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Table of Content

    15 December 2008, Volume 17 Issue 4
    Contents

    Graphical contents list

    Journal of Chinese Pharmaceutical Sciences
    2008, 17(4):  259-262. 
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    Review
    Structure modifications based on KRN7000 and their SARs in activating NKT cells
    Lei Zhang, Xin-Shan Ye*
    2008, 17(4):  263-271. 
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    α-Galactosylceramides, which can be recognized by natural killer T (NKT) cells, are now attracting more and more attetion due to their therapeutic potential in cancer, infection and autoimmune diseases. Advances have been achieved in discovering compounds with better activities and efforts have been made to understand the structure-activity relationships (SARs) of these NKT cell ligands. In this review, we discuss the structure modifications based on KRN7000, the principal glycolipid used in the study of NKT cell stimulation, and the SARs based on these modified structures.

    Full Papers
    Facile synthesis of a core trisaccharide of laminin as a potential metastatic antagonist
    Xiao-Feng Jin, Xiang-Bao Meng, Kai-Jun Liao, Qing Li, Zhong-Jun Li*
    2008, 17(4):  272-276. 
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    A core trisaccharide of laminin, β-D-Gal-(14)-β-D-GlcpNAc-(16)-α-D-Manp-OMe, with potential anti-tumor metastatic activity was designed and prepared. 2-Iodoglactosyl azide was used as the donor to construct 2-N-acetamido-2-deoxylactosyl moiety through an azidoiodo-glycosylation reaction. Simultaneously, 1, 2-trans-β-glycosic bond was formed stereoselectively in one step with a moderate yield. This novel procedure avoided the use of 2-amino-2-deoxyglucose as both donor and acceptor.

    One-pot synthesis of 1,3,4-oxadiazole-5-thioethers in water
    Xu Yan, Ze-Mei Ge*, Tie-Ming Cheng, Run-Tao Li*
    2008, 17(4):  277-280. 
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    An efficient and environmental-friendly one-pot procedure has been developed for the synthesis of 1,3,4-oxadiazole-5-thioethers by the reaction of acylhydrazine with carbon disulfide and organic halides or α, β-unsaturated carbonyl compounds. The reactions were carried out in water in the presence of potassium phosphate within 2–4 h to afford the expected products in excellent yields.
    A convenient synthesis of 1-alkyl-5-amino-6-phenylethyluracils as potential non-nucleoside HIV-1RT inhibitors
    Xiao-Yan Ma, Zhi-Jian Cheng, Yan-Li Chen, A-Min Li, Zhi-Li Zhang, Xiao-Wei Wang, Jun-Yi Liu*
    2008, 17(4):  281-284. 
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    1-Alkyl-5-amino-6-phenylethyluracils (1a, 1b) were synthesized as potential non-nucleoside HIV-1RT inhibitors. A convenient synthetic procedure was developed for the preparation of 1-alkyl-5-amino or 5-aminosubstituted-6-phenylethyluracils, which were synthesized in three or four steps from 6-methyluracil in good yield. The development of a one-pot reaction that simultaneously removed the benzyl protection group and reduced the nitro group greatly improved the yield of the synthesis. Compounds 1a and 1b are analogs of MKC-442, which is an efficient inhibitor of HIV-1 reverse transcriptase. 1a and 1b were tested for their inhibition of HIV-1RT, and moderate activity was found for 1a.

    Optimization of the biphasic release of indomethacin from HPMC/pectin/calcium chloride matrix tablet by response surface methodology

    Bao-Jian Wu, Xiu-Li Wei, Yi Lu, Wei Wu*
    2008, 17(4):  285-290. 
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    We studied the effect of two independent variables, the pectin/calcium chloride weight ratio and the overall matrix weight in HPMC/pectin/calcium matrix tablet, on the release of indomethacin. A two-factor 5-level central composite experimental design was employed. Responses of the Peppas correlation parameters n and K and the 10% release time (T0.1) were optimized by response surface methodology. Significant effect of the independent variables on the biphasic release parameters, n and K, was observed. N, K and T0.1 were well fitted with the second-order quadratic equations rather than linear equations. Moreover, the mathematic fitting and the response surfaces showed significant cross-interaction between the pectin/calcium chloride ratio and the overall matrix weight. The optimal formulation with larger n, longer T0.1 and smaller K consisted of medium pectin/calcium chloride ratio around 1.0 and medium matrix weight around 200 mg. Validation studies on the optimal formulations showed good predictability of the n, K and T0.1 values with biases within the range of -7.33% and 6.26%. Our results support that central composite design can be used to optimize drug release from HPMC/pectin/calcium matrix tablet with high predictability.
    Effect of poly(ethylene glycol) modified polyethylenimine polyelectrolyte complex on pharmaceutical characteristics and uptake on breast cancer cell
    Li-Ting Liu, Xian-Rong Qi*
    2008, 17(4):  291-296. 
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    Cationic polyethylenimine (PEI) with dextran fluorescein anionic (DFA) or oligodeoxynucleotide (ODN) could form polyelectrolyte complex by self-assembly as a gene delivery vector. This study was designed to investigate the effects on pharmaceutical characteristics and cell uptake PEI after a long-circulation modification with poly(ethylene glycol) (PEG). DFA or ODN reacted with PEI or PEI-PEG to form polyelectrolyte complexes. Surface characters of these complexes and the retardation of ODN by PEI and PEI-PEG were evaluated. The uptake rates of DFA/PEI and DFA/PEI-PEG complexes by MCF-7 cells were evaluated by flow cytometry. Confocal laser scanning microscopy was utilized to visualize the internalization of these complexes. ODN/PEI complex showed the dependence of their size and ξ potential on the N/P ratio. ODN/PEI-PEG complex were much less affected by N/P ratio and their size was around 30 - 100 nm. PEI and PEI-PEG retarded ODN even at N/P ratio as low as 4, and complete retardation was found at N/P ratio of 8. The uptake rate by MCF-7 cells was direct correlated to the DFA concentration and incubation time, and the uptake rate could exceed 99% under the selected condition. The results in this study showed that PEI self-assembly polyelectrolyte complex after stealth or long circulation modification may increase the ability as a gene vector to delivery genes into cells.

    Pharmacokinetics of two modified release system of dipyridamole in beagle dogs
    Zhi-Hong Zhang, Chang-Guang Wang, Guang-Mei Sun, Ning Li, Bo Peng, Wei-San Pan*
    2008, 17(4):  297-302. 
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    A novel floating osmotic pump controlled release system (FOP) and traditional matrix sustained release tablets (MT) of dipyridamole (DIP) were characterized in terms of pharmacokinetics, drug release, and in vitro-in vivo correlation. In vivo study was performed by a three-crossover study in six beagle dogs relative to the conventional tablet (CT). A HPLC method for the determination of DIP in the plasma was developed. Cumulative percent of absorption fraction was compared to that of in vitro cumulative release. Both FOP and MT displayed obvious extended release characteristic in vivo while FOP showed a better extended release behavior. The bioavailability of FOP was higher than that of MT and a zero-order release linear correlation of DIP between fraction absorbed in vivo and fraction dissolved in vitro was established for FOP while not for MT. The results indicated the existence of an absorption window in upper part of the GI track of DIP, which meant that floating system could be excellent for the drug delivery. In addition, the in vitro model was a good choice for depicting in vivo absorption and for optimization of the formulation of FOP if it is needed to be bio-equivalent to MT.
    Preparation of stealthy etoposide proliposomes and the pharmacokinetics in rabbits
    Jin-Ming Li, Yan-Zhuo Zhang*, Jun-Gang Ren, Yun-Zhi Qu
    2008, 17(4):  303-308. 
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    The objectives of the present study were to prepare stealthy etoposide proliposomes and study the pharmacokinetics in rabbits. Blank stealthy liposomes were prepared by film dispersion method. Stealthy etoposide liposomes were prepared by using the ammonium sulfate gradient loading procedure. Vacuum freeze-drying technique was used to dry stealthy etoposide liposomes. Encapsulation efficiency of stealthy etoposide proliposomes was determined by Sephadex chromatography. The morphology was observed by transmission electronic microscope. The particle size and zeta potential were measured by using electrophoretic light scattering technology. The pharmacokinetics in rabbits was evaluated by comparison with etoposide injection and conventional liposomes, respectively. Mean encapsulation efficiency of stealthy etoposide proliposomes was 83.92% ± 3.65% (n = 3). The liposomes were round or oval. Mean particle size was (124.5 ± 26.9) nm, and zeta potential was (-39.50 ± 1.04) mV. Following intravenous injection administration at a dose of 1.5 mg/kg etoposide, the three kinds of etoposide preparations were fitted with the two-compartment model. T1/2 β and AUC values of stealthy etoposide proliposomes were (19.26 ± 3.16) h and (26.04 ± 3.53) μg/h/mL, respectively. T1/2 β and AUC values of etoposide injection were (0.94 ± 0.21) h and (0.98 ± 0.26) μg/h/mL, respectively. T1/2 β and AUC values of conventional liposomes were (7.99 ± 1.36) h and (11.65 ± 1.70) μg/h/mL, respectively. Results indicated that the stealthy etoposide proliposomes could significantly extend the duration of etoposide in blood circulation.

    Metabolites of baicalein 6,7-diacetate in rats
    Yun Hu, Xiao-Yu Guo, Lin Yang, Qing-Ming Che*
    2008, 17(4):  309-313. 
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    To investigate the metabolites of baicalein 6,7-diacetate in rats. HPLC-DAD and LC/MSn methods were used to analyze the metabolites in intestinal tract and plasma after oral administration of baicalein 6,7-diacetate to rats. Baicalein 6,7-diacetate was degraded into baicalein 6-monoacetate and baicalein in rat intestinal tract, and four baicalein glucuronides, baicalein 6-O-glucuronide, baicalein 6-methoxyl-7-O-glucuronide, baicalein 6,7-di-O-glucuronide, and baicalein 6-O-glucose-7-O-glucuronide were detected and tentatively identified in rat plasma. This is the first time to report the metabolites of baicalein 6,7-diacetate in rats. Six metabolites were identified in rat intestinal tract and plasma.

    Antioxidant phenanthrenes and lignans from Dendrobium nobile
    Xue Zhang, Jie-Kun Xu, Nai-Li Wang, Hiroshi Kurihara, Xin-Sheng Yao*
    2008, 17(4):  314-318. 
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    To study the antioxidant constituents from the stems of Dendrobium nobile, and to discuss their structure-activity relationship. Compounds were isolated from a 60% ethanolic extract by various chromatographic techniques and were identified by spectral analysis. The antioxidant activities of compounds were evaluated by DPPH free radical scavenging assay. Five phenanthrenes and four lignans were obtained from the active fractions of D. nobile. Their structures were identified as fimbriatone (1), confusarin (2), flavanthrinin (3), 2,5-dihydroxy-4,9-dimethoxyphenanthrene (4), 3,7-dihydroxy-2,4-dimethoxyphenanthrene (5), syringaresinol (6), pinoresinol (7), medioresinol (8) and lirioresinol-A (9), respectively. Compounds 2 and 6 exhibited more potent DPPH scavenging activities than vitamin C. All the above compounds were reported from this plant for the first time, and compounds 3, 4 and 9 were reported for the first time from the genus of Dendrobium. For all phenanthrenes and lignans, an electron-donating methoxyl group in the ortho position to the phenolic hydroxyl group exhibits enhanced antioxidant activities.

    Synthesis and reversal effect of a novel N-substituted phthalimide-sugar on doxorubicin resistant of human breast cancer cells

    Wen-Yuan Yi, Min Li*, Ya-Ping Yang, Zhuo-Yuan Lu, Bo Xu, Dong Han, Zhong-Jun Li**, Jing-Rong Cui

    2008, 17(4):  319-323. 
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    Thalidomide (α-N-phthalimido-glutarimide, TLD) is a kind of anti-angiogenic and anti-inflammatory drug, and showed effects in the treatment of several disease entities. In this study, the biological effects of a novel N-sugar substituted phthalimide (STA-35) on the regulation of multidrug resistance (MDR) to doxorubicin (ADR) were investigated. The proliferation of cancer cells was detected by a SRB assay. The activity of P-glycoprotein (P-gp) was determined by a Flow cytometry. The expression of P-gp was measured by western blotting. The results showed that STA-35 inhibited the proliferation of human breast cancer cell line MCF-7 and its ADR resistant cell line MCF-7/ADR, and the relative resistance was only 1.19. Meanwhile, STA-35 could sensitize the cytotoxicity of ADR in MCF-7/ADR cells. In addition, we found that STA-35 reduced the activity of P-gp by suppressing the P-gp expression, which was indicated by the increase in the accumulation of rhodamine 123 in MCF-7/ADR cells. These results suggested a promising application of STA-35 as the MDR reversing agent. The underlying mechanism of the effects might be attributed to the inhibition of P-gp.

    Therapeutic effects of flavonoids from Ceylon green tea on hypoxic human brain epithelial cells
    Shan-Hong Huang, Ranil De Silva*
    2008, 17(4):  324-331. 
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    We have extracted and purified flavonoids as active ingredients from Ceylon green tea (Dilmah). In this project, an in vitro hypoxic model using human brain epithelial cells (HBEC) was studied with treatment of the tea extract before inducing hypoxia. We have tested the hypothesis that flavonoids extracted from Ceylon green tea act as potential therapeutic ingredient (s) to reduce oxidative stress in hypoxic cells through its antioxidant properties and its ability to reduce cerebral cellular death. The biochemical antioxidant tests show that the Ceylon green tea has 68% ± 2.8% inhibition property of scavenging of ABTS. The inhibition of pyrogallol red bleaching by HOCl from Ceylon tea was 79% ± 4.5%. After exposing to hypoxia, the cell viability was 29% ± 2.3% in the hypoxia control group but 41% ± 4.7% for flavonoids extract treated group. In LDH assay, flavonoids extract treated group had 75% ± 3.7% reducing of LDH release. The flavonoids extract treated groups significantly increased in antioxidant enzyme activity assays: the activity level of SOD [(1.5 ± 0.6) µmol/min/mg protein], CAT [(0.61 ± 0.06) µmol/min/mg protein], GPx [(2.6 ± 0.41) µmol/min/mg protein] and GST [(6.0 ± 2.4) µmol/min/mg protein] are significantly increased as compared with hypoxic control [(0.5 ± 0.52, 0.51 ± 0.04, 1.2 ± 0.35 and 3.1 ± 1.6) µmol/min/mg protein, respectively]. The study demonstrated a great clinical potential and opened a new avenue to prevent stroke by drinking Ceylon tea.
    Risk factors analysis of rosiglitazone in patients with diabetes mellitus
    Bao-Chen Xi, Qing-Ming Ding, Lu-Wen Shi*
    2008, 17(4):  332-336. 
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    According to the drug-related risk factors indicated in the latest product monograph, we made this research to analyze and discuss the risk factors associated with rosiglitazone in clinical application in China-Japan Friendship Hospital. We collected and reviewed all cases involving inpatients who had used rosiglitazone in the hospital over the past two years. The focus of our study is on the identification and discussion of the incidence of adverse reactions, contraindications and drug induced problems associated with monotherapy or combined therapy of rosiglitazone. Three hundred and ninety eight cases were reviewed in the study including 3 patients with type 1 DM (0.75%) and 395 patients with type 2 diabetes mellitus (99.25%). Peripheral edema developed in 9 patients (2.26%) in the course of rosiglitazone therapy; one patient (0.25%) was found to have macula edema before rosiglitazone therapy; Cardiac abnormalities were identified in 6 patients (1.51%) in the course of treatment, of which 2 patients were NYHA class I, 3 patients were NYHA class II and 1 patient was NYHA class IV. Abnormal hepatic function (elevated ALT) was found in 79 patients (19.85%) during their stay in hospital. In these patients, ALT levels of 1 - 2.5 times, 2.5 - 3 times over the upper limit were identified in 70 patients, 3 patients and 6 patients, respectively. Of the 398 patients on rosiglitazone, 123 patients (30.90%), 165 patients (41.46%), 104 patients (26.13%), 3 patients (0.75%) and 1 patient (0.25%) were found to use concurrently insulin, metformin, organic nitrate, gemfibrozil and rifampin, respectively. We analyzed the risk factors associated with the clinical use of rosiglitazone, and identified the potential risks, and put forward suggestions to improve the effectiveness and safety of rosiglitazone therapy.

    Notes
    Apparent dose dependent antibody response in chickens immunized with orthopox virus antigens
    Xiao-Ying Zhang*, Rüdiger Schade, Heinz Ellerbrok
    2008, 17(4):  337-339. 
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    Dose-dependent IgY antibody response to different amounts of orthopox virus (OPV) antigen has been studied in immunized chickens for two different OPV strains (vaccinia virus, 7.0×106 PFU and cowpox virus, 9.2×107PFU). The antibody responses to different immunizations were tested and compared by indirect immunofluorescence antibody test. Our results, together with the literature, show that the antigen dose used for immunization plays an important role for the production of specific Abs. An increase in antigen concentration may achieve higher Ab titers but, dependent on the immunogenicity of OPV antigen, it can also lead to an immune depression. However, in this study we found that OPV played a positive correlation between antigen concentration and Ab-titer.

    Others
    Contents of Volume 17
    Keywords Index of Volume 17
    Author Index of Volume 17
    Acknowledgements
    Journal of Chinese Pharmaceutical Sciences
    2008, 17(4):  344-354. 
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