Journal of Chinese Pharmaceutical Sciences

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2007, 16(4): 1-04.

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A simulation study of sampling time point designing for therapeutic drug monitoring based on a population pharmacokinetic model

Yang Zhang, Ying Zhou, Xiang-Lin Zhang, Xiao Liu, Yi-Min Cui, Wei Lu^*

2007, 16(4): 241-251.

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Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using a one-compartment open model with the first order absorption to determine PK parameter estimates with different sampling strategies as a validation of the method. The estimated parameters were further verified by comparing to the observed values. Results The samples collected at the single time point close to the non-informative sampling time point designed by this method led to bias and inaccurate parameter estimations. Furthermore, the relationship between the estimated non-informative sampling time points and the values of the parameter was examined. The non-informative sampling time points have been developed under some typical occasions and the results were plotted to show the tendency. As a result, one non-informative time point was demonstrated to be appropriate for clearance and two for both volume of distribution and constant of absorption in the present study. It was found that the estimates of the non-informative sampling time points developed in the method increase with increases of volume of distribution and the decrease of clearance and constant of absorption. Conclusion A rational sampling strategy during therapeutic drug monitoring can be established using the method present in the study.

Studies on in vitro release of cyclosporine A-loaded microspheres

Bin Zhao, Li-Juan Yang, Jian-Cheng Wang^*, Qiang Zhang

2007, 16(4): 252-256.

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Aim This study was to prepare cyclosporine A (CyA) microspheres (Ms) using 75:25 poly (D, L-lactide-co-glycolide) polymer (PLGA), and to evaluate the in vitro release of the CyA microspheres. Methods CyA-Ms were prepared by an oil-in-water (o/w) emulsion solvent extraction/evaporation process and characterized for drug content, particle size, surface morphology, and differential scanning calorimeter (DSC). Accelerated in vitro release of cyclosporine A from the micropsheres was studied at various conditions, such as temperatures, surfactants, pH values and organic solvents for a short period. Results CyA-Ms were in spherical shape with average particle size of 50 μm and loading efficiency of 13.0%. The results of DSC measurements suggested that at the dry state, CyA did interact very strongly with the hydrophilic PLGA polymer. In vitro release test in various release medium showed slight increase of CyA-Ms release profiles under various conditions of temperatures, surfactants and pH values. However, dramatical increase of CyA-Ms release was seen in the medium containing 30% isopropanol. Conclusion It was demonstrated that CyA could be incorporated into polymeric Ms prepared from PLGA using a solvent evaporation technique. The release medium containing 30% isopropanol might be the ideal condition for CyA-PLGA microspheres in vitro quality control test.

Determination of fleroxacin in human plasma by HPLC with fluorescence detection and the pharmacokinetic study

Zeng-Jun Fang, Bin Zhang, De-Qing Sun^*

2007, 16(4): 257-261.

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Aim To develop a sensitive and accurate HPLC method for the determination of fleroxacin in human plasma, and study its pharmacokinetics in healthy subjects. Methods The analytes were isolated from plasma by simple protein precipitation with methanol, separated on a Diamonsil C₁₈ column by isocratic elution with the mobile phase consisted of 1% triethylamine at pH 4.8 (adjusted with phosphoric acid) and acetonitrile (80/20, V/V) at a flow rate of 1.0 mL·min^-1, and analyzed by fluorescence detector with an excitation at 290 nm and emission 458 nm. The pharmacokinetic study of fleroxacin was performed according to a double period crossover design. Results The weighted (1/x) calibration curve was linear over the plasma concentration range of 0.025 – 8.00 mg·mL^-1. The inter- and intra-day precisions (RSD/%) were no more than 5.16%, and the method accuracies and extraction recoveries at three concentrations ranged from 99.1% to 100.9%, and 86.7% to 92.0%, respectively. Following oral administration at a dose of 400 mg fleroxacin, the main pharmacokinetic parameters for test and reference capsules were C_max 5.08 ± 0.78 and 5.38 ± 1.40 μg·mL^-1, t_max 1.72 ± 0.79 and 1.82 ± 0.78 h, t_1/2 11.68 ± 1.27 and 11.38 ± 1.51 h^-1, AUC_0-∞ 78.44 ± 11.44 and 76.53 ± 13.24 μg·mL^-1·h, respectively. Conclusion The method is sensitive and accurate, and suitable for human pharmacokinetic study of fleroxacin.

Synthesis of novel ADPR analogues: substitution of pyrophosphate linkage by dipeptide

Chao Zhang, Zhen-Jun Yang, Liang-Ren Zhang^*, Li-He Zhang

2007, 16(4): 262-267.

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For investigating the biological function of ADPR, four novel analogues (compounds 2–5) in which the pyrophosphate linkage was replaced by the aspartic acid dipeptide were synthesized. 5'-Amino adenosine or its analogues was used as the starting material, liquid phase peptide synthesis strategy was used to construct these ADPR analogues. The structures were characterized by 1H NMR and HRMS spectra. This study provides a versatile synthesis of peptide modified ADPR analogues and helps to understand the structure-activity relationship of ADPR.

Synthesis and antitumor activities of 2-(E)-(4-cyclopentyloxy-3-methoxylbenzylidene)cyclopentanone derivatives

Xing Yan, Yu-Zhuo Ma, Jing-Bo Chen, Ying-Xiang Liu^*

2007, 16(4): 268-271.

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Aim To design and synthesize a series of 2-(E)-(4-cyclopentyloxy-3-methoxylbenzylidene)cyclopentanone derivatives, and to determine their antitumor activities in vitro. Method The target compounds were synthesized. Their antitumor activities were assayed using human hepatic carcinoma cell line (Bel-7402) and human oral cavity epidermis squamocellular carcinoma cell line (KB). Results Five compounds were obtained. Three of them were not reported in the literature and their chemical structures were confirmed by IR, 1H NMR, MS and elemental analysis. Preliminary screening results showed that compound 5 possessed better biological activity with IC50 1.62 μmol·L–1 against Bel-7402 and 8.04 μmol·L–1 against KB, but much weaker than 5-Fluorouracil. Conclusion Mannich base derivatives of 2-(E)-(4-cyclopentyloxy-3-methoxylbenzylidene)cyclopentanone exhibited some antitumor activities.

Selective protection of ribostamycin by cyclic carbamates

Pan Pan, Gui-Hui Chen, Ying Chen, Xiang-Bao Meng, Zhong-Jun Li^*, Jing-Rong Cui^*

2007, 16(4): 272-276.

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Aim To develop a novel selective protection strategy for the synthesis of ribostamycin cyclic carbamate derivatives. Methods Ribostamycin protected by carbobenzoxy group was treated with NaH, to give different protected intermediates under respective controllable cyclization reaction conditions. New ribostamycin derivative was obtained after the cleavage of carbobenzoxy groups. Result The novel selective protection of ribostamycin was achieved by the synthesis of protected intermediates. New ribostamycin derivative was obtained, but showed no expected antibacterial activity. Conclusion Several ribostamycin cyclic carbamate derivatives were obtained by novel selective protection strategy, which shows the practicability and convenience of the protection strategy. But these new ribostamycin derivatives containing cyclic carbamates structure may not be an ideal leading compound for antibiotic activity.

Fingerprint analysis of different Panax herbal species by HPLC-UV method

Feng Zeng, Xiao-Ming Wang, Min Yang, Zhi-Qiang Lu, De-An Guo^*

2007, 16(4): 277-281.

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Aim To establish a method for differentiating commercial samples of Panax species including notoginseng, cultivated ginseng (Chinese ginseng and Korean ginseng), wild ginseng, red ginseng, three types of American ginsengs, and one American ginseng preparation with their HPLC fingerprints for assnrning the quality of different commercial samples of Panax species. Methods HPLC-UV method was used to establish their fingerprints, Zorbax Extend C18 (250 mm × 4.6 mm, 5 μm) was used as the analytical column, and acetonitrile/KH2PO4 aqueous solution was used as the mobile phase with gradient elution. Results The fingerprints of different commercial samples of Panax species varied in their holistic chromatograms and some specific constituents. Conclusion This method is reliable, reproducible and simple. It could be applied in the routine authentication of different commercial samples of Panax species.

Chemical constituents of the flower buds of Tussilago farfara

Yu-Feng Liu, Xiu-Wei Yang^*, Bin Wu

2007, 16(4): 288-293.

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Aim To study the chemical constituents of the flower buds of Tussilago farfara L. in the China National GAP Base of Traditional Chinese Materia Medica and provide scientific basis for quality control. Methods The constituents were separated and purified by different chromatographic methods, and their structures were elucidated by IR, MS and NMR techniques. Results Twenty eight compounds were isolated from the flower buds of T. farfara. Their structures were identified as n-heptacosane (1), bis(2-ethylhexyl)phthalate (2), 7-[3'-ethylcrotonoyloxy]-lα-[2'-methylbutyryloxy]-3,14-dehydro-Z-notonipetranone (3), 7-[3'-ethylcrotonoyloxy]-lα-[2'-methylbutyryloxy]-3,14-dehydro-E-notonipetranone (4), tussilagone (5), dibutyl phthalate (6), bauer-7-ene-3β,16α-diol (7), isobauerenol (8), stigmasterol (9), β-sitosterol (10), 2,2-dimethyl-6-acetylchromanone (11), n-hexadecanoic acid (12), 7β-hydroxysitosterol (13), 7α-hydroxysitosterol (14), 7,14-bisdesacylnotonipetrone (15), 2,3-dihydroxypropylpalmitate (16), daucosterol (17), 6-hydroxy-2,6-dimethylhept-2-en-4-one (18), ferulic acid (19), isoferulic acid (20), caffeic acid (21), α-D-glucose (22), sucrose (23), phthalic acid (24), p-hydroxybenzoic acid (25), gallic acid (26), uridine (27), and adenosine (28). Conclusion Compounds 1, 1216, 18 and 20 were obtained from the genus Tussilago for the first time.

Liriodendrin protects SH-SY5Y cells from dopamine-induced cytotoxicity

Da-Long Zhao, Da-Wei Shen, Yu-Tao Chi, Fang Liu, Li-Bo Zou, Hai-Bo Zhu^*

2007, 16(4): 294-299.

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Aim To investigate the effect of liriodendrin, an extract from Fraxinus sielboldiana blume belonging to the Oleaceae family, on dopamine-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Methods Cell viability was processed when treated with 50 μmol·L^–1 of dopamine for 24 h by MTT assay. Early apoptosis, late apoptosis/necrosis were analyzed by flow cytometry using Annexin V-FITC and propidium iodide (PI) double-staining, respectively. Generation of reactive oxygen species (ROS) was assessed by DCFH-DA, an oxidation-sensitive fluorescent probe. To evaluate mitochondrion membrane potential (ΔΨm) using flow cytometry with the fluorescent dye Rhodamine 123. The transcriptional level of P53 was studied using RTPCR. Results The dopamine-induced loss of cell viability was significantly attenuated by liriodendrin treatment at the concentration of 10^–8, 10^–7, 10^–6, 10^–5 and 10^–4 mol·L^–1. The protective effects of liriodendrin (10^–7, 10^–6 and 10^–5 mol·L^–1) on dopamine-induced cytotoxicity may be ascribed to its anti-oxidative properties by reducing ROS level and anti-apoptotic effect via protection of ΔΨm. In addition, the effect of liriodendrin may involve the P53 pathway in apoptosis. Conclusion Liriodendrin may provide a useful therapeutic strategy for the treatment of neurodegenerative diseases such as Parkinson’s disease (PD).

Effect of berberine on glucolipid metabolization in diabetic skeletal muscle and its mechanism

Ji-Yin Zhou, Shi-Wen Zhou^*

2007, 16(4): 300-306.

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Aim To investigate the effect of berberine on damaged morphology and glucolipid metabolization in skeletal muscle of diabetic rat and the relationship between peroxisome proliferator-activated receptor (PPARs) α/γ/δ protein expression. Methods Type 2 diabetes mellitus rats were induced by an injection of 35 mg·kg^-1 streptozotocin (STZ) and a high-carbohydrate/high-fat diet for 16 weeks. From week 17 to 32, diabetic rats were given low-, middle-, high-dose berberine (75, 150, 300 mg·kg^-1), fenofibrate (100 mg·kg^-1) and rosiglitazone (4 mg·kg^-1) by oral administration, respectively. The skeletal muscle structure was observed with hematoxylin-eosin (HE) staining, glycogen and triglyceride contents were measured by spectrophotometry and PPAR α/γ/δ protein expressions were detected by immunohistochemistry. Results Fiber distribution remained normal in skeletal muscles of all the groups, middle-, high-dose berberine partly improved diabetic fibre atrophy, increased glycogen and decreased triglyceride levels in diabetic muscle (P < 0.01). Middle-, high-dose berberine and rosiglitazone all significantly reduced PPARγ protein level in diabetic skeletal muscle (P < 0.01); middle-, high-dose berberine and fenofibrate strikingly increased both PPARα and PPARδ expression (P < 0.01). Conclusion Berberine modulates PPAR α/γ/δ protein expression in diabetic skeletal muscle which may contribute to ameliorate fibre damage and glucolipid metabolization.

Induction of apoptosis and G₂/M cell cycle arrest by oridonin in human gastric cancer BGC-823 cells

Jian Han, Min Ye, Xue Qiao, Wan-Ying Wu, Gui-Qin Qu, De-An Guo^*

2007, 16(4): 307-314.

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Aim To investigate in vitro apoptosis-induction effects of oridonin on gastric tumor cells BGC-823 and its effects on cell cycle, mitochondrial membrane potential and intracellular Ca²⁺ to shed light on the mode of its anticancer action. Methods The MTT method was used to investigate the inhibitory effect of oridonin on BGC-823 cells. The apoptosis-induction effect was evaluated by confocal laser microscopy and flow cytometry. The change of mitochondrial membrane potential and the increase of intracellular Ca²⁺ were assessed by fluorescence probe rhodamine123 and Fluo 3-AM, respectively, with flow cytometry. The expression of apoptosis and cell cycle related proteins was studied using western blotting. Results Oridonin inhibited BGC-823 cells growth with IC₅₀ of 22.21 μmol·L^-1. It induced apoptosis in a dose-dependent manner. In addition, it decreased mitochondria membrane potential, increased intracellular Ca²⁺, and activated pro-caspase 3. BGC-823 cells were arrested in G2/M cell cycle phase with lower expression of cyclin A protein. The up-regulation of p53 was observed before apoptosis and cell cycle arrest occurred. Conclusion Oridonin inhibits the proliferation of BGC-823 cells through G2/M cell cycle arrest and apoptosis induction, which is mediated by influx of Ca²⁺, up-regulation of p53, activation of caspase-3, and down-regulation of cyclin A.

2007 Anniversary Symposium of the State Key Laboratory of Natural and Biomimetic Drugs and The 1st Round-Table Symposium of Chemical Biology on Nucleic Acid and Carbohydrate Successfully Held

Zhuo Wang, Zhen-Jun Yang

2007, 16(4): 315-316.

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