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15 March 2008, Volume 17 Issue 1

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Journal of Chinese Pharmaceutical Sciences

2008, 17(1):  1-04. 

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Full Papers

Effects of 5-hydroxytryptophan on morphine-induced sensitization in mice

Jun-Xu Li, Su-Qing Chen, Yan-Ping Deng, Jian-Hui Liang^*

2008, 17(1):  1-5. 

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To investigate the involvement of central serotonergic system in behavioral sensitization to morphine in mice. Male Kunming mice were treated (i.p.) with saline or morphine 10 mg/kg twice daily for 3 d and then drug manipulation was suspended for 5 d. On day 9, a challenge dose of morphine (10 mg/kg) was given and the locomotor activity was measured for 60 min to confirm the establishment of behavioral sensitization in mice. Moreover, 5-hydroxytryptophan (5-HTP), a precursor of serotonin, at the doses of 20–80 mg/kg was given i.p. in combination with daily morphine treatment (induction), during the morphine treatment suspension (transfer) or prior to the challenge dose of morphine (expression) and locomotor activity was measured on day 9 after the challenge dose of morphine. Twice daily of morphine injection induced robust behavioral sensitization in mice as evidenced by significantly higher locomotion on day 9 for multiple treatment with morphine than saline in mice. 5-HTP treatment selectively and dose-dependently blocked the induction, but not the transfer nor the expression of morphine induced behavioral sensitization. This study provides clear evidence that up-regulation of central serotonergic system may suppress the induction of morphine sensitization in mice.

Pharmacokinetics of exendin-4 in Wistar rats

Guo Ai, Zhi-Hang Chen, Cheng-Qi Shan, Jin-Jing Che, Yu-Nan Hou, Yuan-Guo Cheng^*

2008, 17(1):  6-10. 

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To characterize the preclinical pharmacokinetics, tissue distribution and excretion profiles of exendin-4 in healthy Wistar rats were studied. Exendin-4 was radioiodinated by the IODOGEN (1,3,4,6-tetrachloro-3 alpha, 6 alphadiphenylglucoluril) method. Pharmacokinetic properties of 125I-exendin-4 were examined after a single s.c. and i.v. injection, respectively. Tissue distribution and urinary, fecal, and biliary excretion patterns of 125I-exendin-4 were also investigated following a single s.c. injection. Exendin-4 was rapidly distributed and cleared with t1/2 of (0.48 ± 0.03) h after a single i.v. injection. Following a single s.c. administration, exendin-4 exhibited rapid and considerable absorption with Tmax of (0.25 ± 0.02) h and declined with the elimination t1/2 of (1.28 ± 0.14) h. The absolute bioavailability was (65.5 ± 10.2) %. The radioactivity was widely distributed and rapidly diminished in most tissues. The kidney contained the highest radioactivity and the distribution of 125I-exendin-4 to the brain was minimal. The major elimination route was urinary excretion. The pharmacokinetic properties of exendin-4 obtained from the present study closely matched those reported in previous studies in rats. Pharmacokinetics profiles of exendin-4 in rats are warranted for the design of future clinical trials.

Antileukemic activity of jaspolide B, an isomalabaricane-type triterpene from marine sponge Jaspis sp. on human promyeloleukemic HL-60 cells

Min Li, Shao-Yin Wei, Sheng-An Tang, Wen-Han Lin, Jing-Rong Cui^*

2008, 17(1):  11-15. 

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The antiproliferative activity and underlying mechanisms of jaspolide B, an isomalabaricane-type triterpene, isolated from the sponge Jaspis sp., were investigated using human promyeloleukemic HL-60 cells. Jaspolide B arrested HL-60 cells in the G2/M phase of the cell cycle and induced apoptosis of HL-60 cells in a dose- and time-dependent manner. Moreover, the poly (ADP-ribose) polymerase (PARP) protein was cleaved by jaspolide in a dose- and time-dependent way. Jaspolide B with an IC50 value of 0.61 μmol/L was found to be comparable efficacy as that of paclitaxel (IC50: 0.78 μmol/L). These results implicate the potential of jaspolide B as a promising anticancer agent in chemotherapy of leukemia by arresting cell cycle progression at G2/M phase and triggering apoptosis.

Protective effects of icariin on human umbilical vein endothelial cell injured by angiotensin II

Qiu-Juan Wang^*, Zhi-Wei Pan, Yu Wang, Juan Yang, Ying Jia, Ling-Yi Kong

2008, 17(1):  16-21. 

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To investigate the effects of icariin (ICA) on angiotensin II(Ang II)-induced injury in human umbilical vein endothelial cells line (ECV-304). The ECV-304 cells were cultured in vitro. After 24 h incubating with icariin, the model of AngII-induced injury in ECV-304 was established. The cell viability (MTT method), Lactate dehydrogenase (LDH) release and Nitric oxide (NO) production in the medium, the capacity of scavenging superoxide anion radicals (O₂^·–) and hydroxyl radicals (·OH) were measured. The activities of superoxide dismutase (SOD), total nitric oxide synthase (T-NOS), inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS) in the cells were determined. Compared with the Ang II-treated group, ICA can significantly raise the viability of EC, increase the activities of SOD, T-NOS and cNOS, increase the production of NO, enhance the capacity of scavenging superoxide anion radicals (O₂^·–) and hydroxyl radicals(·OH), and lower LDH leakage and iNOS activity. The results suggest that ICA can protect endothelial cells (ECV-304) from Ang II-induced injury.

Construction of universal quantitative models for the determination of cefoperazone sodium/sulbactam sodium for injection from different manufacturers using near-infrared reflectance spectroscopy

Huan-Huan Pang, Yan-Chun Feng, Xue-Bo Zhang, Chang-Qin Hu^*

2008, 17(1):  22-29. 

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To develop near-infrared (NIR) reflectance spectroscopic methods for the quantitative analysis of cefoperazone sodium/sulbactam sodium from different manufacturers for injection powder medicaments. Various powders of cefoperazone sodium/sulbactam sodium were directly analyzed by non-destructive NIR reflectance spectroscopy using the spectrometer EQUINOX55. Two quantitative methods via integrating sphere (IS) and fiberoptic probe (FOP) models were explored from 6 batches of commercial samples and 42 batches of laboratory samples at a content ranging from 30% to 70% for cefoperazone and 60% to 20% for sulbactam. The root mean square errors of cross validation (RMSECV) and the root mean square errors of prediction (RMSEP) of IS were 1.79% and 2.85%, respectively, for cefoperazone sodium, and were 1.86% and 3.08%, respectively, for sulbactam sodium; and those of FOP were 2.93% and 2.92%, respectively, for cefoperazone sodium, and were 2.23% and 3.01%, respectively, for sulbactam sodium. Based on the ICH guidelines and Ref. 12, the quantitative models were then evaluated in terms of specificity, linearity, accuracy, precision, robustness and model transferability. The non-destructive quantitative NIR methods used in this study are applicable for rapid analysis of injectable powdered drugs from different manufacturers.

Identification of the metabolite and cytochrome P450 isoforms involved in rat liver microsomal metabolism of TM208

De-Tao Kong, Xiao-Mei Ling^*, Fang-Bin Han, Jing-Li Gong, Ze-Mei Ge, Run-Tao Li, Jing-Rong Cui^**

2008, 17(1):  30-34. 

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To identify the metabolite and CYP450 isoforms involved in rat liver microsomal metabolism of TM208. The present study investigated the metabolism of TM208 and the effects of selective CYP450 inhibitors on the metabolism of TM208 in rat liver microsomes. Various specific inhibitors of CYP were used to identify the isoforms of CYP involved in the metabolism of TM208. The inhibitor of CYP2D and that of CYP2B had strong inhibitory effects on TM208 metabolism in a concentration-dependant manner, the inhibitor of CYP1A had a modest inhibitory effect, and the inhibitor of CYP3A seemed not to have an obvious inhibitory effect on TM208 metabolism. TM208 might mainly be metabolized by CYP2D and CYP2B in rat liver microsomes.

Flow injection chemiluminescence determination of meloxicam using potassium permanganate and formaldehyde system

Bao-Xiu Jia^*, Ming-Liang Cao, Cai-Hong Liu, Yu-Qin Li, Ke Li, Yong-Xiu Qi

2008, 17(1):  35-40. 

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A simple, rapid and sensitive flow injection chemiluminescence (FI-CL) method has been developed for the determination of meloxicam. The method is based on the CL-emitting reaction between meloxicam and potassium permanganate in a hydrochloric acid medium, enhanced by formaldehyde (HCHO). Under optimum conditions, calibration curve over the range of 1.0–20.0 μg/mL was obtained. The proposed method was successfully applied to the determination of meloxicam in capsules with no evidence of interference from common excipients. The detection limit of this method was 25.6 ng/mL. The relative standard deviation was 2.1% for 10.0 μg/mL meloxicam. The sample throughput was found to be 120 samples/h.

An accelerated method to evaluate thymopentin release from microspheres in vitro

Guo Ai, Xing-Guo Mei^*

2008, 17(1):  41-45. 

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To design an accelerated method to evaluate thymopentin release from PLGA microspheres in vitro. Microspheres were prepared by double emulsion technique, using poly(lactide-co-glycolide) (PLGA) as carrier. At higher medium temperature (45 °C, 50 °C and 55 °C), an accelerated release testing in short time was studied and correlated with the conventional release (37 °C) in vitro. The release in vitro of thymopentin from PLGA microspheres at 45 °C, 50 °C and 55 °C was significantly accelerated (P < 0.05). In particular, at 50 °C, an accelerated release (30 h) of the hydrophilic peptide from the PLGA matrix was achieved and correlated well with the conventional release (30 d). An accelerated release testing in vitro at higher temperature could be used to monitor thymopentin release from PLGA microspheres.

Population pharmacokinetic analysis of baicalin after oral administration of different Shuang-Huang-Lian formulations to rats

Guan-Min Zhang, Wen-Qian Chen, Liang Li, Yu-Hui Hu, Yan-Qing Zhang, Hong Yi, Hua Yang, Wei Lu^*

2008, 17(1):  46-54. 

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Population pharmacokinetics of paeoniflorin in guanxin II prescription

Wen-Qian Chen, Yu-Hui Hu, Yan-Qing Zhang, Guan-Min Zhang, Liang Li, Wei-Ning Yang, Wei Lu^*

2008, 17(1):  55-63. 

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To evaluate the effect of components in Guanxin II prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract (PPE) and oral administration of PPE and three types of decoctions in Guanxin II prescription, respectively, were determined by HPLC analyses. NONMEM (nonlinear mixed-effect modeling) method was used to analyze full set of pharmacokinetic data directly. A two-compartment model with first-order degradation in absorption compartment was employed for the data analysis. The mean of population parameters, CL1, V1, CL2, V2, Ka0, and Ka1, were measured to be 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135/h, and 0.0135/h, respectively. Inter-individual variabilities were estimated and dose formulation (DF) was identified as a significant covariate of Ka1, Ka0, and V1. It is concluded that the pharmacokinetic behaviors of paeoniflorin in rats can alter with different dose formulations.

Synthesis and analgesic activities studies on bispiperazinium (BPZ) salts

Qi Sun, Cai-Qin Yue, Jia Ye^*, Chang-Ling Li, Tie-Ming Cheng, Run-Tao Li^**

2008, 17(1):  64-69. 

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Selecting compound 97-9-G4 as lead compound, a series of bispiperazinium salts 5a-h were designed, synthesized and evaluated for their analgesic activities. The results show that phenylethyl group of 97-9-G4 is a crucial pharmacophore; the introduction of electron-withdrawing group on benzene ring is favorable to the activity.

Preliminary in vitro biological evaluation of novel O⁶-benzylguanine derivative-precursors of PET tracers for the DNA repair protein AGT

Wei-Wei He, Zhao-Fei Liu, Dan Liu, Bing Jia, Fan Wang^*, Yu-Xin Cui^**

2008, 17(1):  70-74. 

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A series of O6-benzylguanine (O6-BG) derivatives was synthesized, and their in vitro AGT (O6-Alkylguanine DNA alkyltransferase) inhibitory ability was evaluated by MTT method to investigate the possibility to be promising precursors of PET tracers. O6-BG and its derivatives, HMBG, MOBG, MOMBG, BABP and PEG, were synthesized from guanine respectively. The AGT inhibitory ability of the compounds were tested by evaluating their effects on increasing sensitivity of HeLa cancer cells to 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) with MTT method. Their order of AGT inhibitory activities follows HMBG≥O6-BG≥MOBG≥MOMBG, whereas the BABP and PEG showed no AGT inhibition activity. HMBG, MOBG and MOMBG would be promising as precursor candidates of PET tracers for tumor imaging.

New lead discovery for novel M1 agonists: pharmacophore model based on DISCO computation and virtual screening

Guang-Tao Gao, Yan Niu, Dong Wang, Xiao-Ping Lei^*, Ying-He Hu^**

2008, 17(1):  75-78. 

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To discover new lead compounds for M₁ agonists. Ten typical M₁ agonists were superimposed to build a M₁ agonists 3D-pharmacophore model using distance-comparisons (DISCO) method without the previous knowledge of the three-dimensional structure of M₁ receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds (ACD-SC) to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M₁ agonists were purchased in order to evaluate their M₁ receptor agonist activity. One of them shows M₁ receptor agonist activity with EC₅₀ of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M₁ agonists.

Itoside O, a new linear monoterpene glycoside from the bark and twigs of Itoa orientalis

Xing-Yun Chai, Zheng-Ren Xu, Li-Ying Tang, Yu-Ping Chen, Chang-Cai Bai, Fei-Ran Zhou, Peng-Fei Tu^*

2008, 17(1):  79-81. 

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To investigate the chemical components of the barks and twigs of Itoa orientalis. A new linear monoterpene glycoside named itoside O was isolated from the crude extract of Itoa orientalis together with 11 known compounds. The new compound was identified to be 3,7-dimethyl-1, 6-octadien-3, 10-dihydroxyl-10-O-α-L-arabinopyranosyl (1→6)-O-β-D-glucopyranoside by 1D and 2D NMR analysis, and all known compounds were isolated from this plant for the first time.

Chemical constituents from Sappan Lignum

Yu-Ping Chen, Lei Liu, Yu-Hong Zhou, Jing Wen, Yong Jiang, Peng-Fei Tu^*

2008, 17(1):  82-86. 

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To study the chemical constituents of Sappan Lignum. Chemical constituents were isolated by method of solvent extraction, repeated chromatography with silica gel, Sephadex LH-20, and ODS. The structures were elucidated based on spectroscopic data. Fourteen compounds were isolated and their structures were identified as brazilin (1), sappanone B (2), (E)-3-(3,4-dihydroxybenzylidene)-7-hydroxychroman-4-one (3), 3-deoxysappanone B (4), brazilide A (5), euxanthone (6), quercetin (7), rhamnetin (8), sappanchalcone (9), 3-deoxysappanchalcone (10), butein (11), 2,4,5-trihydroxybenzaldehyde (12), 3,8,9-trihydroxy-6H-benzo[c]chromen-6-one (13) and β-sitosterol (14). Compounds 12 and 13 were two new natural compounds, and the 13C NMR data of compound 13 were reported for the first time. Compound 6 was the first xanthone isolated from the genus Caesalpinia.