Effect of Cerebralcare Granule® combined with memantine on Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: In elderly people, Alzheimer's disease (AD) is the most common form of dementia. It has been shown that traditional Chinese medicine (TCM) based on phytomedicines enhances the therapeutic effects of modern medicine when taken in conjunction with them. Modern medicine N-methyl-D-aspartate receptor (NMDA) antagonist memantine (Mm) are mainly used in the clinical treatment of AD. TCM Cerebralcare Granule® (CG) has long been an effective treatment for headaches, dizziness, and other symptoms. In this study, we employ a blend of CG and Mm to address Alzheimer's disease-like symptoms and explore their impacts and underlying mechanisms. AIM OF THE STUDY: The objective of our study was to observe the effects of CG combined with Memantine (Mm) on learning and memory impairment of AD mice induced by D-galactose and to explore the mechanism at work. MATERIALS AND METHODS: CG and Mm were combined to target multiple pathological processes involved in AD. For a thorough analysis, we performed various experiments such as behavioral detection, pathological detection, proteomic detection, and other experimental methods of detection. RESULTS: It was found that the combination of CG and Mm was significantly effective for improving learning and memory in AD mice as well as brain pathology. The serum and hippocampal tissue of AD mice were significantly enhanced with catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were decreased with this treatment. In AD mice, a combination of Mm and CG (CG + Mm) significantly increased the levels of the anti-inflammatory factors IL-4 and IL-10, decreased the levels of pro-inflammatory factors (IL-6, IL-1ß) and tumor necrosis factor-alpha (TNF-α), improved synaptic plasticity by restoring synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) expression in the hippocampus, enhanced Aß phagocytosis of microglia in AD mice, and increased mitochondrial respiratory chain enzyme complexes I, II, III, and IV, lead to an increase in the number of functionally active NMDA receptors in the hippocampus. Proteomic analysis GO analysis showed that the positive regulation gene H3BIV5 of G protein coupled receptor signal pathway and synaptic transmission was up-regulated, while the transsynaptic signal of postsynaptic membrane potential and regulation-related gene Q5NCT9 were down-regulated. Most proteins showed significant enriched signal transduction pathway profiles after CG + Mm treatment, based on the KEGG pathway database. CONCLUSION: The data supported the idea that CG and Mm could be more effective in treating AD mice induced by D-galactose than Mm alone. We provided a basis for the clinical use of CG with Mm.

Evaluation of herb-drug interactions between compound Danshen dripping pills and clopidogrel based on the pharmacokinetics and pharmacodynamics in rats.

Compound Danshen dripping pills (CDDP), a well-known traditional Chinese medicine, is widely used to prevent and treat cardiovascular diseases. CDDP is usually prescribed in combination with clopidogrel (CLP), but the herb-drug interactions are rarely reported. This study evaluated the effects of CDDP on the pharmacokinetics and pharmacodynamics of coadministered CLP, and ensured the safety and efficacy of their usage. The trial design included a single-dose administration and multidose test for 7 consecutive days. Wistar rats received CLP alone or CLP combined with CDDP. After the final dose, plasma samples were collected at various time points, and the active metabolite H4 of CLP was analyzed by ultrafast liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The main pharmacokinetic parameters of Cmax (maximum [or peak] serum concentration), Tmax (peak plasma time), t1/2 (half-time), AUC0-∞ (area under the concentration-time curve from dosing (time 0) to infinite time), and AUC0-t (area under the concentration-time curve from dosing [time 0] to time t) were calculated using the non-compartment model. In addition, prothrombin time, activated partial thromboplastin time, bleeding time, and adenosine diphosphate-induced platelet aggregation were evaluated for anticoagulation and antiplatelet aggregation activity. In this study, we found that CDDP had no significant effect on the metabolism of CLP in rats. In pharmacodynamic studies, the combination group showed significant synergistic antiplatelet activity compared with the CLP or CDDP groups alone. Based on pharmacokinetic and pharmacodynamic results, CDDP and CLP have synergistic effects on antiplatelet aggregation and anticoagulation.

Exploring the mechanism of YangXue QingNao Wan based on network pharmacology in the treatment of Alzheimer's disease.

It is clinical reported that YangXue QingNao Wan (YXQNW) combined with donepezil can significantly improve the cognitive function of AD patients. However, the mechanism is not clear. A network pharmacology approach was employed to predict the protein targets and affected pathways of YXQNW in the treatment of AD. Based on random walk evaluation, the correlation between YXQNW and AD was calculated; while a variety of AD clinical approved Western drugs were compared. The targets of YXQNW were enriched and analyzed by using the TSEA platform and MetaCore. We proved that the overall correlation between YXQNW and AD is equivalent to clinical Western drugs, but the mechanism of action is very different. Firstly, YXQNW may promote cerebral blood flow velocity by regulating platelet aggregation and the vasoconstriction/relaxation signal pathway, which has been verified by clinical meta-analysis. Secondly, YXQNW may promote Aß degradation in the liver by modulating the abnormal glucose and lipid metabolisms via the adiponectin-dependent pathway, RXR/PPAR-dependent lipid metabolism signal pathway, and fatty acid synthase activity signal pathway. We also verified whether YXQNW indeed promoted Aß degradation in hepatic stellate cells. This work provides a novel scientific basis for the mechanism of YXQNW in the treatment of AD.

LTM-TCM: A comprehensive database for the linking of Traditional Chinese Medicine with modern medicine at molecular and phenotypic levels.

Benefiting from the development of network pharmacology, Traditional Chinese Medicine (TCM) shows great potential in modern drug discovery. Recently, more and more TCM-related databases have been established for both academic and industry research, but they are still insufficient in data standardization, integrity, and precision. To better accelerate the TCM research and overcome these shortcomings, we construct a web-based TCM platform, LTM-TCM, which is currently the most comprehensive TCM database that includes the following advantages: (1) High-quality data integration from fourteen TCM authoritative databases, especially with additional manual collected 41,025 clinical treatment records and 213 ancient Chinese medical books. (2) Accurate correction of multi-source TCM interactions (between symptoms, prescriptions, herbs, ingredients and targets) through in-house Biomedical Natural Language Processing (BioNLP) approaches in more than 30 million articles. (3) Diverse cross-field pipelines (e.g., bioactive ingredients screening, targets prediction, and mechanism prediction, etc.) help integrating traditional medicine with modern science in common aspects at both the molecular and phenotypic levels. In summary, LTM-TCM contains 1928 symptoms, 48,126 prescriptions, 9122 plants, 34,967 ingredients, 13,109 targets and 1170,133 interactions among all TCM related components. LTM-TCM has both Chinese and English interfaces, and it is accessible at http://cloud.tasly.com/#/tcm/home.

Enhancing effect of borneol on pharmacokinetics of ginsenoside Rb1 , ginsenoside Rg1 , and notoginsenoside R1 in healthy volunteers after oral administration of compound Danshen dropping pills.

Borneol (Bingpian), a monoterpenoid pharmaceutical ingredient, is commonly used as a main composition in traditional Chinese medicine preparations such as compound Danshen dropping pills (CDDP) and has also been approved by the U.S. Food and Drug Administration as a flavoring substance or adjuvant in food. Borneol plays a regulating and guiding role as a messenger drug in CDDP. However, the effect of borneol on the pharmacokinetics of the components of CDDP in human plasma is unclear. In this study, we investigate the effects of borneol on the pharmacokinetics of ginsenoside Rb1 (Rb1 ), ginsenoside Rg1 (Rg1 ), and notoginsenoside R1 (NR1 ) in CDDP. We used a double-cycle crossover-administration model in 12 healthy male volunteers, administered CDDP with borneol (drug T) and without borneol (drug R). The selective response monitoring mode was used for MS quantification in the positive mode. As a result, we found that borneol could significantly affect the pharmacokinetic parameters of notoginsenosides and increase the absorption and systemic exposure of Rb1 , Rg1 , and NR1 in human plasma by ~1.85-3.71 times.

A Rapid and Accurate 1HNMR Method for the Identification and Quantification of Major Constituents in Qishen Yiqi Dripping Pills.

BACKGROUND: Qishen Yiqi dripping pills (QSYQ), composed of four herbal medicines-Salvia miltiorrhiza, Astragalus membranaceus, Panax notoginseng, and Dalbergiaodorifera-are widely used to treat ischemic cerebrovascular and hemorrhagic cerebrovascular conditions. OBJECTIVE: In this study, a rapid and accurate proton NMR (1HNMR) spectroscopy method was established to control the quality of QSYQ and ensure their clinical efficacy. METHOD: Firstly, different types of metabolites were identified based on the proton signal peaks of chemical shifts, coupling constants, and related information provided through two-dimensional NMR spectroscopy. Secondly, a quantitative 1HNMR method was established for the simultaneous determination of major constituents in QSYQ samples. In addition, an HPLC method was performed to verify the results obtained by the quantitative proton NMR (qHNMR)  method. RESULTS: In the present study, 26 metabolites were identified in the 1HNMR spectra of QSYQ. In addition, a rapid and accruate qHNMR method was established for the simultaneous determination of protocatechualdehyde, rosmarinic acid, danshensu, calycosin-7-O-ß-D-glucoside, and ononin in ten batches of QSYQ samples for the first time. Moreover, the proposed qHNMR method and HPLC method were compared using Bland-Altman and plots Passing-Bablok regression, indicating no significant differences and a strong correlation between the two analytical methods. CONCLUSIONS: This method is an important tool for the identification and quantification of major constituents in QSYQ. HIGHLIGHTS: Compared with traditional HPLC, the established qHNMR method has the advantages of simple sample preparation, short analysis time, and non-destructive analysis.

UFLC-MS/MS Determination and Population Pharmacokinetic Study of Tanshinol, Ginsenoside Rb1 and Rg1 in Rat Plasma After Oral Administration of Compound Danshen Dripping Pills.

BACKGROUND AND OBJECTIVES: As a traditional Chinese Materia Medica (CMM), the Compound Danshen Dripping Pill (CDDP) is widely used for the treatments of cardiovascular diseases. In view of its undefined applicable population and dosage, a population pharmacokinetic (PPK) study is required. The objective of this study was to explore the feasibility of multi-component CMM PPK in rat plasma after oral administration of CDDP based on sparse sampling. METHODS: In this research, a simple, rapid and highly sensitive UFLC-MS/MS method for the simultaneous determination of tanshinol (TSL), ginsenoside Rb1 (GRb1) and ginsenoside Rg1 (GRg1) has been successfully developed in rat plasma. Moreover, the validated method has been applied to a PPK study of CDDP based on sparse data. We established the PPK models for these three main active constituents using a nonlinear mixed-effects model, taking into account of factors such as gender, age in weeks and weight. RESULTS: The PPK models of TSL and GRb1 were best described by a one-compartment model with linear elimination and first-order absorption. The model of GRg1 was best described by a two-compartment model with first-order absorption. Bootstrap validation and a visual predictive check confirmed the predictive ability, the model stability and the precision of the parameter estimates from these models. CONCLUSION: As a preliminary exploration toward the clinical population pharmacokinetic research, this study provides a reference for the population pharmacokinetic study of traditional CMM.

Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism.

Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.

Compound danshen dripping pills normalize a reprogrammed metabolism of myocardial ischemia rats to interpret its time-dependent efficacy in clinic trials: a metabolomic study.

INTRODUCTION: Clinical trials of Compound danshen dripping pills (CDDP) indicated distinct improvement in patients with chronic stable angina. Daily fluctuation of therapeutic effect agreed with a peak-valley PK profile during a 4-week CDDP regimen, but stabilized after 8-week treatment. OBJECTIVES: This article aims to explore the underlying mechanism for the time-dependent drug efficacy of the up-down fluctuation or stabilization in clinic trials. METHODS: A rat model of myocardial ischemia was established via isoproterenol induction. Metabolomics was employed to analyze the energy-related substances both in circulatory system and myocardium in the myocardial ischemia model. RESULTS: CDDP treatment ameliorated myocardial ischemia, reversed the reprogramming of the metabolism induced by ISO and normalized the level of most myocardial substrates and the genes/enzymes associated with those metabolic changes. After 1- or 2-week treatment, CDDP regulated plasma and myocardial metabolome in an analogous, time-dependent way, and modulated metabolic patterns of ischemic rats that perfectly matched with the fluctuated or stabilized effects observed in clinical trials with 4 or 8-week treatment, respectively. CONCLUSION: Metabolic modulation by CDDP contributes to the fluctuated or stabilized therapeutic outcome, and is a potential therapeutic approach for myocardial ischemia diseases.

Simultaneous determination of three saponins in human plasma after oral administration of compound danshen dripping pills by LC-MS/MS and its application in a pharmacokinetic study.

As one of the main constituents of Compound Danshen Dripping Pills (CDDP), Panax notoginseng (PN) plays a pivotal role in the treatment of cardiovascular diseases. Numerous researches have proved that the dammarane type saponins including notoginsenoside R1 (NR1), ginsenoside Rg1 (GRg1) and ginsenoside Rb1 (GRb1) are the main bioactive components of PN in CDDP. An efficient, realiable and sensitive liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis method for simultaneously detecting NR1, GRg1 and GRb1 in human plasma was established and applied to the pharmacokinetics study of the three PN saponins after oral administration of CDDP. The human plasma samples were processed using acetonitrile and the target materials were separated on an Eclipse plus C18 column (100 × 4.6 mm, 3.5 µm) with a gradient mobile phase consisted of water (containing 0.1% formic acid) and methanol. Within the concentration ranges of 0.25-50 ng/mL, each calibration curve exhibited an excellent linear relationship (r>0.998). The precision deviations of intra-day and inter-day analysis were lower than 9.0%, and accuracy error (RE%) ranged between 1.5% and 10.5%. The average recoveries of analytes were >64.0%. The established method was successfully applied to determine the pharmacokinetics of the three saponins in human plasma. In addition to providing guidance for clinical safe medication, the experimental results also provided a valuable and reliable basis for further pharmacological studies of PN in the human body after oral administration of CDDP.

Simultaneous Determination of 19 Bioactive Constituents in QishenYiqi Dropping Pills by Ultra-Performance Liquid Chromatography Coupled with Triple Quadrupole Mass Spectrometry.

Background: QishenYiqi dripping pills (QSYQ), consisting of Salvia miltiorrhiza, Astragalus membranaceus, Panax notoginseng, and Dalbergia odorifera, is a widely used to treat ischemic cerebrovascular and hemorrhagic cerebrovascular in China. Objective: In this study, a rapid and sensitive ultra-HPLC coupled with a triple quadrupole MS (UHPLC-QQQ-MS) method was established for the simultaneous quantification of 19 bioactive components. Methods: Chromatographic separation was performed on an Agilent Eclipse Plus C18 Rapid Resolution High Definition (RRHD) column (2.1 × 50 mm, 1.8 µm) with a mobile phase composed of a 0.1% (v/v) formic acid aqueous solution and acetonitrile in a gradient elution manner. A QQQ-MS was used in positive and negative ionization mode with multiple reactions monitoring for quantitative analysis. Results: The established methods were validated with linearity, precision, repeatability, stability, recovery, and matrix effect. All calibration curves exhibited excellent linear relationship with the correlation coefficient (r) >0.9985 for each analyte within the test range. This method was successfully applied to quantify target compounds of different structural types in 12 batches of QSYQ. Conclusions: The results suggest that the established method is rapid, sensitive, and reliable. The developed UHPLC-QQQ-MS method can provide scientific basis and reference to quality control and consistency evaluation of QSYQ sample and other formulations. Highlights: A rapid, sensitive, and reliable UHPLC-QQQ-MS method has been developed and validated for simultaneous determination of 19 compounds including phenolic acids, saponins, isoflavonoids, and tanshinones in QSYQ for the first time.

A review of the mechanism of action of Dantonic® for the treatment of chronic stable angina.

Chronic stable angina (CSA) presents as a complication of coronary heart disease, leading to a high incidence and mortality rate worldwide. Dantonic® or Compound Danshen Dripping Pills (CDDP) is a well-known traditional Chinese medicine used for the treatment of myocardial ischemic diseases, such as angina pectoris (AP), myocardial infarction, and sudden death. Dantonic® has been extensively utilized in clinical practice in China for more than 14 years and has proved to be an effective therapy for the treatment of many myocardial ischemic diseases since its approval by CFDA in 1994. Clinical studies in China have shown that Dantonic® is an effective and safe drug for the treatment of angina pectoris manifested with ameliorating anginal symptoms and showing few adverse effects. Nevertheless, the mechanism of Dantonic® for the treatment of angina has been underestimated. Therefore, in this review, we mainly focus on discussing the pharmacological mechanism of action (MoA) of Dantonic® for the treatment of CSA, including the promotion of coronary microcirculation, the optimization of myocardial energy metabolism, and the inhibition of platelet aggregation.

Determination of quality markers of Xuezhiling tablet for hyperlipidemia treatment.

BACKGROUND: The massive number of ingredients in traditional Chinese medicines (TCMs) makes quality control very difficult. The concept of quality markers (Q-marker) was recently proposed to evaluate the quality of TCMs. Xuezhiling tablets (XZL) are widely used for the treatment of hyperlipidemia in China owing to its noticeable effectiveness and mild adverse effects, but there are no proper Q-markers for this Chinese patent medicine. PURPOSE: The aim of the present study was to determine the Q-markers of XZL against hyperlipidemia through an integration of investigations on its lipid-lowering effect, metabolomics, content determination and pharmacokinetics. METHODS: XZL was prepared in accordance with the method described in the Chinese pharmacopoeia (Ch.P.). Hyperlipidemia was induced in rats through the administration of a high-fat diet (HFD). The hypolipidemic effect of XZL was investigated through the detection of the blood levels of total glyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C). A metabolomics study was conducted to analyze the overall effects of XZL on the regulation of lipid metabolism. The main bioactive compounds of XZL were identified and determined in the XZL preparation and the medicated plasma of hyperlipidemic rats. RESULTS: XZL lowered the levels of TG, TC, and LDL-C through alterations of metabolic patterns. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucopyranoside (THSG), chrysophanol-1-O-ß-glucopyranosyl-(1→3)-O-ß-D-glucopyranosy1-(1→6)-O-ß-D-glucopyranosyl-(1→6)-O-ß-D-glucopyranoside (SHJ), cassiaside, rubrofusarin gentiobioside, aurantio-obtusin, chryso-obtusin, and obtusinfolin were identified and determined both in the preparation and the blood of hyperlipidemic rats. CONCLUSION: SHJ, obtusinfolin, THSG, rubrofusarin gentiobioside, and aurantio-obtusin, which are more abundant in the preparation, leading to greater exposure in vivo, were suitable Q-markers to guarantee the medicinal quality of XZL and ensure the clinical effectiveness on hyperlipidemia.

A quality marker study on salvianolic acids for injection.

BACKGROUND: The quality of Chinese medicine (CM) has being an active and challenging research area for CM. Prof. Chang-Xiao Liu et al first proposed the concept of quality marker (Q-Marker) for the quality evaluation and control on CM. This article describe the exploratory studies of Q-Marker in salvianolic acids for injection (SAI) based on this new concept. PURPOSE: This study was designed to screen Q-Marker of SAI and establish its quality control method based on the concept of CM Q-Marker. METHODS: Based on the concept of CM Q-Marker, the SAI was investigated for the identification of chemical components and their sources. The pharmacological effects on cerebral ischemia and reperfusion induced injury in rats were also investigated. Furthermore, the target cell extracts and pharmacokinetic studies were conducted to screen Q-Markers. Finally, the fingerprints and determination based on Q-Markers were established to assess the quality of SAI more effectively. RESULTS: Overall, 20 constituents in SAI were identified. It was found that salvianolic acid B (SA-B), rosmarinic acid (RA), lithospermic acid (LA), salvianolic acid D (SA-D) and salvianolic acid Y (SA-Y) are major chemical components of SAI. Based on chemical components identifications, analysis of their sources, target cell extracts and pharmacokinetic studies, four phenolic acids, namely SA-B, RA, LA and SA-D, were screened and determined as effective Q-Markers of SAI. CONCLUSION: This study demonstrated that the described method is a powerful approach for detecting Q-Markers, which can be used as control index for the quality assessment of CM.

An integrated evidence-based targeting strategy for determining combinatorial bioactive ingredients of a compound herbal medicine Qishen Yiqi dripping pills.

ETHNOPHARMACOLOGICAL RELEVANCE: Qishen Yiqi is a widely used Chinese herbal medicine formula with "qi invigorating and blood activating" property. Its dripping pill preparation (QSYQ) is a commercial herbal medicine approved by the China Food and Drug Administration (CFDA) in 2003 and is extensively used clinically to treat cardiovascular diseases, such as ischemic heart failure and angina pectoris, as well as for the secondary prevention of myocardial infarction. However, the bioactive ingredients of QSYQ remain unclear. As QSYQ is a compound herbal formula, it is of great importance to elucidate its pharmacologically active ingredients and underlying synergetic effects. AIM OF THE STUDY: This experimental study was conducted to comprehensively determine the combinatorial bioactive ingredients (CBIs) in QSYQ and to elucidate their potential synergetic effects. The established strategy may shed new light on how to rapidly determine CBIs in complex herbal formulas with holistic properties. MATERIALS AND METHODS: An integrated evidence-based targeting strategy was introduced and validated to determine CBIs in QSYQ. The strategy included the following steps: (1) Chemical ingredients in QSYQ were analyzed via UPLC-Q-TOF/MS in the negative and positive modes and were identified by comparison with standard compounds and previously reported data. Their potential therapeutic activities were predicted based on the ChEMBL database to preliminarily search for candidate bioactive ingredients, and their combination was defined as the CBIs. (2) The CBIs were directly trapped and prepared from QSYQ with a two-dimensional chromatographic separation system, and the remaining part was defined as the rest ingredients (RIs). (3) As animal and cell models, left anterior descending coronary artery ligation (LAD)-induced heart failure in rats and hypoxia-induced cardiac myocyte injury in H9c2 cells were applied to compare the potency of QSYQ, CBIs and RIs. (4) The synergetic effects on cardiac myocyte protection of multiple ingredients in CBIs were examined in this cell model. RESULTS: (1) Forty-three ingredients in QSYQ were identified via UPLC-Q-TOF/MS. Based on evidence-based screening using the ChEMBL database, 24 ingredients were predicted to be bioactive ingredients, and their combination was considered the CBIs. (2) The CBIs and RIs were successfully prepared according to a two-dimensional chromatographic system. The CBIs were directly trapped and knocked out from QSYQ by hydrophilic interaction liquid chromatography coupled with reverse-phase liquid chromatography. The remaining part was used as RIs. (3) The results from pharmacological evaluation revealed that CBIs and QSYQ, but not RIs, significantly prevented myocardium injury; improved the ejection fraction (EF) and fractional shortening (FS); decreased the release of cardiac enzymes, including CK, CK-MB, and LDH; alleviated mitochondrial dysfunction; and protected the cell nucleus number and mitochondrial mass. Furthermore, QSYQ and CBIs possessed similar potency. (4) In hypoxia-stimulated H9c2 cells, CBIs showed far greater potency regarding the protection of cardiac myocyte injury than the individual ingredients in QSYQ, exhibiting obvious synergetic effects. CONCLUSIONS: An integrated evidence-based targeting strategy was successfully established and validated to determine CBIs from QSYQ with excellent efficiency. Importantly, the holistic property of QSYQ was retained in the CBIs. Hence, this study may shed new light on how to rapidly reveal combinatorial bioactive ingredients from complex prescriptions and will be greatly helpful in the establishment of an appropriate approach to quality control for herbal medicines.

Integrated pharmacokinetics of ginsenosides after intravenous administration of YiQiFuMai powder injection in rats with chronic heart failure by UFLC-MS/MS.

YiQiFuMai powder injection (YQFM), derived from the classical traditional Chinese medicine (TCM) formula Shengmai San, is a modern preparation widely used to combat cardiovascular diseases, chronic heart failure (CHF) for example, in clinical practice in China. Ginsenosides are the major components of YQFM, which are responsible for its therapeutic effect. In this research, we developed a rapid, sensitive and simple method for simultaneous determination of ten ginsenosides from YQFM in CHF rat plasma with ultra-fast liquid chromatography tandem mass spectrometry (UFLC-MS/MS). After solid phase extraction (SPE), chromatography was done on an Acquity UPLC HSS T3 column (1.8µm, 100mm×2.1mm, i.d.) through an 8.0min gradient elution with acetonitrile and 0.1% formic acid in water, while mass spectrometry was performed in the positive ion electrospray ionization (ESI) mode. A good linearity was achieved for each analyte with correlation coefficient (r) >0.9920. The lower limits of quantification (LLOQ) were 1.25ng/mL for ginsenoside Rg1, Rd, Re and Rh1, 2.5ng/mL for ginsenoside Rf, Rg3, Rb2 and Rb3 and 5.0ng/mL for ginsenoside Rb1 and Rc, respectively. All the precision (RSD) data ranged from 1.7-14.5% and the accuracy (RE) data was within ±13.73%. Moreover, the validated method has been applied to investigate the integrated pharmacokinetic profiles of ginsenosides in CHF rats following intravenous administration of YQFM successfully.

GC-MS/MS method for the determination and pharmacokinetic analysis of borneol and muscone in rat after the intravenous administration of Xingnaojing injection.

A simple and sensitive gas chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of borneol and muscone in rat plasma. The analytes and internal standard, naphthalene, were extracted using a convenient one-step liquid-liquid extraction method with ethyl acetate. The chromatographic separation was realized on a HP-5MS capillary column and detected in multiple reaction monitoring mode. Excellent linearity (R2  ≥ 0.996) was shown over 10.0-5000 ng/mL for borneol and 2.5-250 ng/mL for muscone. The lower limit of quantitation was 10 and 2.5 ng/mL for borneol and muscone, respectively. The intra- and interday precisions were less than 7.52%, and the accuracy values were between  -8.03 and 14.52%. The extraction recovery, matrix effect, and stability were sufficient to meet the Food and Drug Administration criteria. Meanwhile, the assay was successfully applied to the preclinical pharmacokinetic study of borneol and muscone following intravenous administration of Xingnaojing injection, a modern Chinese herbal medicine preparation.

Compound danshen dripping pills modulate the perturbed energy metabolism in a rat model of acute myocardial ischemia.

The continuous administration of compound danshen dripping pills (CDDP) showed good efficacy in relieving myocardial ischemia clinically. To probe the underlying mechanism, metabolic features were evaluated in a rat model of acute myocardial ischemia induced by isoproterenol (ISO) and administrated with CDDP using a metabolomics platform. Our data revealed that the ISO-induced animal model showed obvious myocardial injury, decreased energy production, and a marked change in metabolomic patterns in plasma and heart tissue. CDDP pretreatment increased energy production, ameliorated biochemical indices, modulated the changes and metabolomic pattern induced by ISO, especially in heart tissue. For the first time, we found that ISO induced myocardial ischemia was accomplished with a reduced fatty acids metabolism and an elevated glycolysis for energy supply upon the ischemic stress; while CDDP pretreatment prevented the tendency induced by ISO and enhanced a metabolic shift towards fatty acids metabolism that conventionally dominates energy supply to cardiac muscle cells. These data suggested that the underlying mechanism of CDDP involved regulating the dominant energy production mode and enhancing a metabolic shift toward fatty acids metabolism in ischemic heart. It was further indicated that CDDP had the potential to prevent myocardial ischemia in clinic.

Qualitative and quantitative analyses of Compound Danshen extract based on 1H NMR method and its application for quality control.

In this study, a new approach using 1H NMR spectroscopy combined with chemometrics method was developed for qualitative and quantitative analyses of extracts of Compound Danshen Dripping Pills (CDDP). For the qualitative analysis, some metabolites presented in Compound Danshen extract (CDE, extraction intermediate of CDDP) were detected, including phenolic acids, saponins, saccharides, organic acids and amino acids, by the proposed 1H NMR method, and metabolites profiles were further analyzed by selected chemometrics algorithms to define the threshold values for product quality evaluation. Moreover, three main phenolic acids (danshensu, salvianolic acid B, and procatechuic aldehyde) in CDE were determined simultaneously, and method validation in terms of linearity, precision, repeatability, accuracy, and stability of the dissolved target compounds in solution was performed. The average recoveries varied between 84.20% and 110.75% while the RSDs were below 6.34% for the three phenolic acids. This 1H NMR method offers an integral view of the extract composition, allows the qualitative and quantitative analysis of CDDP, and has the potential to be a supplementary tool to UPLC/HPLC for quality assessment of Chinese herbal medicines.

UFLC-MS/MS determination and pharmacokinetic studies of six Saikosaponins in rat plasma after oral administration of Bupleurum Dropping Pills.

A rapid and sensitive ultra fast liquid chromatography tandem mass spectrometry method (UFLC-MS/MS) was developed and validated for the simultaneous determination of six Saikosaponins (SSs) (SSa, SSb1, SSb2, SSd, SSc, SSf) of Bupleurum Dropping Pills (BDP) in rat plasma using chloramphenicol as the internal standard (IS). The SSs were separated using an ACQUITY UPLC(®) BEH C18 column (50 mm × 2.1mm, 1.7 µm) and detection of these compounds were done by using a Qtrap 5500 mass spectrometer coupled with negative electrospray ionization (ESI) source under the multiple reaction monitoring (MRM) mode. According to regulatory guidelines, the established method was fully validated and results were showed within acceptable limits. The lower limit of quantifications (LLOQs) of all analytes were 0.2 ng/mL. The validated method was successfully applied into a pharmacokinetic study of orally administered BDP in rats.