Journal of Chinese Pharmaceutical Sciences

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2009, 18(2): 93-98.

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Cell penetrating peptides and their applications in siRNA delivery

Xiao-Feng Wang, Yang Liu, Zhuo Wang, Zhen-Jun Yang^*, Li-He Zhang

2009, 18(2): 99-105.

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Given its ability to knock down essentially any gene of interest, siRNA has been one of the promising candidates for gene therapy. However, like other nucleic-acid-based drugs, its poor cellular uptake poses a major challenge. Here we briefly summarize the use of cell penetrating peptides (CPPs) as a novel and promising approach for siRNA delivery. The main advantages of CPPs are their low toxicity and high efficiency.

Mechanisms of cerebral protection of Chinese herbal extract-Braintone on middle cerebral artery occluded rats

Kok-Poh Loh, Wan-Hui Wong, Li-Shan Low, Hong Wang, Benny Kwong-Huat Tan, Vincent Chou, Yi-Zhun Zhu^*

2009, 18(2): 106-113.

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Free radical induced neuronal damage is involved in stroke. Several in vitro and in vivo studies have proved that antioxidant could act as neuroprotective agent through intervening with free-radical mediated apoptosis in the ischemic penumbra. In particular, natural products which contain antioxidant properties have undoubtedly potential for stroke treatment. In the present study, therapeutic effects of Braintone on Wistar rats undergone middle cerebral artery occlusion (MCAO) was evaluated. Gene expression levels of pro-apoptotic genes (AT2 receptor, FAS, BAX and BCL-XS) were showed to be significantly reduced in Braintone treated groups (0.4-, 0.72-, 0.76-, 0.32-fold, P<0.05) as compared to vehicle group. Significant reduction of immunoreactivity of protein production of these genes, together with least nuclear green fluorescence observed in TUNEL, Braintone as an antioxidant drug, is concluded to have promising therapeutic effect for stroke treatment.

Allicin induces apoptosis, cell cycle arrest and microtubule disassembly in human nasopharyngeal carcinoma KB cells

Ya-Ping Yang, Min Li^*, Bo Xu, Wei Guo, Jing-Rong Cui, Kui Wang

2009, 18(2): 114-120.

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Allicin, a major biologically active component of garlic, is produced from its inactive precursor alliin by the enzyme alliinase. In this study, we investigated its effects on human nasopharyngeal carcinoma KB cells. After incubation for 48 h, allicin inhibited the growth of KB cells in a concentration-dependent manner with an IC50value of (2.2±0.2) μg/mL. Incubation with allicin for 48 h caused a concentration-dependent induction of apoptosis in the concentration range of (16–48) μg/mL, and the induction of apoptosis was confirmed by the changes of mitochondrial membrane potential, F-actin contents and nuclear condensation in KB cells. Moreover, allicin concentration-dependently arrested KB cells at the S-phase of the cell cycle in the range of (16–48) μg/mL. In addition, treatment with the compound caused concentration-dependent disassembly of microtubule cytoskeleton in KB cells, which is similar to the effect of colchicine, a well-known microtubule destabilizing agent. We concluded that the abilities of allicin to inhibit the proliferation of KB cells probably relate to its apoptosis induction, cell cycle arrest and microtubule destabilizing properties

Characterization of subtype selection properties of R-(-)-DM-phencynonate hydrochloride and its racemate on muscarinic receptors

Li-Yun Wang, Hong-Liang Sun, Nan Mou, Bo-Hua Zhong, Ke-Liang Liu, Jian-Quan Zheng^*

2009, 18(2): 121-127.

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In order to compare the potential selectivity of R-(-)-DM-phencynonate hydrochloride with its racemate (±)-DM-phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylcholine muscarinic receptor subtypes (M1–M5) (CHO-hm1-5R) were cloned and expressed in Chinese hamster ovary (CHO-K1) cell line. The specific mRNAs of the five acetylcholine muscarinic receptor subtypes were detected by the reverse transcription-polymerase chain reaction (RT-PCR) method, demonstrating the definite expression of muscarinic receptor subtype genes (CHO-hm1-5R). The affinity and saturability of different muscarinic receptor subtypes to [³H] N-methylscopolamine ([³H]-NMS) were obtained by radioligand binding assay. Equilibrium binding assay revealed that the maximum binding capacity of [³H]-NMS (Bmax value) to CHO-hm1-5R were 40.22±3.23, 24.53±4.11, 29.65±2.65, 25.41±2.46, 32.78±4.81 pmol/mg·protein, respectively. Kd values of [³H]-NMS to muscarinic receptors M1 to M5 were 0.97±0.22, 1.16±0.14, 0.99±0.06, 0.56±0.08, 1.12±0.06 nM, respectively. R-(-)-DM-phencynonate hydrochloride was found to block the M4 receptor with a much higher potency (pD2 = 7.48) than those displayed on M1 (pD2 = 6.20), M2(pD2 = 5.99), M3(pD2 = 5.99) and M5(pD2 = 6.70) subtypes. However, for (±)-DM-phencynonate hydrochloride, no significant subtype receptor selectivity was found. Both (±)-DM- and R-(-)-DM-phencynonate hydrochloride showed allosteric effects on muscarinic receptors, the Hill coefficient (nH) of five receptor subtypes was less than 1, respectively. The results revealed that R-(-)-DM-phencynonate hydrochloride showed selectivity torwards M4 subtype, and there were allosteric effects for both R-(-)-DM-phencynonate hydrochloride and (±)-DM-phencynonate hydrochloride on muscarinic receptors.

Study on the binding of novel antitumor drug Ethaselen to bovine serum albumin

Wan-Chen Tang, Ge Fu, Xu Wang, Jian-Guo Zhang, Hui-Hui Zeng^*

2009, 18(2): 128-131.

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The binding pattern of Ethaselen to bovine serum albumin (BSA) was studied by fluorescence spectroscopic technique and Autodock 3.0.5 analysis. The result showed that the binding constant K of Ethaselen and BSA is 3.5×10⁴L/mol and the number of binding sites n = 0.9. The binding between Ethaselen and BSA or human serum albumin (HSA) is mainly through hydrophobic interactions.

Vasorelaxant effect of 3,4-dihydro-2-(4-morpholinylmethy)-1(2H)-naphthalenone on the vascular smooth muscle of rabbits

Xue Li, Yuan-Yuan Wei, Shou-Ting Fu^*, Lan Zhu, Bing Wang

2009, 18(2): 132-135.

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The purpose of this study was to examine the relaxation effect of CY on the vascular smooth muscle (VSM) from rabbits. Experiments were carried out on isolated thoracic aorta of rabbits. CY (3×10^–3mM – 3 mM) could relax the VSM preparations pre-contracted by adrenaline (AD), noradrenaline (NE), high-K⁺solution or BaCl2 with respective EC50 values of (0.31±0.11) mM, 0.19±0.03 mM, 0.20±0.04 mM and 0.25±0.04 mM. Moreover, CY (10^–2 mM, 0.1 mM and 1 mM) inhibited norepinephrine (NE), CaCl2 and KCl-induced vasoconstriction in a concentration dependent manner. The phasic contraction produced by NE was concentration dependently attenuated with CY (10^–2 mM, 0.1 mM and 1 mM) in calcium-free medium, similar to that caused by verapamil. The present findings suggest that CY relaxed thoracic aortic rings by blocking voltage-dependent Ca²⁺ channels. The inhibition of intracellular Ca²⁺release may be one of the main vasorelaxant mechanisms of CY.

The anti-hyperlipidemia activities of six herbs before and after fermentation with white rot fungi

Jun-Yan Tao^#, Guo-Hua Zheng^#, Lei Zhao, Zhi-Jun Huang, Qiong-Guang Zhang, Jian-Guo Wu, Xiao-Yu Zhang^*

2009, 18(2): 136-140.

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Hyperlipidemia has high morbidity. We explored the novel activities of six Chinese herbs before and after fermentation for preventing hyperlipidemia. The herbs were fermented with white rot fungi Ganoderma lucidum, a strain of EN2. Lovastatin was used as the positive control. Mice were treated with those herbs before and after fermentation treatment for 15 d and then injected peritoneally with Triton 3393. After the treatment, the serum total cholesterol (TC) and triglyceride (TG) were measured. Moreover, the changes of the ingredients of those herbs were analyzed by fingerprint chromatography. The results showed that Herba leonuri before fermentation, Ramulus mori and Caulis lonicerae after fermentation, Radix sophorae flavescentis before and after fermentation showed activities to prevent hypertriglyceridemia, while Ramulus mori and Herba leonuri before fermentation showed activities to prevent hypercholesterolemia. In addition, some new ingredients were appeared after fermentation. In conclusion, the novel activities of these herbs to prevent hyperlipidemia were identified and the new ingredients that emerged after fermentation warrant further exploration.

Structural determination of two triterpenoid saponins from Gymnocladus chinensis Baill.

Kan Wang, Hong-Zheng Fu^*

2009, 18(2): 141-145.

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Two triterpenoid saponins (compound I and II) have been isolated from Gymnocladus chinensis Baill., and compound I was determined as a new compound. The structure of compound I was assigned as 2β,23-dihydroxy-acacic acid-3-O-α-L-arabinopyranosyl-21-O-{(6S)-2-E-2,6-dimethyl-6-O-[4-O-(6S)-2-E-2,6-dimethyl-6-O-β-D-glucopyranosyl-α-L-arabinopyranosyl-2,7-octadienoyl}-28-O-β-D-xylopyranosyl(1→3)-β-D-xylopyranosyl(1→4)-α-L-rhamnopyranosyl(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside by extensive MS and NMR studies.

Chemical constituents isolated from Saruma henryi

Shi-Wen Dong, Ming-Ying Shang, Xuan Wang^*, Shu-Xiang Zhang, Chen Li, Shao-Qing Cai

2009, 18(2): 146-150.

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Chemical constituents of the whole herb of Saruma henryi Oliv. were investigated. The herbal extract was separated by repeated column chromatography over silica gel and celite. The structures were elucidated by spectroscopic analysis. Thirteen compounds were obtained and identified as 7-methoxyl-aristololactam IV (1), aristololactam II (2), aristolochic acid I (3), aristololactam AII (4), daucosterol (5), aristololactam Ia (6), N-trans-feruloyl tyramine (7), aristololactam I (8), 4β,10β-aromadendranediol (9), aristololide (10), aristolic acid I (11), meso-dihydroguaiaretic acid (12), and calopiptin (13). These compounds were obtained from the genus Saruma for the first time, and they provided chemical evidences for the chemotaxonomy of plants of the Aristolochiaceae family. Since aristolochic acids and aristololactams are toxic to kidney, the results of this investigation suggest that it should be cautious to use Saruma henryi as a medicine.

Insights into the discovery of new 5-HT1A receptor ligands: receptor based pharmacophore

Zhi-Yu Yang, Wei Lv, Ran Tian, Hong-Wei Jin, Hui-Hui Zeng^*

2009, 18(2): 151-155.

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5-HT1A receptor is a crucial therapeutic target for the treatment of anxiety, depression, pain, etc. Design and preparation of potent 5-HT1Areceptor ligands for drug discovery has attracted extensive attention in the past few years. In this paper, a three dimensional model of human 5-HT1A receptor was constructed by means of homology modeling. And the docking of MP349 to the receptor suggested a reliable binding mode for 5-HT1A receptor ligand. Based on this ligand-receptor binding mode, an elaborate receptor structure based pharmacophore model was established, which revealed many important features responsible for ligand and 5-HT1A receptor interactions. A virtual screening experiment verified the ability of this pharmacophore model to discover true 5-HT1A receptor ligand. The results of this research would provide important information for further optimizations of 5-HT1A receptor ligands and guide related new lead discoveries.

Fenofibrate solid dispersion pellets prepared by fluid-bed coating: physical characterization, improved dissolution and oral bioavailability in beagle dogs

Ning Tang, Jie Lai, Ya-Pin Chen, Yi Lu^*, Wei Wu^*

2009, 18(2): 156-161.

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Solid dispersion of fenofibrate (FNB), a poorly water-soluble drug, was prepared by a fluid-bed coating technique with PEG 6000 as the carrier. The physical state was characterized by DSC and X-ray powder diffractometry, which indicated the existence of fenofibrate in crystalline form in the solid dispersion. In vitro dissolution was studied in water containing 1% sodium lauryl sulfate, FASSIF and FESSIF. Significant enhancement in dissolution was achieved at PEG/FNB ratio of 4/1 with near complete dissolution within 30 min. Moderate improvement in dissolution rate was observed at smaller PEG/FNB ratios. Oral bioavailability was studied in beagle dogs after oral administration of fenofibrate solid dispersion pellets by monitoring fenofibric acid in plasma. The oral bioavailability of PEG/FNB 3/1 and 4/1 solid dispersion pellets was improved by 3.4 and 4.4-fold as compared to Lipanthyl^®, a commercial micronized fenofibrate formulation. There was a strong dependence of oral bioavailability on the in vitro dissolution rate. Good correlation was observed between the in vivo absorption fraction and the in vitro dissolution rate in each of the dissolution media, water containing 1% sodium lauryl sulfate, FASSIF and FESSIF. It could be concluded that PEG/FNB solid dispersion pellets were able to improve the dissolution and oral bioavailability of fenofibrate.

A comparison study of the targeting properties of NGR-liposomes and RGD-liposomes towards human umbilical vein endothelial cells

Xiao-Mei Chen, Xun Wang, Yue Huang, Xuan Zhang^*, Qiang Zhang

2009, 18(2): 162-169.

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Endothelial cells in the angiogenic vessels of solid tumors over-express several proteins, which could be recognized by some peptide ligands. In this study, the targeting properties of two peptides, RGD (arginine-glycine-aspartic acid) and NGR (asparagine-glycine-arginine), towards human umbilical vein endothelial cells (HUVEC) were compared in vitro using doxorubicin entrapped liposomes as vehicles. The doxorubicin-loaded sterically stabilized liposomes (SSL-DOX) and RGD or NGR modified liposomes (RGD-SSL-DOX or NGR-SSL-DOX) were prepared and characterized. The studied properties included particle size, zeta potential, encapsulation efficiency and in vitro release rate. Flow cytometry, confocal microscopy and SRB assay were used on HUVEC to assess the targeting effect of the two peptides towards endothelial cells of tumor vasculature. All of the liposomes prepared in this study were obtained with encapsulation efficiencies of above 98%, particle sizes of about 65–75 nm and slight negative surface charges. The in vitro release results demonstrated that the modification of RGD or NGR did not alter the release behaviors of liposomes. It was observed in flow cytometry that the uptake of doxorubicin by HUVEC from SSL-DOX, NGR-SSL-DOX, RGD-SSL-DOX and doxorubicin solution followed the order of doxorubicin solution>RGD-SSL-DOX >NGR-SSL-DOX>SSL-DOX, and the internalized doxorubicin distributed in both nuclei and cytoplasm for ligand modified SSL and only in nuclei for non-targeted SSL. The order of cytotoxicity in SRB assay was the same as that of the uptake study. The characterization study indicated that modifications did not significantly change the properties of the sterically stabilized liposomes. HUVEC treated with both modified liposomes showed higher uptake of doxorubicin as compared to those with SSL-DOX as a result of the receptor-mediated endocytosis. Moreover, RGD-SSL-DOX exhibited better targeting effect than NGR-SSL-DOX.

Increased stability and solubility of dihydroartemisinin in aqueous solution through the formation of complexes with 2-hydroxypropyl-β-cyclodextrin

Xiao-Yun Zhang, Jian-Ping Liu*, Hua Qiao, Kui-Yuan Huang, Yan-Bin Shi, Shu-Mei Song, Jing-Man Ni

2009, 18(2): 170-176.

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The effect of various concentrations of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) on the solubility of dihydroartemisinin (DHA) in aqueous solution at different pHs was investigated. The influence of different concentrations of 2-hydroxypropyl-β-cyclodextrin on the stability of dihydroartemisinin at 50, 60, 70 and 80 ºC was also studied. Inclusion complex of dihydroartemisinin with 2-hydroxypropyl-β-cyclodextrin was prepared and characterized by X-ray diffraction and differential scanning calorimetry. The 2-hydroxypropyl-β-cyclodextrin effectively inhibited the hydrolysis of dihydroartemisinin and greatly increased its solubility. Furthermore, we showed that the higher concentrations of 2-hydroxypropyl-β-cyclodextrin, the better stability and solubility of dihydroartemisinin. When the temperature was increased, the stability of dihydroartemisinin decreased. Our results indicated that 2-hydroxypropyl-β-cyclodextrin can be used as a stabilizer and solubilizer of dihydroartemisinin.

Determination of biapenem in human plasma and urine by a simple HPLC method for its pharmacokinetics study

Xiao-Jie Wu, Ji-Cheng Yu, Jing Zhang^*, Guo-Ying Cao, Yao-Guo Shi, Ying-Yuan Zhang

2009, 18(2): 177-182.

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A simple high-performance liquid chromatography (HPLC) method was established and subsequently used to study the pharmacokinetics of biapenem in healthy volunteers. Chromatography separation was carried out using a C18 reverse-phase column with an isocratic mobile phase consisting of 0.05 M ammonium acetate–methanol, either for plasma (94:6, v/v, and flow rate 1.0 mL/min) or for urine samples (97.5:2.5, v/v, flow rate 1.5 mL/min). The UV detector was set at 300 nm. The assay was linear over the range of 0.25 mg/L-50 mg/L for plasma samples and 0.50 mg/L-200 mg/L for urine samples. The intra-day and inter-day RSD values were lower than 2.8% and 4.6%, respectively, for biapenem in plasma, 2.4% and 2.5%, respectively, for biapenem in urine. Biapenem was stable at room temperature for up to 6 h in plasma and 8 h in urine when MOPS was added immediately after sample collection. An intravenous single dose of 600 mg biapenem was administered to 12 healthy male volunteers. The pharmacokinetic parameters were calculated by Winnonlin with a noncompartment model. The pharmacokinetic parameters were obtained as following: Cmax 37±6 mg/L, t1/2 1.27±0.21 h, AUC0–8 h 56±8 mg/L/h, and AUC0–∞ 57±8 mg/L/h.The accumulated urine excretion rate in 24 h was 58%±5%. The established HPLC method was validated and suitable for the pharmacokinetic study of biapenem.

A new aristololactam from Asarum maximum

Jie Yu, Chao-Mei Ma, Chang-Feng Long, Xuan Wang, Ming-Ying Shang, Shao-Qing Cai^*, Masao Hattori, Tsuneo Namba

2009, 18(2): 183-185.

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A new aristololactam, aristololactam VII (1), was isolated from the root and rhizome of Asarum maximum Hemsl. On the basis of spectroscopic analysis, its structure was identified as 10-amino-7,8-dimethoxy-3,4-methylenedioxy-phenanthrene-1-carboxylic acid lactam.

A HPLC method for the determination of entrapment efficiency of a new
5-FPE liposome formulation

Rong Xiang, Shi-Wu Chen, Fu-Min Zhang, Jing-Man Ni^*, Xuan Tian

2009, 18(2): 186-189.

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A simple HPLC method was established for the determination of entrapment efficiency of a new 5-FPE liposome formulation. Chromatographic separation was performed on a Kromasil 100 A C18 column (350 mm×4.6 mm, 5 μm). The mobile phase was consisted of methanol-water (58:42, v/v). The flow rate of mobile phase was set at 0.8 mL/min. The UV detection wavelength was 271 nm, and the column temperature was 30 ºC. The linear range of 5-FPE was from 0.8-12.8 µg/mL, r = 0.9999. The RSD of intra-day and inter-day precision were less than 2.97%. The average recovery was from 96.8%-104.6% with RSD less than 2.24%. The method was simple, rapid, accurate, and sensitive. It is suitable for the determination of entrapment efficiency of the 5-FPE liposome formulation.

Determination of silymarin in microemulsion by RP-HPLC

Xin-Ru Li, Yan-Fang Li, Yan-Xia Zhou, Xiao-Yan Li, Yan Liu^*

2009, 18(2): 190-192.

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We established a RP-HPLC method for the analysis of silymarin in microemulsion. Silymarin was separated using a ODS C18 column and monitored at the wavelength 288 nm. The mobile phase consisting of methanol-water-acetic acid (42:58:0.5, v/v/v) was pumped at a flow rate of 1.0 mL/min. The linear range of calibration curve was 10-1000 μg/mL. The average recovery was 99.0%-100.7% for silybin isomers. The RSD values of inter-day and intra-day assays were lower than 1.6% for silybin isomers. The method is simple, rapid, reproducible and precise for the quantitative determination of silymarin in microemulsion.

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Journal of Chinese Pharmaceutical Sciences

2009, 18(2): 193-196.

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