potential benefits on attenuating angina symptoms, improving ECG and decreasing serum ET-1 level for CSX patients. However, more rigorous RCTs with high quality are needed to confirm its efficacy and safety.

Clinical effect of Tongxinluo capsule in the treatment of women with microvascular angina / 中国基层医药

Objective To analyze the clinical effect of Tongxinluo capsule in the treatment of female patients with microvascular angina .Methods 122 female patients with microvascular angina pectoris were selected ,and they were randomly divided into conventional group and observation group ,61 cases in each group .On the basis of the two groups in the same treatment ,including antiplatelet ,lipid,the observation group was given Tongxinluo capsule orally , treatment for 3 months.The therapeutic effect was compared between the two groups .Results The total effective rate of the observation group was 93.44％,which of the conventional group was 80.33％,the difference between the two groups was statistically significant (χ2 =4.603,P=4.603).The total effective rate of exercise electrocardiogram ( ECG ) improvement in the observation group was 91.80％, which of the conventional group was 75.41％, the difference between the two groups was statistically significant (χ2 =4.552,P=0.048).Conclusion Tongxinluo capsule in the treatment of female patients with microvascular angina pectoris has good clinical curative effect ,it can obviously improve the clinical symptoms ,promote disease recover ,which is worthy of popularizing .

Tongxinluo Capsule () for Cardiac Syndrome X: A Systematic Review and Meta-Analysis / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of Tongxinluo Capsule (, TXL) for patients with cardiac syndrome X (CSX).</p><p><b>METHODS</b>Randomized controlled trials (RCTs) regarding TXL in the treatment of CSX were searched in Chinese Biomedicine Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, PubMed, EMBASE, Cochrane Central Register of Controlled Trial, websites of the Chinese and International Clinical Trial Registry platform up to June 30, 2015. The intervention was either TXL alone or TXL combined with conventional treatment, while the control intervention was conventional treatment with or without placebo. Data extraction, methodological quality assessment and data analyses were performed according to the Cochrane criteria. The primary outcome was a composite event of death, acute myocardial infarction (AMI), angina requiring hospitalization, revascularization, and heart failure. The secondary outcome measures were angina symptom improvement, electrocardiograph (ECG) improvement, and serum endothelin-1 (ET-1) level. The adverse events were also recorded. RevMan 5.3 software was applied for data analyses.</p><p><b>RESULTS</b>Twelve RCTs (696 patients) were included. Compared with conventional treatment, the addition of TXL to conventional treatment showed some benefits on relieving angina symptoms [risk ratio (RR): 1.46, 95% confidence interval (CI) (1.25, 1.71), P<0.01], and improving ECG [RR: 1.45, 95% CI (1.21, 1.74), P<0.01]. The pooled result did not support a benefit of TXL on reducing the incidence of primary outcome [RR: 0.20, 95% CI (0.02, 1.61), P=0.13]. In addition, TXL decreased serum ET-1 concentration of CSX patients [standardized mean number:-1.63, 95% CI (-2.29,-0.96), P<0.01]. No serious adverse events were reported.</p><p><b>CONCLUSIONS</b>TXL documents potential benefits on attenuating angina symptoms, improving ECG and decreasing serum ET-1 level for CSX patients. However, more rigorous RCTs with high quality are needed to confirm its efficacy and safety.</p>

Protective effects of Tongxinluo on cerebral ischemia/reperfusion injury related to Connexin 43/Calpain II/Bax/Caspase-3 pathway in rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL) is a multifunctional traditional Chinese medicine and has been widely used in the treatment of cardiovascular and cerebrovascular diseases. Numerous studies demonstrate that TXL is a novel neuroprotective drug, however, the mechanisms are largely unknown. AIM OF THE STUDY: we aimed to demonstrate the protective effect of TXL on cerebral ischemia/reperfusion (I/R) injury and provide the evidence for the involvement of Connexin 43/Calpain II/ Bax/Caspase-3 pathway in TXL-mediated neuroprotection. METHODS: Focal cerebral I/R injury were induced by transient middle cerebral artery occlusion (MCAO, for 90min) in adult male Sprague-Dawley rats. We estimated the effects of TXL on I/R injury including neurological deficit assessment and cerebral infarct volume measurement via TTC staining, and detected the protein expression of Connexin 43 (Cx43) by western blot. Furthermore, after the intracerebroventricular injection of carbenoxolone (CBX, the inhibitor of Cx43) at 30min before MCAO surgery, Calpain II, Bax and cleaved Caspased-3 immunoreactivity in ischemic penumbra region was detected by immunofluorescent staining, and cell apoptosis was detected by TUNEL staining. RESULTS: TXL treatment greatly improved neurological deficit and reduced the infarction volume compared to MCAO with buffer treatment (P<0.05), and TXL pre-post treatment showed better results than TXL pre-treatment. TXL pre-post treatment significantly up-regulated Cx43 protein expression at 3d, 7d and 14d post-injury compared to MCAO with buffer treatment (P<0.05). Meanwhile, the immunoreactivity of Calpain II, Bax and cleaved Caspase-3 in ischemic penumbra region was obviously decreased by TXL pre-post treatment compared to MCAO group (P<0.05). However, with the treatment of the Cx43 inhibitor, CBX, the down-regulated effect of TXL on Calpain II, Bax and cleaved Caspase-3 immunoreactivity was abolished (P<0.05). Moreover, the protective effect of TXL against neuron apoptosis in penumbra region was conteracted by CBX (P<0.05). CONCLUSIONS: TXL could effectively protect against I/R injury and reduced cell death via Cx43/Calpain II/Bax/Caspase-3 pathway, which contribute to I/R injury prevention and therapy.

Advances in mechanisms of Tongxinluo Capsule in treatment of ischemic stroke / 中草药

Globally, stroke is the second leading cause of death and a major global disability. In China, it has exceeded heart disease to become the leading cause of death. Thus, it is urgent to prevent and treat stroke, particularly ischemic stroke. At present, except the tissue plasminogen activator (tPA) only therapy for ischemic stroke with proven efficacy, the others still lack evidence of evidence-based medicine or their curative effects are insufficient. However, in recent years, Chinese medicine, such as Tongxinluo Capsule, in treatment of ischemic stroke has attracted extensive attention. This article reviewed the research progress in mechanisms of Tongxinluo Capsule in treatment of ischemic stroke from two aspects: vascular protection and neuroprotection.

Effect of Tongxinluo capsule combined with metoprolol on elderly patients with coronary heart disease and angina pectoris and its influence on hemorheology and inflammatory factors / 中国基层医药

Objective To investigate the effect of Tongxinluo capsule combined with metoprolol on elderly patients with coronary heart disease and angina pectoris and its influence on hemorheology and inflammatory factors.Methods 135 elderly patients with angina pectoris of coronary heart disease were selected,and they were randomly divided into treatment group (68 cases) and control group (67 cases).The treatment group was treated with Tongxinluo capsule combined with metoprolol,while the control group was treated with metoprolol.The two groups were treated for 8 weeks.The curative effect of the two groups was compared,the number and duration of angina pectoris,the changes of hemorheology and inflammatory factors before and after treatment were compared.Results The total effective rate of the treatment group (94.12％) was higher than 76.12％ of the control group (P ＜ 0.05).After treatment,the frequency and duration of angina pectoris in the treatment group were (6.03 ± 1.21) times/week and (3.02 ± 0.76) min/time,respectively,which were significantly lower than those in the control group [(9.87 ± 1.46) times/week and (4.86 ± 0.98) min/time] (t =16.649,12.201,all P ＜ 0.05).After treatment,the whole blood viscosity at high shear rate [(3.76 ± 0.41) mPa/s],whole blood viscosity in low shear [(8.13 ± 0.76) mPa/s],plasma viscosity [(1.23 ± 0.08) mPa/s],erythrocyte aggregation index [(2.06 ± 0.27)],fibrinogen [(2.46 ± 0.41) g/L] in the treatment group were lower than those in the control group[(4.53 ± 0.52) mPa/s,(9.61 ± 0.89) mPa/s,(2.09 ± 0.27) mPa/s,(2.63 ± 0.35),(3.53 ± 0.62) g/L] (t =9.562,10.396,25.170,10.604,11.844,all P ＜ 0.05).After treatment,the interleukin-6 (IL-6) [(8.49 ± 1.76) pg/mL],intercellular adhesion molecule-1 (ICAM-1)[(85.25 ± 8.92) pg/mL],C reactive protein (CRP) [(8.74 ± 1.76) mg/L] in the treatment group were lower than those in the control group[IL-6 (11.32 ± 2.10) pg/mL,ICAM-1 (103.42 ± 10.72) pg/mL,CRP (14.98 ± 2.24)mg/L] (t =8.491,10.712,18.012,all P＜0.05).Conclusion Tongxinluo capsule combined with metoprolol in the treatment of elderly patients with coronary heart disease angina pectoris has obvious curative effect,and can improve the patients'blood rheology and inflammatory reaction.

Effects of Tongxinluo Capsules on Serum CyPA and MMP-9 Levels in Patients with Coronary Heart Disease after PCI / 中国药房

OBJECTIVE:To investigate the effects of Tongxinluo capsules on the levels of serum cyclophilin A (CyPA) and matrix metalloproteinase-9 (MMP-9) in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI).METHODS:A total of 115 CHD patients undergoing PCI were randomly divided into control group (59 cases) and observation group (56 cases).Control group was given conventional treatment.Observation group was additionally given Tongxinluo capsules 0.78 g,3 times a day,for consecutive 6 months,on the basis of control group.The levels of CyPA and MMP-9 as well as the occurrence of ADR were observed in 2 groups before and after treatment.RESULTS:Before treatment,there was no statistical significance in serum level of CyPA and MMP-9 between 2 groups (P＞0.05).The levels of CyPA in 2 groups 1 d and 1 month after surgery as well as the level of CyPA in control group 6 months after surgery were all significantly higher than before surgery,but the observation group was significantly lower than the control group 1 and 6 months,this index was decreased gradually as time,with statistical significance (P＜0.05).There was no statistical significance in the levels of CyPA between 2 groups 1 d after surgery or in observation group between 6 months after surgery and before surgery (P＞0.05).The levels of MMP-9 in 2 groups 1 d and 1 month after surgery were significantly higher than before surgery,and the observation group was significantly lower than the control group,this index was decreased gradually as time,with statistical significance (P＜0.05).There was no statistical significance in the levels of MMP-9 of 2 groups between 6 months after surgery and before surgery(P＞0.05).There was no statistical significance in the incidence of ADR between 2 groups (P＞0.05).CONCLUSIONS:Based on routine treatment,Tongxinluo capsules can significantly reduce the levels of CyPA and MMP-9 in CHD patients after PCI.

Effects of Tongxinluo capsule and Shen Mai injection in treatment of patients with acute decompensated heart failure and its effect on level of left ventricular ejection fraction, hs-CRP, BNP and QTcd / 中国生化药物杂志

Objective To study the effects of Tongxinluo capsule and Shen Mai injection in treatment of patients with acute myocardial infarction and its effects on level of left ventricular ejection fraction (LVEF),high sensitive C-reactive protein (hs-CRP),natriuretic peptide (BNP) and QT in acute decompensated heart failure ( QTcd) .Methods 82 patients with acute decompensated heart failure were selected in our hospital from May 2014 to April 2015, those patiens were divided into observation group and control group according to the method of lottery, 41 cases each group.The control group was treated with basic treatment and Huangxin injection, and the obsevation group was treated with Tongxinluo capsule on the basis of the control group.The changes of blood pressure, heart rate, LVEF, hs-CRP, BNP and QTcd were compared between the two groups before and after treatment. Results After treatment, the total effective rate of the observation group was significantly higher than the control group [92.68% (38/41) vs 60.97%(25/41)](P<0.05).The heart rate of the observation group was significantly lower than the control group (P<0.05), but the blood pressure level of the two groups had no significant difference.The levels of BNP, hs-CRP and QTcd in the observation group were significantly higher than the control group [(45.98 ±4.57)% vs(39.07 ±3.12)%](P<0.05) L, BNP, hs-CRP and QTcd were significantly lower than the control group [(2432.12 ± 114.32)ng/L,(17.32 ±1.87) mg/L, (34.76 ±3.02) ms vs (3565.87 ±174.76) ng/L, (14.08 ±1.23) mg/L,(38.45 ±3.86)].Adverse reactions were not observed in the observation group and the control group.Conclusion Tongxinluo capsule combined with Shen Mai injection can effectively increase the left ventricular ejection fraction and reduce hs-CRP, BNP and QTcd in patients with acute decompensated heart failure.The clinical curative effect is good and the safety is high.

The effect of Tongxinluo capsule combined with Jinlida sintervention on vascular ;endothelial fuction and blood glucose in the patients with Type 2 diabetes / 国际中医中药杂志

Objective To observe the effect of Tongxinluo capsule combined with Jinlidas intervention on vascular endothelial fuction and blood glucose in the patients with Type 2 diabetes. Methods A total of 100 patients with Type 2 diabetes were randomly divided into treatment and control groups with 50 patients each. Both groups were received subcutaneous injection insulin, oral admistration of Simvastatin and Aspirin. And the treatment group were received Tongxinluo capsule and Jinlida sintervention based on the standard treatment. The changes of serum levels of FPG, 2hPG, HbAlc, VEGF, NO, ET-1 were observed before and after treatement. All the patients were treated for 12 weeks. Results After the treatment, the serum of FPG (7.03 ± 2.11 mmol/L vs. 8.09 ± 2.03 mmol/L, t=1.911), 2hPG (9.27 ± 2.03 mmol/L vs. 12.06 ± 3.54 mmol/L, t=1.946), HbAlc (6.98%± 1.58%vs. 8.06% ± 2.13%, t=2.013) were decreasd (P<0.05). Besides, VEGF (684.61 ± 84.37 ng/L vs. 514.28 ± 79.52 ng/L, t=2.136), NO (43.28 ± 6.40 ng/L vs. 34.64 ± 6.70 ng/L, t=2.097) of treatment group were siginificantly higher than the control group (P<0.05), while ET-1 (53.13 ± 7.24μmol/L vs. 60.09 ± 7.18μmol/L, t=2.271) were siginificantly lower (P<0.05). Conclusion Tongxinluo capsule combined with Jinlida sintervention could decreased the level Blood glucose and improve vascular endothelial fuction in the patients with Type 2 diabetes.