Journal of Chinese Pharmaceutical Sciences

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2011, 20(5): 421-424.

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Recent progress in the research on lamellarins and related pyrrole-derived alkaloids from marine organisms

Ai-Li Fan, Wen-Han Lin, Yan-Xing Jia^*

2011, 20(5): 425-441. DOI: 10.5246/jcps.2011.05.054

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Lamellarins and related pyrrole-derived alkaloids are a large family of marine alkaloids with novel structures and promising bioactivities. They have been isolated from diverse marine organisms and all of them feature a 3,4-diarylpyrrole 2-carboxylic acid ester or amide moiety. This article provides an overview of recent literatures on lamellarins and related pyrrole-derived alkaloids, including their isolation, total synthesis, biological and structure activity relationship (SAR) studies.

Advances in the nanoparticle drug delivery systems of silymarin

Mei-Wan Chen, Wen Tan, Sheng-Peng Wang, Zhang-Feng Zhong, Yi-Tao Wang^*

2011, 20(5): 442-446. DOI: 10.5246/jcps.2011.05.055

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The recent advances in nanoscience and nanotechnology have greatly facilitated the development of nanoparticle drug delivery system. A nanoparticle drug delivery system of silymarin will improve its poor solubility in water and oil, thus enhancing its bioavailability. A variety of nanoparticle formulations of silymarin such as solid lipid nanoparticles, microemulsion and self-emulsifying drug delivery system, and liposomes have been extensively investigated. This paper reviews the advances of these formulations on their preparation and characterization, absorption and bioavailability, as well as in vivo and in vitro studies, in order to provide an assessment of current research for further pharmaceutical studies of silymarin.

Design, synthesis and anti-HIV-1 activity of 4,6-dibenzyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

A-Min Li, Xiang-Yi Liu, Xiao-Wei Wang^*, Jun-Yi Liu^*

2011, 20(5): 447-453. DOI: 10.5246/jcps.2011.05.056

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An effective synthesis method for preparing 4,6-disubstituted pyridinones was reported. Ethyl 3-oxo-4-phenylbutyrate was an important intermediate, by which 6-substituted pyridinones could be prepared. The decarboxylation condition was optimized for compound 4. After protected with a methoxy group, the compound was reacted with BnBr to form the target compound 11. The structures were characterized by ¹H NMR, ¹³C NMR and HRMS, and its enzyme inhibition activity was also determined.

Synthesis of telbivudine 3'-O-acetyl-5'-O-phenyl-N-alkylphosphramidates and evaluation of their anti-HBV activities

Liang-Liang Shi, Hai-Nan Wei, Chang-Mei Cheng^*, Lang-Qiu Chen^*, Yi-Gang Tong

2011, 20(5): 454-459. DOI: 10.5246/jcps.2011.05.057

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A series of telbivudine 3'-O-acetyl-5'-O-phenyl-N-alkylphosphramidate derivatives have been synthesized and their structures were confirmed by EI-MS, ¹H NMR and ¹³C NMR. We evaluated their anti-HBV activity in vitro. Two compounds 6d and 6f, turned out to be more active than telbivudine.

Effects of dichloroacetate on the activation of the mitochondrial pathway in C6 cells in vitro

Xin Zhao, Xin Wang, Ke-Fu Yu, Yu Duan, Jie-Si Li, Bing-Xiang Zhao, Xuan Zhang^*, Qiang Zhang

2011, 20(5): 460-465. DOI: 10.5246/jcps.2011.05.058

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Mitochondria are increasingly recognized as important targets for tumor treatment because of their central roles in apoptotic pathways and cellular metabolism. Dichloroacetate (DCA), a low molecular weight mitochondria-targeting agent, exhibits potential therapeutic effects for tumors. Based on the effects of DCA on tumor cellular metabolism, we carried out this study to investigate the anti-tumor activity of DCA in C6 glioma cells in vitro. The results showed that DCA was able to increase the activity of pyruvate dehydrogenase (PDH), induce the production of reactive oxygen species (ROS) and reduce the mitochondrial membrane potential (MMP) in C6 cells in vitro (P<0.05 or 0.01), indicating that the anti-tumor effects of DCA in C6 cells could be through the activation of the mitochondrial pathway. In conclusion, mitochondria could be a viable therapeutic target for the treatment of glioma.

Enhancement of transdermal delivery of docetaxel by surfactant-ethanolic liposomes

Yu-Qin Qiu, Shuang Li, Fang Li, Suo-Hui Zhang, Yun-Hua Gao^*

2011, 20(5): 466-472. DOI: 10.5246/jcps.2011.05.059

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One major problem encountered in transdermal drug delivery is the low permeability of drugs through the skin barrier. In the present study, we developed a surfactant-ethanolic liposomal system to improve the transdermal delivery of docetaxel (DTX), a model drug for high molecular weight and poorly water-soluble drugs. Surfactant-ethanolic liposomes (SEL) were composed of phospholipids, ethanol, sodium cholate, DTX and PBS which were prepared by thin film dispersion method. The developed formulations were characterized by determining the vesicle shape and surface morphology, size and size distribution, entrapment efficiency and drug loading capacity. The effects of the developed formulations on the permeation of DTX across rat skin in vitro were investigated using the modified Franz diffusion cell under both occlusive and non-occlusive application conditions. The DTX SELs with optimum composition (phospholipid–surfactant, 85:15, w/w) provided a significantly higher steady-state amount of flux and cumulative permeation, compared to the tranditional liposomes, surfactant liposomes and ethanolic liposomes. The optimal SELs exhibited stable vesicle size, morphology and drug loading capacity. Our results indicated that SELs were promising carriers to enhance the transdermal delivery of DTX.

Development of ciclesonide dry powder inhalers and the anti-asthmatic efficacy in guinea pigs

Fei Liu, Gui-Ling Wang, Yan Zhang, Ying Men, Ju Du, Rui-Jun Ju, Liang Zhang, Xue Ying, Wan-Liang Lu^*, Qiang Zhang^*

2011, 20(5): 473-482. DOI: 10.5246/jcps.2011.05.060

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Ciclesonide is a new corticosteroid currently in clinical development for the treatment of asthma by oral inhalation. The objectives of the present study were to develop ciclesonide dry powder inhalers (DPIs, 80 μg) and investigate the anti-asthmatic effect in animals. For preparing a ciclesonide capsule-type DPI, sphere-shaped lactose was used as a diluent carrier, mixed with micronized ciclesonide, and filled into a capsule, and then put into a dry powder inhaler for oral inhalation. The asthmatic model was established with guinea pigs, and the therapeutic efficacy of ciclesonide was performed on the asthmatic guinea pig model. Results showed that the pulmonary deposition ratio of ciclesonide DPIs was approximately 26% and their content uniformity met the requirements of China Pharmacopoeia. The established pathological model exhibited the typical features of asthma with a widened pulmonary alveolar interval, narrowed alveolar space and detached bronchial mucosal epithelium with topical necrosis, goblet cell hyperplasia, and inflammatory cell infiltration. After treating with ciclesonide, the impaired indicators in asthmatic guinea pigs were significantly recovered or alleviated, exhibiting decreased total cells, decreased eosinophils and a decreased IL-5 level while there was an increased IFN-γ level in the bronchoalveolar lavage fluid (BALF). This study develops a new pulmonary ciclesonide delivery system for treating asthma, and proves the therapeutic efficacy in asthmatic guinea pigs.

Formulation and pharmacokinetics of the parenteral fat nano-emulsion of ubenimex

Xiao-Li Sun, Dong-Hua Liu, Peng Li, Wen-Fang Xu, Na Zhang^*

2011, 20(5): 483-492. DOI: 10.5246/jcps.2011.05.061

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The fat nano-emulsion, which has been used as a drug carrier, especially for the poorly water soluble drug, has drawn favorable attention recently. Ubenimex is a poorly soluble drug with no parenteral treatment available for patients. This study was aimed at the manufacture of a ubenimex loaded fat nano-emulsion for intravenous delivery by SolEmuls^® technology. The formulation and the process parameters were optimized by single-factor design and the obtained ubenimex loaded fat nano-emulsion was stable even after autoclaving. The average particle size was near 200 nm with narrow size distribution and a negative zeta potential of -44 mV. The in vitro release behavior of ubenimex from the fat nano-emulsion could be described by the double phase kinetics model and expressed by the following equation: 100 - Q = 75.27e^-0.369t + 15.94e^-0.0324t, Rα = 0.9863, Rβ = 0.9878. The pharmacokinetic study showed that the pharmacokinetic curves of both the ubenimex fat nano-emulsion and the i.v. ubenimex suspension, were similar and the main parameters showed no significant difference except t1/2. In conclusion, the fat nano-emulsion with ubenimex has potential as a safe and effective parenteral delivery system for poorly water soluble anti-cancer drugs.

Development and validation of an RP-HPLC-UV method for the determination of daphnoretin in rat plasma

Li-Xin Sun^*, Yang Chen, Wen-Wen Yang, Jun-Yang Guo, Ting Zhao, Li-Jin Tong

2011, 20(5): 493-497. DOI: 10.5246/jcps.2011.05.062

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A sensitive RP-HPLC-UV method has been developed and validated for the quantification of daphnoretin in rat plasma. Daphnoretin was extracted from rat plasma by protein precipitation and liquid-liquid extraction. Separation was performed on a Diamonsil C18 column (200 mm×4.6 mm, 5 μm) with a mobile phase of methanol-20 mmol/L ammonium acetate (adjusted to pH 3.2 with acetic acid, 42:58, v/v) at a flow rate of 1.0 mL/min. The UV detector was set at 345 nm and column temperature was set at 40 °C. The calibration curves were linear over the concentration range of 0.020-2.00 μg/mL. The lower limit of quantification (LLOQ) of daphnoretin in rat plasma was 0.020 μg/mL. The intra- and inter-day relative standard deviation (RSD) for measurement of quality control (QC) samples (0.050, 0.200 and 1.60 μg/mL) ranged from 5.0%-10.6%. Relative error (RE) was from ±(1.2%-2.5%). The validated method was used successfully in a pharmacokinetic study of daphnoretin in rats after intraperitoneal injection.

Vanadium stimulates mitochondrial ROS production in different ways

Zhe Shi, Hui-Xue Liu^*, Xiao-Da Yang^*

2011, 20(5): 498-504. DOI: 10.5246/jcps.2011.05.063

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Vanadium compounds show potential in diabetes and cancer treatment, although the toxicity remains a great concern. Previous studies have shown that vanadium-induced oxidative stress affecting mitochondrial function is intensively responsible for the toxicity. In this work, we investigated the effects of the vanadium compounds sodium metavanadate (NaVO3) and vanadyl acetylacetonate (VO(acac)2) on mitochondrial ROS generation and respiratory complex activities. The experimental results showed that vanadium compounds affected the ROS generation and complex activities in different patterns depending on the chemical species. NaVO3 inhibited mitochondrial complexes I and II activities and stimulated ROS generation at low concentration range; while VO(acac)2 promoted complex II activity but resulted in electron leakage from the complex I-involved pathway. The present results provide new evidence for understanding the toxicity of antidiabetic vanadium compounds.

Intestinal permeability of atractylenolides across the human Caco-2 cell monolayer model

Jie Guo, Wei Xu, Xiu-Wei Yang^*

2011, 20(5): 505-509. DOI: 10.5246/jcps.2011.05.064

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The intestinal permeability of three sesquiterpene lactones, atractylenolide I, II, and III, was investigated using the human Caco-2 cell monolayer model. The bidirectional permeability of the three compounds from the apical (AP) to the basolateral (BL) side and in the reserved direction was studied. The three compounds were assayed using HPLC. The Papp values of atractylenolide I, II, and III were all at the level of 10^-5 cm/s, suggesting high intestinal permeability and good absorption. The bidirectional transport of the three compounds was time- and concentration-dependent, and indicated the main mechanism of the passive diffusion of the three compounds across the intestinal epithelium membrane. Moreover, atractylenolide I might be partly actively transported.

Application of a yeast two-hybrid based screening system in the identification of amyloid-beta aggregation inhibitors in pharmaceutical plants

Li-Wei Wang, Yan-Fang Yang, Ying-Tao Zhang^*

2011, 20(5): 510-517. DOI: 10.5246/jcps.2011.05.065

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The aggregation of amyloid-beta (Aβ) peptide, has been demonstrated to be critical for the development of Alzheimer's disease (AD). Aβ aggregation inhibitors are thus considered to be drug candidates for AD therapy. In the present study, we developed a novel screening tool based on the yeast two-hybrid system to screen Aβ aggregation inhibitors. The human Aβ42 peptide cDNA was cloned using assembly PCR and inserted into each of the yeast expression plasmids containing either the GAL4 activation domain (GAL4AD) or the DNA-binding domain (GAL4BD). Co-transformation of the above plasmids led to the expression of the fusion proteins GAL4AD-Aβ42 and GAL4BD-Aβ42 in the AH109 yeast strain. The self interaction of Aβ42 fragments reconstructed the GAL4 transcriptor and thus activated the GAL4 responsive transcription of four reporter genes including HIS3, ADE2, lacZ and MEL1. The expression of the reporter genes rendered the multiple auxotrophic yeast cells capable of growing on the synthetic SD media lacking adenine and histidine. Growth arrest was used as a marker for screening Aβ aggregation inhibitors in this system, and the evaluation of Rhodiola species revealed potential resources for the development of Aβ aggregation inhibitors.

Flavonoids from the herb of Bidens pilosa L.

Xin Tian, Si-Xiang Zhou, He-Lin Wei, Nan Hu, Zhi Dai, Zhi-Gang Liu, Zheng-Zhou Han, Peng-Fei Tu^*

2011, 20(5): 518-522. DOI: 10.5246/jcps.2011.05.066

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Chemical constituents of the whole herb of Bidens pilosa L. were investigated. By using various column chromatography (CC) and spectroscopic methods, 13 flavonoids were isolated and identified as follows: 2'-hydroxy-4,4'-dimethoxy-chalcone (1), isoliquiritigenin (2), 3,2',4'-trihydroxy-4-methoxy-chalcone (3), licochalcone A (4), 4'-O-β-D-glucopyranosyl-2',3-dihydroxy-4-methoxy-chalcone (5), butein (6), apigenin (7), luteolin (8), diosmetin (9), chrysoeriol (10), 3,5,6,7,3',4',5'-heptamethoxyflavone (11), 7-O-β-D-glucopyranosyl-5,3'-dihydroxy-3,6,4'-trimethoxyflavone (12), and sulfuretin (13). Compounds 1-5, 9, 11 were obtained from the genus Bidens for the first time.

Echinacoside suppresses cellular senescence of human fibroblastic cells by down-regulation of p53

Hui Zhu, Cong Cheng, Chi Zhang, Zhao Wang^*

2011, 20(5): 523-528. DOI: 10.5246/jcps.2011.05.067

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Echinacoside is one of the phenylethanoids isolated from the stems of Cistanches salsa. Our previous research showed that echinacoside has anti-senescence activity. To investigate the mechanism of echinacoside's anti-senescence activity, the expressions of p53, p21, p16 and Rb at the mRNA and protein levels were determined. Results showed that the expression of p53 was down-regulated significantly in a dose dependent manner after treatment with echinacoside. Further experiments suggested that the down-regulation of p53 may be correlated with the upregulation of SIRT1. In addition, echinacoside may exhibit considerable higher affinity towards SIRT1 than resveratrol, according to our molecular docking simulation. In conclusion, we expect that echinacoside might be a promising candidate for regulating cell senescence.

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Journal of Chinese Pharmaceutical Sciences

2011, 20(5): 530-530.

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