Hospital Centralized Monitoring of Post-market Clinical Safety of Naoxintong Capsules in 7 345 Patients / 中国实验方剂学杂志

ObjectiveTo evaluate the clinical safety of Naoxintong （NXT） capsules after marketing， find out the potential risk factors of the drug as soon as possible， and reveal the incidence， nature， and clinical manifestations of the adverse events （ADE） and adverse reactions （ADR） of NXT capsules， so as to provide a basis for safe use of the drug in clinical practice. MethodA prospective， large-sample， multi-center observational cohort study was conducted to monitor all the 7 345 inpatients and outpatients orally taking NXT in 14 hospitals in China from January to December in 2018， with at least one follow-up. The demographic characteristics， disease type， NXT medication， ADR occurrence， characteristics， and prognosis of the patients were collected. SPSS 23.0 was used for single-factor and multivariate logistic regression to predict the influencing factors of ADR. ResultThe male and female patients accounted for similar proportions. There were 5 081 patients （79.40%） aged ≥60 years and 3 153 patients （49.27%） with body mass index （BMI） exceeding the normal standard. There were 344 （5.38%） patients with a history of allergy to medicines and food， 9 （0.14%） patients with a family history of allergy， and 52 （0.81%） patients with a history of allergic diseases. The ADRs associated with NXT occurred in 22 patients， with the incidence of 0.34%. The clinical manifestations of ADR appeared in 31 cases， involving 10 organs/systems， of which gastrointestinal system damage was the most common （17， 54.84%）. All ADRs were mild or moderate. Most ADRs （19， 86.36%） occurred within 4 weeks after administration. The patients with alleviated NXT-associated ADRs accounted for 81.82%. No indicators related to significant increases in ADR risks were found. ConclusionNXT is well tolerated in the general population. The hospital centralized monitoring for the clinical safety of oral Chinese patent drugs based on HIS data and Web tracking and follow-up system is an essential means for the post-market research on the safety of drugs.

Naoxintong Capsules Treat Cardiac Injury after Cerebral Ischemia via TLR2/TLR4 Signaling Pathway / 中国实验方剂学杂志

ObjectiveAfter the brain and heart injuries were simulated by myocardial injury caused by acute cerebral ischemia， this study explored the mechanism of Naoxintong capsules in treating brain and heart injuries under cerebral ischemia state with Toll-like receptor （TLR） 2/TLR4 as the breakthrough point. MethodC57BL/6 male mice were randomly assigned into the sham operation， model， Naoxintong， and Ginaton groups. The middle cerebral artery occlusion （MCAO） method was used to establish a mouse model of cerebral ischemia. The neuroethological score， cerebral infarction area， cell apoptosis， ionized calcium-binding adaptor molecule 1 （IBA-1）-positive microglia proportion， and serum levels of N-terminal pro-brain natriuretic peptide （NT-proBNP）， creatine kinase-MB （CK-MB）， and lactic dehydrogenase （LDH） were determined to evaluate the pharmacodynamic effects of Naoxintong capsules on heart and brain injuries after cerebral ischemia in mice. Western blotting was employed to determine the expression of TLR2/TLR4 protein in the brain and heart of mice. ResultCompared with the sham operation group， the model group showed increased cerebral infarction area， neuroethological score， apoptosis rate， IBA-1-positive microglia proportion， and serum levels of NT-proBNP， CK-MB， and LDH （P<0.01）. Naoxintong capsules reduced the cerebral infarction area， neuroethological score， apoptosis rate， IBA-1-positive microglia proportion （P<0.01）， and serum NT-proBNP and CK-MB levels （P<0.05） in mice compared with the model group. Western blotting results showed that Naoxintong Capsules down-regulated the expression levels of TLR2 （P<0.05） in the brain and TLR2 （P<0.01） and TLR4 （P<0.05） in the heart. ConclusionCerebral ischemia can cause myocardial damage， reflecting the pathological process of cardiac injury after cerebral ischemia. Naoxintong capsules can mitigate brain and heart injuries after cerebral ischemia and achieve the simultaneous treatment of the brain and the heart， in which TLR2/TLR4 plays a role.

Protective Effect of Naoxintong Capsule () Combined with Guhong Injection () on Rat Brain Microvascular Endothelial Cells during Cerebral Ischemia-Reperfusion Injury / 中国结合医学杂志

OBJECTIVE@#To investigate the synergistic effect of Naoxintong Capsule (NXTC, ) and Guhong Injection (GHI, ) on cerebral ischemia-reperfusion (I/R) injury.@*METHODS@#Forty-eight Sprague-Dawley rats were divided into 6 groups: control group, oxygen and glucose deprivation (OGD) group, nimodipine group (9.375 mg/kg), NXTC group (0.5 g/kg), GHI group (5 mL/kg) and NXTC+GHI group (0.5 g/kg NXTC+5 mL/kg GHI), after the onset of reperfusion and once per day for the following 7 days. Blood was collected 1 h after final administration, and the sera were collected. Cultured primary rat brain microvascular endothelial cells (rBMECs) were subjected to OGD to establish a cell injury model. Untreated rBMECs were used as blank control. The cell counting kit-8 assay was used to assess cell viability using the sera. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assessed using an enzyme-linked immunosorbent assay. Apoptosis was evaluated after Hoechst33342 staining using fluorescence microscopy and flow cytometry. JC-1 staining was performed to assess changes in mitochondrial membrane potential.@*RESULTS@#Statistical analysis indicated that more than 95% of the cells were rBMECs. Compared with the OGD group, the cellular morphology of the all drug delivery groups improved. In particular, the combined drug group had the most significant effect. Compared with the OGD group, all drug intervention groups induced a decrease in the apoptotic rate of rBMECs, increased the SOD levels, and decreased the MDA levels (all P<0.01). Compared with the mono-therapy groups, the NXTC+GHI group exhibited a significant improvement in the number of apoptotic rBMECs (P<0.01). All drug intervention groups showed different degrees of increase in membrane potential, and the NXTC+GHI group was higher than the NXTC or GHI group (P<0.01).@*CONCLUSION@#The combinationa application of NXTC and GHI on cerebral I/R injury clearly resulted in protective benefits.

Efficacy of Naoxintong capsule combined with butylphthalide injection on acute cerebral infarction and its effects on inflammatory factors, oxidative stress response and hemorheology / 中国基层医药

Objective:To investigate the effect of Naoxintong capsule combined with butylphthalide injection on inflammatory factors, oxidative stress response and hemorheology in patients with acute cerebral infarction. Methods:Eighty-six patients with acute cerebral infarction who received treatment in Zhuji Hospital of Traditional Chinese Medicine from December 2017 to December 2019 were included in this study. Thrombolysis and thrombectomy were contraindicated in these patients. They were randomly assigned to receive treatment either with butylphthalide injection (control group, n = 43) or butylphthalide injection and Naoxintong capsule (observation group, n = 43) for 2 weeks. Therapeutic effects, Barthel Index, inflammatory factors (C-reactive protein, intercellular adhesion molecule-1 and interleukin-6), oxidative stress response (malondialdehyde and superoxide dismutase) and hemorheology (whole blood viscosity at high and low shear rates, plasma viscosity and fibrinogen) were compared between the two groups. Results:Total effective rate in the observation group was significantly higher than that in the control group (93.02% vs. 72.09%, χ2 = 6.541, P < 0.05). After treatment, Barthel Index in the observation group was significantly higher than that in the control group [(61.51 ± 5.24) points vs. (50.43 ± 4.81) points, t = 10.215, P < 0.05). After treatment, serum levels of C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 in the observation group were (4.42 ± 1.03) mg/L, (84.23 ± 5.05) μg/L and (94.33 ± 10.22) μg/L, respectively, which were significantly lower than those in the control group [(8.32 ± 1.71) mg/L, (103.51 ± 6.35) μg/L, (118.92 ± 13.31) μg/L, t = 12.810, 15.583, 9.609, all P < 0.05]. After treatment, serum malondialdehyde level in the observation group was significantly lower than that in the control group [(3.76 ± 0.78) μmol/L vs. (4.94 ± 0.90) μmol/L, t = 6.497, P < 0.05]. Serum superoxide dismutase level in the observation group was significantly higher than that in the control group [(35.76 ± 2.65) U/L vs. (30.34 ± 2.11) U/L, t = 10.492, P < 0.05]. After treatment, whole blood viscosity at high and low shear rates, plasma viscosity and fibrinogen levels in the observation group were (4.10 ± 0.51) mPa · s, (9.31 ± 1.36) mPa · s, (1.24 ± 0.26) mPa · s and (2.71 ± 0.40) g/L respectively, which were significantly lower than those in the control group [(5.72 ± 0.76) mPa · s, (11.49 ± 1.59) mPa · s, (2.21 ± 0.32) mPa · s and (3.92 ± 0.54) g/L, t = 11.607, 6.832, 15.427 11.807, all P < 0.05). Conclusion:Naoxintong capsule combined with butylphthalide injection is highly effective in the treatment of acute cerebral infarction. It can reduce inflammatory reaction and improve oxidative stress response and hemorheological changes.

Effects of Active Components of Naoxintong Capsule on the Proliferation of HUVEC and Its JAK/STAT Signal Pathway，Vasoactive Substances ，Adhesion Molecules and Inflammatory Factors / 中国药房

OBJECTIVE：To study the effects of the main active components of Naoxintong capsule （NXTC）on the proliferation of human umbilical vein endothelial cell（HUVEC） and its key protein JAK/STAT signal pathway ， vasoactive substances ，adhesion molecules and inflammatory factors so as to clarify the m echanism of NXTC for promoting blood circulation and removing blood stasis. METHODS ：The effects of different concentration of 12 active components [caffeic acid（1.56-200 μmol/L），ferulic acid （1.56-200 μmol/L），senkyunolide H （3.125-200 μmol/L），n-butylidenephthalide（3.125-200 μmol/L），ligustilide（1.56-200 μmol/L），cryptotanshinone（0.625-80 μmol/L），tanshinol sodium （1.56-200 μmol/L），paeoniflorin （1.56-200 μmol/L），formononetin（1.56-200 μmol/L），salvianolic acid B （1.56-200 μmol/L），catechin（1.56-200 μmol/L）and astragaloside Ⅳ（1.56-200 μmol/L）] on the proliferation of HUVECs were evaluated by CCK- 8 assay. The effects of above active components（3 dose groups ，setting up 0 μmol/L blank control group，hereinafter）on mRNA expression of key proteins JAK 2， STAT3，Akt，ERK in JAK/STAT signal pathway were measured by RT-PCR. The effects of each active component on the expression of PAI- 1，VCAM-1，ICAM-1，VEGF and NF-κB p65 were detected by ELISA. RESULTS ：Ferulic acid （6.25，25-200 μg/mL），senkyunolide H （6.25-200 μmol/L），ligustilide（200 μmol/L），cryptotanshinone（10-80 μmol/L），paeoniflorin（1.56， 6.25，12.5 μmol/L），salvianolic acid B （1.56-12.5 μmol/L，200 μmol/L）and catechin （25 μmol/L）could significantly inhibit the proliferation of HUVECs ；caffeic acid （1.56，12.5 μmol/L），ligustilide（50 μmol/L），trashinol sodium （6.25 μmol/L）and paeoniflorin（1.56，100，200 μmol/L）could significantly promote the proliferation of HUVECs （P＜0.05 or P＜0.01）. Compared with blank control group ，mRNA expression of JAK 2，STAT3 and Akt were decreased significantly in some dose groups of ferulic acid，formononetin，salvianolic acid B and astragaloside Ⅳ（P＜0.05 or P＜0.01）；the expression of PAI- 1 were significantly decreased in some dose groups of caffeic acid ，ferulic acid and n-butylphthalide；the expression of ICAM- 1 and VCAM- 1 were decreased significantly in some dose groups of caffeic acid ，ferulic acid ，n-butenylphthalide，cryptotanshinone，formononetin and catechin；the expression of NF-κB p65 were decreased significantly in some dose groups of ferulic acid ，n-butenylphthalide， formononetin，salvianolic acid B and astragaloside Ⅳ；the expression of VEGF were increased significantly in some dose groups of caffeic acid and catechin （P＜0.05 or P＜0.01）. CONCLUSIONS ：The active components of Naoxintong capsule may play the role of promoting blood circulation and removing blood stasis by inhibiting the expression of JAK/STAT signal pathway key protein mRNA and PAI- 1，ICAM-1，VCAM-1，NF-κB p65 in HUVEC ，and promoting the expression of VEGF.

Clinical comprehensive evaluation of Naoxintong Capsules in treatment of cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris / 中国中药杂志

Through investigating the current research on the effect of Naoxintong Capsules in the treatment of cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris, this study conducted a clinical comprehensive evaluation in "6+1" dimensions [safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine(TCM)], so as to highlight the advantages and clinical value of Naoxintong Capsules. By combining qualitative and quantitative methods, we used the multi-criteria decision analysis(MCDA) model to measure each dimension, and the results thereby were divided into four grades of A, B, C, and D in high-to-low order. Through literature review and evaluation, the adverse effects of Naoxintong Capsules are mainly caused by the gastrointestinal system. Since the safety risk is controllable based on current research, the safety evaluation is grade B. The effectiveness of Naoxintong Capsules combined with conventional western medicine in the treatment of cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris is evaluated as grade A, as compared with conventional therapy alone. The economy of Naoxintong Capsules, compared with Tongxinluo Capsules, is assessed as grade B. According to literature reports, Naoxintong Capsules exhibits outstanding clinical innovation in optimizing the current anti-platelet therapy strategy for patients with coronary heart disease after percutaneous coronary intervention(PCI), and the innovation is class A. Given the capsule formulation is convenient for storage and transportation, and its usage is easy for patients to grasp and accept, the suitability is grade B. The accessibility is grade A considering the price level, availability, and affordability, and the characteristics of TCM are evaluated as grade A from the perspectives of theoretical characteristics and human experience. The results of the comprehensive drug evaluation showed that the clinical value of Naoxintong Capsules is class A for treating cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris. According to the Guidelines for the Management of Comprehensive Clinical Evaluation of Drugs(trial 2021 version) issued by the National Health Commission, relevant policy results for basic clinical drug management can be formulated directly by procedure.

Naoxintong Inhibits LPS Induced BV2 Cell Pyroptosis by NLRP3/Caspase-1 Signaling Pathway / 中国实验方剂学杂志

Objective::To explore the effect of Naoxintong ethanol extract (NXT) on pyroptosis of BV2 microglia cells induced by lipopolysaccharide (LPS), and to explain the mechanism of pyroptosis based on NOD like receptor thermoprotein domain 3 (NLRP3)/cysteine-proteinase-1 (Caspase-1) pathway. Method::BV2 cells was treated with different concentrations of NXT(2, 10, 50 mg·L-1) after induced by LPS(1 mg·L-1) in vitro. Real-time PCR was used to detect mRNA expression of pro-inflammatory cytokine such as interleukin 1 beta (IL-1β), tumor necrosis factor (TNF)-α, and NLRP3.Western bolt and immunofluorescence were used to observe the protein expression of NLRP3/Caspase-1 signaling pathway. Result::Compared with control group, after LPS(1 mg·L-1) stimulation, BV2 cells viability was decreased. The mRNA expression levels of IL-1β, TNF-α and NLRP3 were significantly elevated(P<0.01), the protein levels of NLRP3 and Caspase-1 p20/Caspase-1 were also increased. After given NXT(2, 10, 50 mg·L-1), BV2 cells viability reversed which induced by LPS. Compared with LPS group, the mRNA expression of IL-1β, TNF-α and NLRP3 reduced obviously with given 50 mg·L-1NXT (P<0.05, P<0.01), significantly inhibited NLRP3 high protein expression and Caspase-1 p20/Caspase-1 expression(P<0.01). Conclusion::NXT can inhibit LPS induced pyroptosis of BV2 cells and the mechanism may closely related to NLRP3/Caspase-1 signaling pathway.

Effect of Naoxintong capsule on blood lipids and hemorheology in the treatment of type 2 diabetes mellitus patients complicated with cerebral infarction with Qi deficiency and blood stasis type / 中国基层医药

Objective To observe the effect of Naoxintong capsule on blood lipid and hemorheology in the treatment of type 2 diabetes mellitus patients complicated with cerebral infarction with Qi deficiency and blood stasis type.Methods From February 2015 to February 2017,96 type 2 diabetes mellitus patients complicated with cerebral infarction with Qi deficiency and blood stasis type who treated in the Traditional Chinese Medicine Hospital of Tongxiang were selected in the research.The patients were randomly divided into two groups according to the digital table,with 48 cases in each group.The control group was treated with routine treatment scheme,while the observation group was added Naoxintong capsule.The blood lipids and hemorheology data before and after treatment were compared between the two groups.Results After treatment,the levels of LDL-C,TG,TC and HDL-C in the observation group were (1.8 ± 0.3) mmol/L,(0.9 ± 0.4) mmol/L,(2.1 ± 0.4) mmol/L,(1.6 ± 0.7) mmol/L,respectively,which were lower than those in the control group [(2.2 ± 0.4) mmol/L,(1.2 ± 0.6) mmol/L,(2.3 ± 0.3)mmol/L,(1.3 ±0.4) mmol/L] (t =5.54,2.88,3.18,2.58,all P ＜0.05).The HCT,ESR,EEP,Fig in the observation group were (41.5 ± 1.3) ％,(16.5 ± 2.1) mm/h,(292.1 ± 18.3) s,(7.6 ± 0.4) g/L,respectively,which were lower than those in the control group[(45.6 ± 1.4)％,(21.1 ± 3.2)mm/h,(332.3 ± 19.2)s,(8.2 ± 0.3) g/L] (t =14.87,8.33,10.50,8.31,all P ＜ 0.05).Conclusion Naoxintong capsule is effective in the treatment of type 2 diabetes mellitus patients complicated with cerebral infarction with Qi deficiency and blood stasis type,and can effectively improve the related indicators of blood lipids and hemorhelogy and stabilize the carotid artery plaque,it is worthy of clinical application.

Mechanisms and Components Identification of Naoxintong Intestinal Absorption Liquid Protecting Cardiac Injury Induced by H2O2 / 中国实验方剂学杂志

Objective: Intestinal absorption liquid as medicine carriers, one or more kinds of traditional Chinese medicine protecting cardiac injury in Naoxintong capsule will be found through separation and combination of prescription. This study also can expand protecting mechanisms of Naoxintong capsule. Method: Naoxintong intestinal absorption liquids of single, combination and total prescription were prepared. H9c2 cell line exposed to H2O2 was established. Cell survival rate was determined with methyl thiazolyl tetrazolium(MTT). Cell apoptosis rate was examined by Annexin Ⅴ-FITC/PI staining with a flow cytometer. Aquaporin1(AQP1) expression was detected by Western blot. One or more kinds of traditional Chinese medicine in Naoxintong capsule which exerted protective effect from cardiac injury were screened through separation and combination of prescription. Result: As compared with control group, the protein expression level of AQP1 was significantly increased(PPPPPPConclusion: Naoxintong capsule acts as a protective role in myocardial injury through decreasing AQP1 expression and inhibiting cell apoptosis. Salviae Miltiorrhizae Radix et Rhizoma, Pheretima, Scorpio are important components in Naoxintong capsule.

Simultaneous determination of seven index components in Naoxintong capsule by HPLC wavelength switching method / 中国药科大学学报

@#An HPLC-DAD wavelength switching method(240 nm, 280 nm, 316 nm, 403 nm)was developed for simultaneous determination of seven index components: hydroxysafflor yellow A, paeoniflorin, ferulic acid, salvianolic acid B, kaempferol, formononetin and tanshinone IIA in Naoxintong capsule. The qualities of different batches of Naoxintong capsules were evaluated by statistical analysis. Seven index components in 20 batches of Naoxintong capsules were simultaneously determined by HPLC wavelength switching method with Capcell PAK C18 MG II column(250 mm × 4. 6 mm, 5. 0 μm). The mobile phase consisted of methanol-acetonitrile(25 ∶75, A)-0. 1% formic acid aqueous solution(B)with a gradient elution program and a flow rate of 1. 0 mL/min, and the column temperature was 30 °C. The results were analyzed by statistical analysis to evaluate the differences in the quality of Naoxintong capsules. Results showed that the seven active components were well separated and showed good linearity hydroxysafflor yellow A(403 nm)2. 30- 11. 50 mg/L(r=0. 999 2), paeoniflorin(240 nm)8. 81- 44. 05 mg/L(r=0. 999 6), ferulic acid(316 nm)1. 22- 6. 10 mg/L(r=0. 999 6), salvianolic acid B(280 nm)11. 61- 58. 05 mg/L(r=0. 999 4), kaempferol(403 nm)1. 16-5. 80 mg/L(r=0. 999 4), formononetin(240 nm)0. 12- 0. 60 mg/L(r=0. 999 5)and tanshinone IIA(280 nm)2. 28- 11. 40 mg/L(r=0. 999 5). The precision was good and RSD was less than 2. 0%, The repeatability was good and RSD was less than 2. 0%. The stability was good in 24 h. The average recoveries were between 97. 35%- 101. 02% and RSD was less than 2. 0%. The contents of target components in Naoxintong capsules, hydroxysafflor yellow A was 0. 213- 0. 369 mg/g, paeoniflorin was 1. 535- 3. 217 mg/g, ferulic acid was 0. 153- 0. 236 mg/g, salvianolic acid B was 2. 563- 3. 271 mg/g, kaempferol was 0. 103- 0. 181 mg/g, formononetin was 0. 022- 0. 028 mg/g, and tanshinone IIA was 0. 466- 0. 698 mg/g. HPLC wavelength change and gradient elution method was established for simultaneous determination of seven index components in Naoxintong capsule. The method is accurate, sensitive, reliable, and repeatable, and can be used for the quality control of Naoxintong capsule.

Identification of effective components from Naoxintong Capsules intestinal absorption liquid in inhibiting ADP-induced platelet aggregation / 中国中药杂志

Intestinal absorption liquid was prepared by using everted intestinal sac method; meanwhile, its recipes were decomposed or restructured. Platelet aggregation activity was examined by biochemical tests and a microplate reader. One or more kinds of Chinese medicines which displayed inhibiting activity in Naoxintong Capsules were screened through separation and combination of prescription. The results showed that Naoxintong Capsules could inhibit ADP-induced platelet aggregation. Recipe decomposition and restructuring results showed that Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Radix Rubra, Cinnamomi Ramulus and Hirudo were the main effective medicines in inhibiting platelet aggregation. Furthermore, Cinnamomi Ramulus played a vital role in inhibiting activity among those four kinds of Chinese medicines. Coumarin derived from intestinal absorption liquid of Cinnamomi Ramulus had inhibiting activity in the range of 50-200 μmol·L⁻¹, and other ingredients such as cinnamyl alcohol and cinnamaldehyde also had inhibiting activities. In conclusion, Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Radix Rubra, Cinnamomi Ramulus and Hirudo are the main components for inhibiting ADP-induced platelet aggregation, and Cinnamomi Ramulus has the most strongest inhibiting activity in Naoxintong Capsules.

Comparison of Aspirin and Naoxintong Capsule () with Adjusted-Dose Warfarin in Elderly Patients with High-Risk of Non-Valvular Atrial Fibrillation and Genetic Variants of Vitamin K Epoxide Reductase / 中国结合医学杂志

<p><b>OBJECTIVE</b>To compared the therapeutic effect of a Chinese patent medicine Naoxintong Capsule (, NXT) and aspirin with adjusted-dose warfarin in Chinese elderly patients (over 65 years) with nonvalvular atrial fibrillation (NVAF) and genetic variants of vitamin K epoxide reductase (VKORC1), who are at high-risk of thromboembolism.</p><p><b>METHODS</b>A total of 151 patients, with NVAF and AA genotype of VKORC1-1639 (a sensitive genotype to warfarin) and a CHADS-VASc clinical risk score of 2 or above, were chosen for this study. Patients were randomized into two groups and orally treated with a combination of aspirin (100 mg/day) and NXT (1.6 g thrice a day) or adjusted-dose warfarin [international normalized ratio 2.0-3.0). The primary end points including ischemic stroke and death as well as the secondary end points including hemorrhage events were followed up for at least 1 year.</p><p><b>RESULTS</b>Baseline clinical data and the rates of primary end points were similar between groups. However, the rate of serious bleeding (secondary event) in the combination therapy group was lower than that in the adjusted-dose warfarin group (0% vs. 7.9%, odds ratio: 0.921, 95% confidence interval: 0.862-0.984, P=0.028).</p><p><b>CONCLUSIONS</b>Aspirin combined with NXT and warfarin displayed comparable rates of primary end point including ischemic stroke and all-cause death during the 1-year follow-up. However, as compared with warfarin, the combination therapy reduced the rate of serious bleeding. Therefore, aspirin combined with NXT might provide an alternative pharmacotherapy in preventing ischemic stroke for elderly patients with NAVF who cannot tolerate warfarin. (No. ChiCTR-TRC-13003596).</p>

Study progress on chemical compounds, pharmacological action and clinical application of Naoxintong capsule / 中国中药杂志

Naoxintong capsule (NXTC) is an oral Chinese preparation produced by modern technology, derived from the classic preparation of Buyang Huanwu decoction which was recorded by WANG Qing-ren (Qing dynasty) in Yilingaicuo Juanxia Tanweilun. NXTC is composed of 16 herbs including insect herbs and some blood circulation herbs, with the effects of supplementing Qi and activating blood circulation, dispersing blood stasis and dredging collaterals. In clinical application, it is mainly used for stroke, cerebral infarction, vascular dementia, ischemic cerebrovascular disease, transient ischemic attack, coronary heart disease, angina pectoris, ischemic cardiomyopathy, diabetic cardiomyopathy, myocardial infarction, chronic heart failure, chronic complications of diabetes, essential hypertension, hyperlipidemia and other cardiovascular and cerebrovascular diseases, and has achieved good therapeutic effect on above diseases or their concurrent diseases. Its clinical efficacy is mainly achieved through the improvement in related links of brain protection, neuroprotection, cardioprotection, hemorheology, et al. Nearly 200 chemical constituents identified in NXTC are important pharmacological basis for its functions. At present, however, most of its pharmacological basic researches are focused on plant herbs, and the three kinds of insect herbs remain to be further studied. The researches on clinical effectiveness are more comprehensive; the safety study of long-term application in real world is ongoing by our team, and its results are yet to be published after finishing the study. Through the systematic and comprehensive combing and elaboration of the research progresses on the chemical compositions, pharmacological action and clinical application of NXTC, it can provide a reference for the in-depth study of this preparation, with a great significance for the quality control, secondary development and internationalization promotion of NXTC.

Protective effects and mechanism of Naoxintong Capsules on rat brain microvascular endothelial cells (rBMECs) induced by oxygen-glucose deprivation / 中草药

Objective: To investigate the protective effects and mechanism of Naoxintong Capsules (NXT) on primary cultured neonate rat brain microvascular endothelial cells (rBMECs) induced by oxygen-glucose deprivation. Methods: The primary cultured rBMECs model was established and the identification of rabbit anti-rat VIII factor was carried out. MTT was used to screen out the concentration range of NXT intestinal absorption solution to pretect rBMEC in vitro, three doses were selected for experiment. The experimental groups were divided into control group, model group, nimodipine group (200 μg/mL, NXT intestinal absorption solution group (62.50 mg/L, 125.00 mg/L, and 250.00 mg/L), and NXT intestinal absorption solution (250.00 mg/L) and LY294002 (20 μmol/L, PI3K/Akt pathway inhibitor) co-administration group. The morphology of rBMECs was observed under inverted microscope. The expression of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the cell supernatant was detected by ELISA kit. The apoptosis was observed by Hoechst33342 staining fluorescence microscope. The early apoptotic rate of rBMECs in each group was detected by FCM, and the expression of PI3K/Akt signaling pathway key proteins was detected by Western blotting. Results: Compared with model group, the administration of NXT could significantly improve the morphology of rBMECs, decrease the intracellular levels of LDH and MMP-9, significantly reduce the number of apoptotic cells and early apoptotic rate of rBMECs, and inhibit the expression of p-Akt, Bcl-2 upregulation, decrease the expression of Bax, and inhibit caspase-3 activity. The addition of LY294002, a specific inhibitor of PI3K/Akt signaling pathway, blocked the signal transduction of this pathway and significantly reduced the protective effect of NXT. Conclusion: NXT have protective effects on rBMECs induced by oxygen-glucose deprivation, and its mechanism is related to the PI3K/Akt signaling pathway.

The Chemical Constituents Study of Naoxintong Capsules Based on UHPLC-Q-Orbitrap HRMS / 中国药学杂志

OBJECTIVE: To establish a novel ultra-high performance liquid chromatography-quadrupole/orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) method to study the chemical composition of Naoxintong capsules rapidly and accurately. METHODS: The information of accurate mass in full-MS and multistage fragment ions was obtained by the novel UHPLC-Q-Orbitrap technology. Chemical constituents were identified by comparing the relative retention time and the mass data of the reference substances, meanwhile consulting the reference literature or the Mass Bank, Chemical Book network database. RESULTS: Forty-four compounds were finally identified in this study, mainly including flavones, authraquinones, terpenoids and organic acids. CONCLUSION: A method is established in this study to identify various chemical constituents of Naoxintong capsules rapidly, accurately and systematically. What's more, our research will lay a sound theoretical foundation and propose a scientific study idea for the quality control improvement, bioactive components recognition and further clinical application of this herbal formulation.

Clinical Efficacy of Levosimendan Combined with Naoxintong Capsule in Treatment of Acute Heart Failure and Effects on Serum NT-proBNP, Galectin-3, ET-1 and Cystatin C Levels / 现代生物医学进展

Objective:To study the clinical efficacy of levosimendan combined with naoxintong capsule in the treatment of acute heart failure and effects on the serum amino terminal B type natriuretic peptide precursor (NT-proBNP),Galectin-3,endothelin 1 (ET-1),Cystatin C levels.Methods:90 patients with acute heart failure from March 2015 to June 2016 in our hospital were selected and divided into observation group (n=45) and control group (n=45) by lottery method.Patients in the control group were treated by levosimendan alone.Patients in the observation group were treated by Naoxintong capsule combined with levosimendan.The clinical effect,changes of serum NT-proBNP,galectin-3,ET-1,cystatin C levels before and after treatment and the incidence of adverse reactions were compared between two groups.Results:After treatment,the total effective rate was 93.33％ in the observation group,which was higher than that in the control group (77.78％) (P＜0.05);the left ventricular fractional shortening,left ventricular ejection fraction,stroke volume of both groups were higher than those before treatment,the blood pressure,heart rate and serum NT-proBNP,galectin-3,ET-1,cystatin C levels were lower than before treatment,and LVFS,LVEF,SV levels of the patients in the observation group were significantly higer than those of the control group (P＜0.05),the blood pressure,heart rate and serum NT-proBNP,galectin-3,ET-1,cystatin C levels were lower than those of the control group (P＜0.05).Conclusion:Levosimendan combined with Naoxintong Capsule could improve the therapeutic effect of acute heart failure with higher safety and reduce the levels of serum NT-proBNP,Galectin-3,ET-1 and Cystatin C.

Effect of Naoxintong Capsule Combined with Nerve Growth Factor in Treatment of Hypertensive Cerebral Hemorrhage and Its Effect on Serum Levels of IL-6, MMP-9 and S 100B / 现代生物医学进展

Objective:To study the effect of naoxintong capsules combined with nerve growth factor on the serum levels of interleukin-6 (IL-6),matrix metalloproteinase-9 (MMP-9) and S100B of patients with hypertensive intracerebral hemorrhage.Methods:88 patients with hypertensive intracerebral hemorrhage who were treated in our hospital from August 2015 to July 2016 were selected and randomly divided into the observation group and the control group The patients in the control group were treated with nerve growth factor,while the patients in the observation group were treated with naoxintong capsules combined with nerve growth factor.Then the clinical efficacy,GCS,GOS score,serum levels ofIL-6,MMP-9 and S100B were observed and compared between the two groups.Results:After treatment,the total effective rate in the observation group was significantly higher than that the control group (P＜0.05).After treatment,the GCS and GOS scores of the two groups were significantly higher than before,and the GCS and GOS of the observation group were higher than those of the control group (P＜0.05).After treatment,the serum levels of IL-6,MMP-9 and S100B in the two groups were significantly lower than before,and the observation group were lower than those of the control group (P＜0.05).There was adverse reactions in the two groups.Conclusion:Naoxintong capsule combined with nerve growth factor can reduce the serum levels of IL-6,MMP-9 and S100B in patients with hypertensive intracerebral hemorrhage,with obvious clinical curative effect and high safety.

Efficacy Analysis of Naoxintong Capsules Combined with Edaravone in the Treatment of Acute Cerebral Infarction / 中国药房

OBJECTIVE:To investigate therapeutic efficacy and safety of Naoxintong capsules combined with edaravone in the treatment of acute cerebral infarction. METHODS:80 patients with acute cerebral infarction were analyzed retrospectively and divid-ed into observation group (40 cases) and control group (40 cases) according to drug use. Both groups was given Aspirin enter-ic-coated tablets 10 mg orally,once a day,to control platelet aggregation,20% Mannitol injection 250 mL intravenously,every 12 hours,to control brain edema,Potassium chloride sustained-release tablets 0.5 g orally,3 times a day,to maintain water and elec-trolyte balance and other conventional treatment. Control group was additionally given Edaravone injection 30 mg added into 0.9%Sodium chloride injection 100 mL intravenously within 30 min,once a day;observation group was additionally given Naoxintong capsules 1.6 g,3 times a day on the basis of control group. Treatment course of both groups lasted for 10 d. Clinical efficacies of 2 groups were observed as well as the ET-1 and NO content,IL-8,hs-CRP,FT3,FT4 and TSH level,NIHSS and ADL score,the occurrence of ADR before and after treatment. RESULTS:Total response rate of observation group was significantly higher than that of control group,with statistical significance(P0.05). After treatment,the ET-1 content,IL-8 and hs-CRP level,NIHSS score in 2 groups were significantly lower than before,and the observation group was lower than the control group;the NO content,TSH,ADL score in 2 groups were significantly higher than before,and the ob-servation groups was higher than the control group,with statistical significance(P0.05). No severe ADR was found in 2 groups. CON-CLUSIONS:Based on routine treatment,Naoxintong capsules combined with edaravone in the treatment of acute cerebral infarc-tion can improve therapeutic efficacy and vascular endothelial function,relieve inflammatory reaction and recue TSH levels,more-over,don't increase the occurrence of ADR.

Effect of Naoxintong capsule on clinical efficacy and inflammatory factors in patients with ischemic stroke / 中国基层医药

Objective To investigate the effect of Naoxintong capsule on clinical efficacy and inflammatory factors in patients with ischemic stroke.Methods 81 patients with ischemic stroke were divided into two groups according to random number table method.40 patients in the control group were treated with treatment guidelines,and the observation group was treated with another Naoxintong capsule.The serum interleukin-10(IL-10),tumor necrosis factor-a(TNF-α),high sensitivity C reactive protein (hs-CRP) level,National Institutes of Health Stroke Scale (NIHSS) and clinical efficacy of two groups were compared.Results After treatment,the hs-CRP,TNF-α levels of the observation group were (12.36 ± 3.09) mg/L,(129.62 ± 29.27) mg/L,which were lower than those of the control group[(1 6.71 ± 4.29) mg/L,(186.52 ± 37.62) ng/L,t =8.189,5.287,all P ＜ 0.05).After treatment for 7d and 30d,the NIHSS scores of the observation group were (14.28 ± 3.24) points,(5.23 ± 1.47) points,which were lower than those of the control group[(18.76 ±4.53)points,(8.16 ±2.42)points,t =14.689,12.827,all P ＜0.05].IL-10 level of the observation group was (49.82 ± 6.59) pg/mL,which was higher than (42.57 ± 9.82) pg/mL of the control group (t =6.759,P ＜ 0.05).The total effective rate of the observation group was 92.68％,which was higher than 77.50％ of the control group (x2 =4.897,P ＜ 0.05).Conclusion Naoxintong capsule has significant therapeutic effect on ischemic stroke,can effectively improve the inflammatory reaction after cerebral infarction,promote the recovery of neurological function and it is worthy of promotion.

Effect of Naoxintong on nuclear transcription factor -κB, matrix metalloproteinase-9 and TNF-αin the brain of ischemic rat models / 临床神经病学杂志

Objective To investigate the effect of Naoxintong on nuclear transcription factor-κB ( NF-κB ) , matrix metalloproteinase-9(MMP-9)and TNF-αin the brain of ischemic rat models.Methods One hundred and ten healthy male SD rats were randomly divided into sham operated group ( n=30 ) , model control group ( n=40 ) and Naoxintong treatment group(n=40).Each group was further divided into five sub group by 0.5d, 1 d, 3 d, 5 d and 7 d after ischemia-reperfusion.The middle cerebral artery occlusion ischemia reperfusion rat models were prepared by Zea Longa method;meanwhile the MRI and the Bederson score were used to select the successful models .In order to observe the changing process of the ischemic brain tissue after given Naoxintong capsule , six rats in each group each timepoint were examined by MRI .The expression levels of protein and mRNA of NF-κB, MMP-9 and TNF-αwere detected respectively by western blot and real time PCR .Results Cerebral infarction volume of Naoxintong treatment group was significantly reduced compared with the model control group .The mRNA and protein levels of NF-κB, MMP-9 and TNF-αof the Naoxintong treatment group decreased significantly compared with the model control group (P <0.05).The mRNA and protein levels of NF-κB, MMP-9 and TNF-αhad no significant difference between the sham group and Naoxintong treatment group .Conclusion Naoxintong has a neuroprotection effect on cerebral ischemia via alleviating the inflammatory factors in the ischemic area .