State Key Laboratories of Pharmacodynamics and Pharmacokinetics

Tianjin, China

State Key Laboratories of Pharmacodynamics and Pharmacokinetics

Tianjin, China
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Zhang J.,College of Logistics | Hu X.,College of Logistics | Gao W.,Tianjin University | Qu Z.,Tianjin University | And 3 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance Radix Aucklandiae (RA), a well known traditional Chinese medicine, is widely used for treating various problems in digestive system. A selective and sensitive high-performance liquid chromatography coupled with mass spectrometry method was first developed and validated for simultaneous quantification of costunolide and dehydrocostuslactone in rat plasma with diazepam as internal standard after oral administration of RA extraction. Materials and methods Plasma samples were extracted via solid-phase extraction and detected by multiple-reaction monitoring mode under positive electrospray. Chromatographic separation was accomplished on an Agilent C18 column (2.1 mm×150 mm, 5 μm), with 0.1% formic acid and acetonitrile (1:1) as the mobile phase at a flow rate of 0.5 mL/min. Results The quantification was performed using the transitions of m/z 233/187 for costunolide, m/z 231/185 for dehydrocostuslactone and m/z 285/193 for diazepam, respectively. Calibration curves were linear over the concentration range of 0.7-769.7 ng/mL for costunolide and 0.9-956.0 ng/mL for dehydrocostuslactone. The intra-day and inter-day precisions (RSD%) for two compounds was less than 8.76% and 9.70% and the accuracy (RE%) range from 6.14% to 5.35%. The time to reach the maximum plasma concentration (Tmax) was 10.46 h for costunolide, 12.39 h dehydrocostuslactone. The elimination half-time (t1/2) of costunolide and dehydrocostuslactone was 5.54±0.81 and 4.32±0.71 (h). The AUC of costunolide and dehydrocostuslactone was 308.83 and 7884.51 respectively (ng h/mL). Conclusions It was the first report for the study of pharmacokinetic profile of costunolide and dehydrocostuslactone in rat plasma after oral administration of RA extract. These results provided a meaningful basis for better understanding the absorption of traditional medicine, RA, and provide useful scientific data for clinical application. © 2013 Elsevier Ireland Ltd.


Man S.,Tianjin University | Gao W.,Tianjin University | Yan Y.,Tianjin University of Traditional Chinese Medicine | Liu Z.,Tianjin University | Liu C.,State Key Laboratories of Pharmacodynamics and Pharmacokinetics
Journal of Ethnopharmacology | Year: 2011

Ethnopharmacological relevance: Diosgenyl and pennogenyl saponins isolated from Rhizoma Paridis, showed pro-apoptosis and immunoregulation with antitumor activity in cultured cells and animal systems. Aim of the study: To evaluate their anti-metastatic mechanism on cancer cells and discuss their structure-activity relationship on anti-tumor effect. Materials and methods: This research used the wound healing and migration assay to detect their anti-invasive effect on B16 melanoma cells. Through the gelatin zymography assay, immunofluorescence analysis and western blot, saponins exhibited different levels of protein expression inhibition of MMP-1, -2, -3, -9 and -14. Results: Through the analysis, diosgenyl and pennogenyl saponins inhibited the metastasis of B16 melanoma cells. Diosgenyl saponins also showed strong suppression of enzyme activity of MMP-2 and -9. Different saponins exhibited different levels of inhibition on MMP expression. Conclusions: 17-α OH increases the sensitivity of diosgenyl saponins to the membrane-bound protease which can stimulate proMMP-2 activation, but it also decreases the anti-metastatic activity of diosgenyl saponin. Furthermore, their combination might provide a potential therapeutic modality for metastasis. © 2011 Elsevier Ireland Ltd. All rights reserved.


Liu Z.,Tianjin University | Li N.,Tianjin University of Traditional Chinese Medicine | Gao W.,Tianjin University | Man S.,Tianjin University of Science and Technology | And 2 more authors.
Journal of Ethnopharmacology | Year: 2012

Ethnopharmacological relevance: The rhizoma of Paris polyphylla var. yannanensis or P. polyphylla var. chinensis called Rhizoma Paridis as a traditional Chinese medicine has an effect of heat-clearing and detoxicating, detumescence and acesodyne in folk for a long time. The increasing application of Rhizoma Paridis resulted in the shortage of wildlife resources. Here, we compared the major activities of other species of genus Paris to find the replacement plants. Materials and methods: Six species (P. polyphylla var. yunnanensis, P. delavayi var. delavayi, P. fargesii var. Fargesii, P. bashanensis Wang et Tang, P. polyphyllar var. minora, and P. polyphylla var. pseudothibetical) were collected from three Provinces in China, and compared the hemostatic, cytotoxic and hemolytic activities by different assays. Results: For the hemostatic activity, all the plants except Paris fargesii var. Fargesii could significantly shorten the tail bleeding time and blood clotting time (P<0.05). For further mechanism study, they reduced the prothrombin time (PT) and activated partial thromboplastin time (APTT), but they had no significant effect on thrombin time (TT). P. fargesii var. Fargesii showed the similar cytotoxicity to P. polyphylla var. yunnanensis (IC50: 18.21 and 15.73 μg/mL, respectively). HD50 was used as the index of hemolytic activity. P. delavayi var. delavayi and P. bashanensis Wang et Tang were the last to have this activity as the values were 3.027 and 1.222 mg/mL. Conclusions: The different species of genus Paris have different activities. Paris delavayi var. delavayi and Paris bashanensis Wang et Tang could be used as the resources of hemostatic drugs and P. fargesii var. Fargesii as the antitumor medicine. © 2012 Elsevier Ireland Ltd.


Zhang J.,Tianjin University | Gao W.,Tianjin University | Liu Z.,Tianjin University | Liu C.,State Key Laboratories of Pharmacodynamics and Pharmacokinetics
Journal of Ethnopharmacology | Year: 2012

Ethnopharmacological relevance: Fructus Aurantii is one of the commonly used traditional Chinese medicines and the compatibility of Fructus Aurantii, Radix et Rhizoma Rhei and Semen Crotonis Pulveratum were the main components in a Chinese traditional patent medicine Weichang'an pill. Naringin and neohesperidin are two main flavonoid glycosides in the extract of Fructus Aurantii. The pharmacokinetics of naringin and neohesperidin, as the main marker constituents were analysis by a simple and accurate method. Materials and Methods: In the present study, pharmacokinetic differences of two flavonoid glycosides were detected after oral administration of the extract of single herb and different compatibility of Fructus Aurantii, Radix et Rhizoma Rhei and Semen Crotonis Pulveratum which at doses of approximately 700 mg/kg naringin and 300 mg/kg neohesperidin. Results: It indicated that the pharmacokinetic process of naringin and neohesperidin in four groups were demonstrated bimodal phenomenon after oral administration. Comparing to pharmacokinetic parameters of the single herbs administration, there were no significant difference after the compatibility of Fructus Aurantii and Radix et Rhizoma Rhei. However, the absorption of two flavonoid glycosides was increased dramatically after the compatibility of Fructus Aurantii or Semen Crotonis Pulveratum. The same results were attained after co-administration of the extract of three herbs. Conclusion: Some components in the extract of Semen Crotonis Pulveratum promoted the absorption of naringin and neohesperidin.


Man S.,Tianjin University of Science and Technology | Gao W.,Tianjin University of Science and Technology | Gao W.,Tianjin University | Wei C.,Tianjin University of Science and Technology | Liu C.,State Key Laboratories of Pharmacodynamics and Pharmacokinetics
Phytotherapy Research | Year: 2012

Many anticancer drugs are obtained from natural sources. Nature produces a variety of toxic compounds, which are often used as anticancer drugs. Up to now, there are at least 120 species of poisonous botanicals, animals and minerals, of which more than half have been found to possess significant anticancer properties. In spite of their clinical toxicity, they exhibit pharmacological effects and have been used as important traditional Chinese medicines for the different stages of cancer. The article reviews many structures such as alkaloids of Camptotheca acuminata, Catharanthus roseus and Cephalotaxus fortunei, lignans of Dysosma versipellis and Podophyllum emodi, ketones of Garcinia hanburyi, terpenoids of Mylabris and Ginkgo biloba, diterpenoids of Tripterygium wilfordii, Euphorbia fischeriana, Euphorbia lathyris, Euphorbia kansui, Daphne genkwa, Pseudolarix kaempferi and Brucea javanica, triterpenoids of Melia toosendan, steroids of Periploca sepium, Paris polyphylla and Venenum Bufonis, and arsenic compounds including Arsenicum and Realgar. By comparing their related phytochemistry, toxic effects and the recent advances in understanding the mechanisms of action, this review puts forward some ideals and examples about how to increase antitumour activity and/or reduce the side effects experienced with Chinese medicine. Copyright © 2012 John Wiley & Sons, Ltd.


Man S.,Tianjin University | Gao W.,Tianjin University | Zhang Y.,Tianjin University of Traditional Chinese Medicine | Huang L.,Chinese Institute of Materia Medica | Liu C.,State Key Laboratories of Pharmacodynamics and Pharmacokinetics
Fitoterapia | Year: 2010

Saponins are a group of naturally occurring plant glycosides, characterized by their strong foam-forming properties in aqueous solution. The presence of saponins has been reported in more than 100 families of plants out of which at least 150 kinds of natural saponins have been found to possess significant anti-cancer properties. There are more than 11 distinguished classes of saponins including dammaranes, tirucallanes, lupanes, hopanes, oleananes, taraxasteranes, ursanes, cycloartanes, lanostanes, cucurbitanes and steroids. Due to the great variability of their structures, saponins always display anti-tumorigenic effects through varieties of antitumor pathways. In addition, there are a large amount of saponins that still either remain to be trapped or studied in details by the medicinal chemists. This article reviews many such structures and their related chemistry along with the recent advances in understanding mechanism of action and structure-function relationships of saponins at the molecular and cellular levels. These aglycones have been described and their classification and distribution have been listed in the review. Some special saponins with strong antitumor effects have also been exhibited. Ginsenosides, belonging to dammaranes, have been found beneficial targeted on inhibition of tumor angiogenesis by suppressing its inducer in the endothelial cells of blood vessels, and then on prevention of adhering, invasion, and metastasis of tumor cells. Dioscin, one of the steroidal saponins, and its aglycone diosgenin also have been extensively studied on its antitumor effect by cell cycle arrest and apoptosis. Other important molecules discussed include oleanane saponins such as avicins, platycodons, saikosaponins, and soysaponins along with tubeimosides. © 2010 Elsevier B.V. All rights reserved.


Liu Z.,Tianjin University | Gao W.,Tianjin University | Liu C.,State Key Laboratories of Pharmacodynamics and Pharmacokinetics
Pharmaceutical Biology | Year: 2013

Context: Currently, famous traditional Chinese medicine formulas have undergone re-evaluation and development in China. Wei-Chang-An-Wan (WCAW) as one of them has been used for treating various gastrointestinal diseases for several decades. The secondary development of WCAW is in progress so as to interpret the effective material basis or find new pharmacological activity. Objective: To evaluate the antinociceptive effect of methanol extract of WCAW (ME) as well as four fractions (P.E., EtOAc, n-BuOH, H2O) and obtain information on the correlation between the contents of the fractions and antinociceptive effect. Materials and methods: ME was divided into four parts extracted by petroleum ether, ethyl acetate and n-butanol. Antinociceptive activity was evaluated by three models of acetic acid-induced writhing, formalin and hot-plate test in mice after repetitive administration of ME at 200, 400 or 800mg/kg, P.E. 132mg/kg, EtOAc 106mg/kg, n-BuOH 176mg/kg and H2O 176mg/kg for six days. The chemical compounds were analyzed by HPLC-ESI-MS. Results: ME at 800mg/kg inhibited acid-induced writhing by 84.69%, and reduced the licking time of second phase in formalin test by 53.23%. The inhibition rates in acid-induced writhing of P.E., EtOAc, n-BuOH and H2O were 27.79, 33.85, 38.97 and 37.69%, respectively, and in formalin test about 50%. They had no effect on the hot-plate test. HPLC-ESI-MS analysis showed that 68 chemical compounds were detected and 41 compounds were identified from ME. Discussion and conclusion: The results obtained herein indicate that WCAW possesses the antinociceptive activity that provides a new aspect in clinical application. © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


Qu Z.,Tianjin University | Zhang J.,College of Logistics | Gao W.,Tianjin University | Chen H.,College of Logistics | And 4 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance Cerebralcare Granule (CG), one of the famous classical recipes in traditional Chinese medicine, is developed from the "Decoction of Four Drugs". It has been used for treatment of cerebrovascular related diseases, such as hypertension. It is well known that vasodilatation plays a very important role in hypertensive. Despite the popular medicinal use of CG, little data was available to its activity and mechanism involved in vasodilatation. Therefore, we aimed to investigate the vasorelaxant effects of CG on isolated rat thoracic aorta so as to assess some of the possible mechanisms. The present study was performed to examine the vasodilative activity of CG and its mechanisms in isolated rat thoracic aorta. Materials and methods CG was studied on isolated rat thoracic aorta in vitro, including endothelium-intact and endothelium-denuded aortic rings. In present study, specific inhibitors including NO synthase inhibitor NG-nitro-l- arginine methyl ester (l-NAME), cyclooxygenase (COX) inhibitor indomethacin (INDO), non-selective K+ channel inhibitor tetraethylammonium chloride (TEA), Kir channel inhibitor BaCl2, K ATP channel inhibitor Glibenclamide (Gli) and cholinergic receptor antagonist atropine were used, they were added 20 min before NE contraction and then added CG-induced vasodilation. Results Removal of endothelium or pretreatment of aortic rings (intact endothelium) with l-NAME (0.1 mM) or INDO (0.01 mM) significantly blocked the CG induced relaxation. Pretreatment with the non-selective K+ channel inhibitor TEA (1 mM), or the Kir channel inhibitor BaCl2 (0.1 mM), neither of them had no influence on the CG-induced response (p>0.05). However, pretreatment with the K ATP channel inhibitor Gli (0.01 mM) produced significant inhibition on the CG-induced response (p<0.01). Besides, CG also inhibited the contraction triggered by NE in endothelium-denuded rings in Ca2+-free medium. CG (0.4, 0.8 and 3.2 mg/mL) produced rightward parallel displacement of CaCl2 curves and reduced the maximum contraction induced by 30 mM CaCl2 to 31.1±9.3%, 18.8±6.9% and 9.4±4.5%, respectively. The relaxation, induced by CG on endothelium-intact rat aortic rings pre-contracted with NE, was significantly attenuated in the presence of atropine (EC50=3.7 mg/mL, p<0.01). Conclusions Our results suggest that CG induces relaxation in rat aortic rings through an endothelium-dependent pathway mediated by NO/cGMP pathway and an endothelium-independent pathway involving blockade of Ca2+ channels, inhibition of Ca2+ mobilization from intracellular stores, opening of KATP channel. In addition, the muscarinic receptor stimulation is also one of the vasorelaxant mechanisms. © 2014 Elsevier Ireland Ltd. All rights reserved.


Qu Z.,Tianjin University | Zhang J.,College of Logistics | Gao W.,Tianjin University | Guo H.,Tianjin University | Liu C.,State Key Laboratories of Pharmacodynamics and Pharmacokinetics
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance Wei-Chang-An pill (WCA pill), a traditional Chinese medicine, has been used for treating various gastrointestinal diseases for several decades. Despite the popular medicinal use of WCA pill, less data was available to its activity and mechanism in gastrointestinal disorders. To examine the effects of the methanol extract of WCA pill (ME) on gastrointestinal tract so as to assess some of the possible mechanisms involved in the clinical treatment. Materials and methods ME was studied on gastrointestinal transit in vivo including gastric emptying and small intestinal motility in normal and neostigmine-induced mice, as well as on the isolated tissue preparations of rat jejunum in vitro. Results In vivo, the gastric emptying decreased and intestinal transit increased after administration of ME in normal mice. However, administration of ME accelerated the intestinal transit ranging from 0.01 to 0.8 mg/mL and reduced it at the concentration of 1.6 and 3.2 mg/mL, while the gastric emptying was inhibited throughout the concentrations in neostigmine-induced mice. in vitro, ME caused inhibitory effect on the spontaneous contraction of rat-isolated jejunum in dose-dependent manner ranging from 0.01 to 6 mg/mL and also relaxed the acetylcholine chloride (Ach, 10 -6 M)-induced and K+ (60 mM)-induced contractions. ME shifted the Ca2+ concentration-response curves to right, similar to that caused by verapamil (0.025 mM). Conclusions These results indicated that ME might play a bidirectional role in gastrointestinal transit modulation and the effects on isolated tissue are probably mediated through calcium influx and muscarinic receptors, which provides pharmacological basis for the clinical use of WCA pill in gastrointestinal tract disorders. © 2014 Elsevier Ireland Ltd. All rights reserved.


Man S.,Tianjin University | Gao W.,Tianjin University | Zhang Y.,Tianjin University of Traditional Chinese Medicine | Liu Z.,Tianjin University | And 3 more authors.
Cancer Biology and Therapy | Year: 2011

Formosanin C (FC) isolated from Rhizoma paridis, showed pro-apoptosis and immunoregulation with antitumor activity in cultured cells and animal systems. However, there is no report about its anti-metastatic effect on cancer cells. This research used the wound healing and the migration assay to detect the anti-invasive effect of FC on LA795 cells. Through the gelatin zymography assay and immunofluorescence analysis, FC showed suppression of enzyme activity of MMP-2 and MMP-9, and protein expression of MMP-1, -2, -3, -9 and -14 excreted from LA795 cells. Finally, FC exhibited much more effective inhibition of tumor growth and pulmonary metastasis in T739 mice than cisplatin did. Overall, the strong inhibition of MMP expression by FC might provide a potential therapeutic modality for lung tumors. © 2011 Landes Bioscience.

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