Efficacy and safety of Shexiang Baoxin pill (MUSKARDIA) in patients with stable coronary artery disease: a multicenter, double-blind, placebo-controlled phase IV randomized clinical trial.

BACKGROUND: The Shexiang Baoxin Pill (MUSKARDIA) has been used for treating coronary artery disease (CAD) and angina for more than 30 years in China. Nevertheless, methodologically sound trials on the use of MUSKARDIA in CAD patients are scarce. The aim of the study is to determine the effects of MUSKARDIA as an add-on to optimal medical therapy (OMT) in patients with stable CAD. METHODS: A total of 2674 participants with stable CAD from 97 hospitals in China were randomized 1:1 to a MUSKARDIA or placebo group for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability and angina frequency. RESULTS: In all, 99.7% of the patients were treated with aspirin and 93.0% with statin. After 2 years of treatment, the occurrence of MACEs was reduced by 26.9% in the MUSKARDIA group (MUSKARDIA: 1.9% vs. placebo: 2.6%; odds ratio = 0.80; 95% confidence interval: 0.45-1.07; P  = 0.2869). Angina frequency was significantly reduced in the MUSKARDIA group at 18 months (P = 0.0362). Other secondary endpoints were similar between the two groups. The rates of adverse events were also similar between the two groups (MUSKARDIA: 17.7% vs. placebo: 17.4%, P = 0.8785). CONCLUSIONS: As an add-on to OMT, MUSKARDIA is safe and significantly reduces angina frequency in patients with stable CAD. Moreover, the use of MUSKARDIA is associated with a trend toward reduced MACEs in patients with stable CAD. The results suggest that MUSKARDIA can be used to manage patients with CAD. TRIAL REGISTRATION: chictr.org.cn, No. ChiCTR-TRC-12003513.

Protective Effects of Salvianolate on Myocardial Injury or Myocardial Infarction after Elective Percutaneous Coronary Intervention in NSTE-ACS Patients: A Randomized Placebo-Controlled Trial.

OBJECTIVE: To evaluate the protective effects of salvianolate on percutaneous coronary intervention (PCI) related myocardial injury or myocardial infarction after elective PCI in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients. METHODS: A total of 149 patients with NSTE-ACS who underwent elective PCI were enrolled. The patients were randomly allocated in a 1:1 ratio to the salvianolate group (74 cases) or the control group (75 cases). After exclusion criteria of coronary angiography, 60 patients with PCI therapy remained in the salvianolate group and 68 in the control group. The incidence and the severity of PCI related myocardial injury or myocardial infarction, in addition to major adverse cardiac events (MACEs) during 1 year follow-up after PCI were studied between the two groups. Multivariate logistic regression analysis was used to determine the independent factors for PCI related myocardial injury or myocardial infarction after elective PCI. RESULTS: Compared with the control group, salvianolate treatment reduced the incidence of PCI related severe myocardial injury or myocardial infarction (11.7% vs. 26.5%, P=0.035). The rate of MACEs or all-cause death within 1 month or 1 year after the procedure was not significantly different between the two groups. CONCLUSIONS: Periprocedural treatment with salvianolate reduces the incidence of PCI related severe myocardial injury or myocardial infarction, although it does not influence clinical prognosis. [Chinese clinical trial registry: ChiCTR1800016992].

Comparative study of bioactive constituents in crude and processed Glycyrrhizae radix and their respective metabolic profiles in gastrointestinal tract in vitro by HPLC-DAD and HPLC-ESI/MS analyses.

Two HPLC methods with diode array detection (HPLC-DAD) and electrospray ionization-mass spectrometry (HPLC-ESI/MS), respectively, were developed to investigate the differences of chemical constituents and their metabolism in gastrointestinal tract in vitro between two decoctions of crude and processed Glycyrrhizae radix. Total of eleven constituents (liquiritin apioside, liquiritin, licuraside, isoliquiritin, ononin, glycyrrhizin, liquiritigenin-7,4'-diglucoside, licorice saponin A3, 22ß-acetoxylglycyrrhizic acid, licorice saponin G2, and yunganoside E2) were identified in the two decoctions, whereas lower contents of these constituents were usually found in the decoction of processed Glycyrrhizae Radix. [corrected] Furthermore, these constituents were metabolized into their respective aglycons in human intestinal bacteria juice, and the metabolism ratios were all higher in processed Glycyrrhizae Radix [corrected] decoction. No change was found in artificial gastric or intestinal juice. This study revealed that the processing can alter the contents of main constituents in crude G. radix and their metabolism in gastrointestinal tract, in which intestinal bacteria play an important role in the metabolism of licorice constituents.

Application of molecular markers in predicting production quality of cultivated Cistanche deserticola.

We developed a set of molecular markers in Cistanche deserticola Y. C. MA to evaluate the production quality of cultivated C. deserticola individuals. This application utilizes the inter-simple-sequence repeat (ISSR) polymerase chain reaction (PCR) and random amplified polymorphic DNA (RAPD) PCR as molecular markers to determine the echinacoside content in cultivated C. deserticola individuals. The unweighted pair-group method using arithmetic average clustering (UPGMA) confirmed that the combined ISSR and RAPD data could categorize all C. deserticola individuals into three groups according to their respective echinacoside content. The stepwise multiple regression analysis (SMRA) revealed six potential markers associated with echinacoside accumulation in C. deserticola and produced 18 echinacoside-marker prediction models, four of which were successfully used to predict the quality of C. deserticola from Neimenggu. Both clustering and SMRA showed a correlation between the echinacoside content and molecular markers in cultivated C. deserticola. The relative average deviation of prediction (RADP) of the prediction models could be improved by simplifying and adjusting the model. It was found that the RADP value could reach 2.6% after adjustment and the simplified prediction models could successfully predict the quality of cultivated C. deserticola individuals.

Three new acylated glycosides from the stems of Casearia velutina and their protective effect against H2O2-induced impairment in PC12 cells.

Chemical investigation of the stems of Casearia velutina led to the isolation and structural elucidation of three new acylated glycosides, casearicosides A-C (1-3), together with 13 known compounds. The structures of the new compounds were established by spectroscopic and chemical methods. These isolates were evaluated for protective effects against H(2)O(2)-induced impairment in PC12 cells and inhibitory activity against snake venom phosphodiesterase I. A brief chemotaxonomy of the genus Casearia is also discussed.

[Effects of shexiang baoxin pill on angiogenesis in atherosclerosis plaque and ischemic myocardium].

OBJECTIVE: To investigate the effects of Shexiang Baoxin Pill (SBP) in intervening atherosclerosis and myocardial infarction (AS-MI) in experimental animals, and inspect its influences on angiogenesis. METHODS: Twenty male New-Zealand rabbits were made into AS-MI model, and randomly divided into 2 groups equally. Group A was fed with high-fat diet for control; Group B was fed with high-fat diet but intervened with SBP. The cardiac function and the positive area of plaque were determined. The CD34 positive response intensity at infarcted marginal zone and aorta vessel wall, and the capillary density of myocardium were measured by immunohistochemical staining. In addition, the protein expressions of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) were detected by Western blot. RESULTS: Compared to Group A, the cardiac function was obviously improved (P<0.05) and the plaque positive area (%) was significantly decreased in Group B (45.82 +/- 3.68 vs 82.56 +/- 4.97, P<0.01). The CD34 positive response intensity and the capillary density as well as VEGF and VEGFR-2 expressions in infarcted marginal zone in Group A were higher than those in Group B (P<0.01); but these parameters at aorta vessel walls were lower in Group A than in Group B (P<0.01). CONCLUSION: SBP could advance the angiogenesis in the marginal zone of infarction, improve heart function, and embarrass angiogenesis in atherosclerotic plaque.

Oral L-arginine supplementation in acute myocardial infarction therapy: a meta-analysis of randomized controlled trials.

OBJECTIVE: The objective was to analyze completed trials assessing the effect of oral L-arginine supplementation on clinical outcomes of patients with acute myocardial infarction (AMI). BACKGROUND: Prior trials suggest that oral L-arginine administration improves endothelial function in patients with stable coronary artery disease (CAD). However, it is still unclear whether oral supplementation of L-arginine has any effect on clinical outcomes in patients with unstable CAD, such as AMI. METHODS: We systematically searched PubMed, Cochrane Library, Embase, reviews, and reference lists of relevant articles. The search strategy paired the term "arginine" with the following: "coronary heart disease," "myocardial infarction," "cardiovascular disease," "ischemia," and "trial." We conducted a meta-analysis of randomized, placebo-controlled L-arginine supplementation trials that evaluated clinical outcomes in AMI patients. Two reviewers independently assessed the trials. Differences were resolved by consensus. RESULTS: Only 2 trials (927 participants) were included. None of the 2 studies showed a significant difference in event rate between the L-arginine and placebo groups. In an overall pooled estimate, there was a 7% reduction in mortality in the L-arginine treatment group (105/459, 22.9%) compared with the control group (111/455, 24.4%), which did not reach statistical significance (risk ratio [RR]: 0.93, 95% confidence interval [CI]: 0.74-1.17; P = 0.54). CONCLUSION: Oral L-arginine supplementation has no effect on the clinical outcomes of patients with AMI.

Effects of Radix et Rhizoma Rhodiolae Kirilowii on expressions of von Willebrand factor, hypoxia-inducible factor 1 and vascular endothelial growth factor in myocardium of rats with acute myocardial infarction.

OBJECTIVE: To investigate the effects of Radix et Rhizoma Rhodiolae Kirilowii on angiogenesis and expressions of hypoxia-inducible factor 1alpha (HIF-1alpha), hypoxia-inducible factor 1beta (HIF-1beta) and vascular endothelial growth factor (VEGF) in myocardium of rats with acute myocardial infarction (AMI), to elucidate the possible mechanism of Radix et Rhizoma Rhodiolae Kirilowii in promoting angiogenesis, and to investigate that whether or not salidroside could be considered as the effective component of Radix et Rhizoma Rhodiolae Kirilowii with regard to the effects mentioned above. METHODS: Thirty-six male Wistar rats had the anterior descending branch of coronary artery ligated as AMI model. Rats were fed with normal saline (untreated group), Radix et Rhizoma Rhodiolae Kirilowii solution (Radix et Rhizoma Rhodiolae Kirilowii group) or salidroside solution (salidroside group) from 7 days before until 7 days after the operation, with twelve rats in each group. All rats were sacrificed 7 days after the operation. Immunohistochemical assay (IHC) was used for detecting the expression of von Willebrand factor (vWF); TaqMan real-time quantitative polymerase chain reaction (PCR) assay was employed for detection of the levels of HIF-1alpha, HIF-1beta and VEGF mRNAs; Western blot analysis was used for detection of the corresponding protein levels. RESULTS: Results of IHC index showed that both at infarct border zone and non-infarct zone, the expressions of vWF were significantly increased in Radix et Rhizoma Rhodiolae Kirilowii group as compared with the untreated group (P<0.05). The expressions of HIF-1alpha, HIF-1beta and VEGF mRNAs and the expressions of HIF-1alpha and VEGF proteins were significantly increased in the Radix et Rhizoma Rhodiolae Kirilowii group as compared with the untreated group (P<0.01). The level of HIF-1beta protein in the Radix et Rhizoma Rhodiolae Kirilowii group was also higher than that in the untreated group but the difference was not statistically significant (P>0.05). All the expression levels, including those of vWF, HIF-1alpha, HIF-1beta and VEGF, in the salidroside group were higher than those in the untreated group while lower than those in the Radix et Rhizoma Rhodiolae Kirilowii group. CONCLUSION: Radix et Rhizoma Rhodiolae Kirilowii may promote angiogenesis in myocardium of rats with AMI through elevating the expressions of HIF-1alpha, HIF-1beta, and VEGF. Salidroside may be one of the effective components in Radix et Rhizoma Rhodiolae Kirilowii, which increases the expressions of HIF-1alpha, HIF-1beta and VEGF during ischemia or hypoxia.

Inhibitory effect of triterpenoid saponins from the leaves of Ilex kudingcha on aggregated LDL-induced lipid deposition in macrophages.

We have investigated the inhibitory effect of triterpenoid saponins from the leaves of Ilex kudingcha C. J. Tseng on aggregated low-density lipoprotein (LDL)-induced lipid deposition in macrophages. A cell-based screening model was initially applied on aggregated LDL (aggLDL)-induced lipid deposition on macrophages to test the inhibitory effects of the 12 triterpenoid saponins from this plant. Eight of these compounds inhibited the formation of foam cells and reduced intracellular total cholesterol and triglyceride contents. Structure-activity relationship analysis showed the essential role of the delta-lactone ring for the biological activity. The promoter action of the OH group at the C-12 position, the number of monosaccharides in the sugar chain and the rhamnose at the terminal of the sugar chain is also discussed.

A new chalcone glycoside, a new tetrahydrofuranoid lignan, and antioxidative constituents from the stems and leaves of Viburnum propinquum.

A new chalcone glycoside ( 2) and a new tetrahydrofuranoid lignan ( 3), along with 12 known compounds, were isolated from the stems and leaves of Viburnum propinquum Hemsl. The structures of all isolated compounds were deduced using spectroscopic and chemical methods. Antioxidative activities of most phenolic compounds were evaluated. Compounds 1 (3,4,2',4'-tetrahydroxy- TRANS-chalcone), 2 (3,4,2',4'-tetrahydroxy- TRANS-chalcone-2'- O- beta- D-glucoside), 12 (quercetin), 13 ((+)-dihydroquercetin), and 14 (eriodictyol) showed antioxidative capacities in the DPPH and hydroxyl free-radical assays, with IC (50) values of 3.80-6.12 microg/mL, and 9.24-11.87 microg/mL, respectively. Compounds 1, 2, 12, 13, and 14 also exhibited inhibitory activities against lipid peroxidation in rat liver homogenate, with an inhibitory rate of 10.8-39.9 % at 20 microg/mL, 38.8-57.2 % at 100 microg/mL, and 44.2-72.4 % at 200 microg/mL, respectively.

Identification of Cistanche species by chemical and inter-simple sequence repeat fingerprinting.

Herba Cistanches is a common traditional Chinese medicine that has been used to reinforce the vital function of kidney and induce laxation for more than two thousands years. Four Cistanche species were found as Herba Cistanches in China herbal markets, including C. deserticola, C. tubulosa, C. salsa and C. sinensis. Phenylethanoid glycosides, particularly echinacoside and acteoside, are considered as active ingredients in Cistanche species. The contents of these compounds showed variation in different species and geographical sources. Standard chemical fingerprints were generated from each of four Cistanche species, which could be identification markers. In genetic analysis of Cistanche species, ninety-four inter-simple sequence repeat (ISSR) primers were used for polymerase chain reaction (PCR) amplification, and of which eight primers were found to be sufficient to distinguish different Cistanche species. As a result, the chemical fingerprint combined with the genetic fingerprint for distinction of Cistanche species could serve as markers for quality control of Herba Cistanches.

A new phenolic glycoside from the stems of Hydnocarpus hainanensis.

A new phenolic glycoside (1) was isolated from the stems of Hydnocarpus hainanensis, along with 11 known compounds. The structures of all compounds were deduced using 1D, 2D NMR spectroscopic methods. The anti-oxidation activities of several compounds were also evaluated.

Itosides J-N from Itoa orientalis and structure - anti-COX-2 activity relationship of phenolic glycosides.

Two new phenolic glycosides, itosides J (1) and K (2), two new cylcohexenoyl glycosides, itosides L (3) and M (4), a new flavone glycoside, itoside N (5), and echitin (6) were isolated from the extract of the bark, twigs, and leaves of Itoa orientalis, together with 22 known compounds. The structures were elucidated by means of UV, IR, MS, and NMR techniques, and the relative configuration of compound 3 was confirmed by X-ray crystallography. NMR data for 6 are reported for the first time. Compounds 1, 3, 5, and phenolic glycosides 7- 22 were also assayed for anti-inflammatory activity against COX-2. Compounds 8, 10, 12- 14, 16, 19, 24, 26, and 27 showed significant inhibitory effects, with inhibitory rates of 49.7-85.3% at 10 microM.

[Studies on chemical constituents from Elaeocarpus sylvestris].

OBJECTIVE: To study the chemical constituents of Elaeocarpus sylvestris. METHODS: The compounds were isolated by chromatographic methods and their structures were elucidated by physico-chemical properties and spectral analysis. RESULTS: Six compounds were isolated and identified as: 2-hydroxy-benzaldehyde (1), coniferyl alcohol (2), umbelliferone (3), scopoletin (4), beta-sitosterol (5), daucosterol (6). CONCLUSION: All above compounds are isolated from Elaeocarpus Genus for the first time.

[Effects of rhodiola on expression of vascular endothelial cell growth factor and angiogenesis in aortic atherosclerotic plaque of rabbits].

OBJECTIVE: To investigate the effects of rhodiola on expression of vascular endothelial cell growth factor (VEGF) and angiogenesis in aortic atherosclerotic plaque of rabbits. METHODS: Thirty male New Zealand rabbits were randomly divided into 3 groups equally, i. e. the control group (A) fed with common diet and treated with distilled water, the high fat diet group (B) and the rhodiola group (C) fed with diet containing 1.5% cholesterol and treated respectively with distilled water and rhodiola (1 mL/kg per day), all the treatments were administered via gastrogavage once a day for 9 successive weeks. Level of blood lipids in various groups was determined and compared at the end of the experiment. Meanwhile, the tissue sample of aorta was taken for observation through HE and Sudan red staining, for detecting the CD34 positive response intensity by immunohistochemical staining and the VEGF expression by Real-time fluorescent quantitative PCR and Western blot. RESULTS: Determination of blood lipids showed that in Group C, TC was 42.01 +/- 1.99 mmol/L, TG 4.83 +/- 0.75 mmol/L and LDL-C 38.40 +/- 0.74 mmol/L, all lower than those in Group B (70.74 +/- 2.66 mmol/L, 8.75 +/- 0.78 mmol/L and 51.05 +/- 0.34 mmol/L, respectively), showing statistical difference between groups (P < 0.05). The intima/media tunica thickness ratio and the CD34 positive area of plaque in Group C were all lower than those in Group B (0.35 +/- 0.03 vs 0.43 +/- 0.03 and 29.12 +/- 2.56% vs 39.28 +/- 3.48%, P <0.05). Besides, the VEGF expression in atherosclerotic plaque was also lower in Group C than that in Group B. CONCLUSION: Rhodiola has the effects of inhibiting atherosclerosis formation, decreasing the VEGF expression and suppressing the angiogenesis in the plaque.

Simultaneous analysis of multiple bioactive constituents in Rheum tanguticum Maxim. ex Balf. by high-performance liquid chromatography coupled to tandem mass spectrometry.

A simple, rapid method was developed using on-line high-performance liquid chromatography (HPLC)-diode array detection (DAD)/electrospray ionization mass spectrometry (ESI-MS) to simultaneously analyze multiple bioactive constituents in the extract of Rheum tanguticum Maxim. ex Balf. (Dahuang), a traditional Chinese medicine (TCM). Many bioactive constituents gave prominent [M-H]- ions in the negative ion ESI mass spectra. Among them, 41 different constituents including 16 anthraquinone derivatives, 7 phenylbutanone glucopyranosides, 4 stilbenes and 14 tannins were unambiguously identified or tentatively characterized based on their retention times, UV spectra and mass spectra in comparison with the data from standards or references. Meanwhile, some principles of fragmentation behavior for different types of constituents were proposed, which could contribute to the elucidation of these constituents in Rheum tanguticum.

Two new phenolic glycosides from the barks of Hydnocarpus annamensis and their anti-inflammatory and anti-oxidation activities.

Two new phenolic glycosides 1 and 2 were isolated from the barks of Hydnocarpus annamensis, along with eighteen known compounds. The structures of all compounds were deduced using spectroscopic methods. Anti-inflammatory and anti-oxidation activities were evaluated. Among the isolates, compounds 1, 5, 15 and 17 exhibited COX-2 inhibitory activities, with an inhibitory rate of 60.3 - 63.4 % at 10 microM. Compounds 7, 12, 13 and 20 showed anti-oxidation capacities in the DPPH free-radical assay, with a scavenging effect of 60.9 - 69.4 % at 50 microM, and 18.5 - 34.6 % at 10 microM.

Development of high-performance liquid chromatographic fingerprint for the quality control of Rheum tanguticum Maxim. ex Balf.

A novel, accurate and valid fingerprint method was developed by using high-performance liquid chromatography-photodiode array detection (HPLC-DAD) to control the quality of Rheum tanguticum Maxim. ex Balf. By comprehensively comparing chromatograms of all samples, our result revealed that the chromatographic fingerprint we developed combining similarity evaluation could efficiently identify and distinguish raw materials of R. tanguticum from different sources. Besides, 21 characteristic peaks in chromatogram of R. tanguticum were unambiguously confirmed by comparison of reference compounds based on their retention time (t(R)) and UV spectra.

Cytotoxic diterpenoids from the roots of Euphorbia ebracteolata.

Three new diterpenoids, yuexiandajisu D (1), E (2) and F were isolated from the roots of Euphorbia ebracteolata, along with eight known diterpenoids, jolkinolide B (4), jolkinolide A, ent-11alpha-hydroxyabieta-8(14),13(15)-dien-16,12alpha-olide (6), ent-(13S)-hydroxyatis-16-ene-3,14-dione, ent-3beta,(13S)-dihydroxyatis-16-en-14-one, ent-3-oxokaurane-16alpha,17-diol, ent-16alpha,17-dihydroxyatisan-3-one and ent-atisane-3beta,16alpha,17-triol. The structures of all compounds were deduced using spectroscopic methods and confirmed for 1 and 2 by single-crystal X-ray diffraction. A biogenetic pathway for the formation of 1 and 2 is proposed briefly. Cytotoxic activities were evaluated against ANA-1, B 16 and Jurkat tumor cells. Jolkinolide B (4) displayed modest activity on ANA-1, B 16 and Jurkat tumor cells with IC50 values 4.46 x 10(-2), 4.48 x 10(-2), 6.47 x 10(-2) microM, and ent-11alpha-hydroxyabieta-8(14),13(15)-dien-16,12alpha-olide (6) showed significant activity against ANA-1 and Jurkat cells with IC50 values 7.12 x 10(-3) and 1.79 x 10(-2) microM. Compound 1 was found to be slightly active against ANA-1 cells with an IC50 value 2.88 x 10(-1)microM. Structure-activity relationships of isolated compounds are also discussed.

[Effect of Zhenju Jiangya Tablet on the endothelial function of hyperlipidemic rabbits].

OBJECTIVE: To study the effect of Zhenju Jiangya Tablet (ZJ) on the injured endothelial cells and endothelium-dependent relaxation function of hyperlipidemia rabbits. METHODS: Male New Zealand rabbits were randomized into four groups: control group, hyperlipidemia group, ZJ group and sivastatin group. The endothelium-dependent relaxation function was evaluated by APV using intravascular Doppler, and the morphology of endothelial cells was detected by light microscopy and electron microscopy, and nitric oxide synthase was evaluated. RESULTS: ZJ reduced the lesions of hyperlipidemia vessels, and the APV after Ach injection of each group was (1.14+/-0.26), (1.74+/-0.59), (1.22+/-0.37) and (1.17+/-0.41) respectively. The eNOS of each group was (4.21+/-0.37), (1.43+/-0.88), (3.95+/-0.67) and (4.08+/-0.46) nmol x min(-1) x g(-1) respectively. CONCLUSION: ZJ can improve the abnormality of endothelial cells and endothelium-dependent relaxation function of hyperlipidemia.