Journal of Chinese Pharmaceutical Sciences

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2010, 19(1): 1-4.

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Photoresponsive nucleic acids for gene regulation

Meng Su, Fan Yang, Cong Lv, Li-Li Yu, Xiao-Yan Gu, Jie Wang, Zhong-Jin Li, Xin-Jing Tang^*

2010, 19(1): 5-14.

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For the main purpose of manipulating the functions of molecules, researchers have made great achievements on photoresponsive molecules using light as a trigger. Light has become a promising scientific tool due to it being a clean and non-invasive external stimulant. By attachment of photoresponsive moieties to molecules, the biological activities of molecules can be attenuated by light activation. With wide applications of laser in life sciences, it will be possible to achieve high spatiotemporal resolution. In this review, we focus on photoresponsive nucleic acids for photomodulating gene expression with light activation. With incorporation of photoswitchable or photocleavable moieties, biological behaviors of nucleic acids are photoregulated reversibly or irreversibly. Recent development and applications of photoresponsive nucleic acid in vitro and in vivo have shown a very promising future for manipulation of specific functional genes or disease genes. We expect that photoresponsive nucleic acids will be powerful scientific tools for studying biological events as well as gene therapy agents for genetic diseases.

Synthesis of 4-phenoxy quinoline mevalonolactones and evaluation of their HMG CoA reductase inhibition activities

Zheng-Yan Cai^*, Jing Pan, Qun Hao, Wei-Cheng Zhou, Lu-Yong Zhang

2010, 19(1): 15-23.

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A series of 4-phenoxy quinoline-based mevalonolactone derivatives have been synthesized and evaluated as 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) inhibitors. One member of this series, (4R,6S)-6-{(E)-2-[6-fluoro-7-chloro-4-(4-fluorophenoxy-quinoline)-3-yl-]-ethenyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (3d), showed more potent activity than rosuvastatin or pitavastatin to inhibit the rat HMG CoA reductase in vitro. This compound was selected for the extensive preclinical development as a potential hypocholesterolemic candidate.

A novel class of cyclophosphamide prodrug: structure-activity relationships of cyclophosphamide piperaziniums

Qing Yang, Ji-Rang Zhu, Qi Sun^*, Jing-Rong Cui, Run-Tao Li, Ze-Mei Ge^*

2010, 19(1): 24-33.

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A new strategy for the modification of cyclophosphamide was carried out and three series of new cyclophosphamide piperazinium salts 10, 11 and 13 were prepared. These compounds, based on compound 9i scaffold, were evaluated for their in vivo anticancer activities against hepatocyte sarcoma 22 (H22). The structure-activity relationship study reveals that 1) the conformation and the substituent at N-3 of cyclophosphamide spiropiperazinium salts 10 greatly affect the activity; 2) different kinds of cyclophosphamide non-spiropiperazinium derivatives 11 show different activities; 3) for 1,2-benzisoxazole phosphoropiperazinium salts 13, it is possible to obtain anticancer drug candidates with suitable quaternary ammonium moiety. These results would help to further design and synthesize analogs of mustard anticancer drugs.

Synthesis of podophyllotoxin derivative GL331 and identification of it binding site on topoisomerase IIα with molecular modeling

Chi-Wen Hu, Ying-Xiang Liu^*

2010, 19(1): 34-37.

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A facile one-pot procedure has been developed for the synthesis of GL331 in 26% overall yield. In addition, molecular modeling study was carried out to predict the binding site of GL331 with human topoisomerase IIα. The result showed that GL331 exhibited high affinity for the ATPase domain of human topoisomerase IIα and suggested that GL331 probably acts as a competitor of ATP for binding with the human topoisomerase IIα.

Quantitative determination of ilexgenin A in rat plasma by liquid chromatography coupled with mass spectrometry and its pharmacokinetics

Wen-Yuan Liu, Ping Li, Feng Feng^*, Cheng-Xia Yu, Li Ding

2010, 19(1): 38-42.

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A sensitive and selective high performance liquid chromatography coupled with electrospray ionization mass spectrometry (LC-MS) was developed for the quantitative determination of ilexgenin A (IA), a major component in Radix Ilicis Pubescentis, in rat plasma. Chromatographic separation was performed on a C18 column, with methanol -5 mM ammonium acetate (80:20, v/v) as the mobile phase. Mass spectrometer was set in negative mode with target ions at m/z 501.1→501.1 for IA and m/z 779.4→779.4 for digoxin (internal standard, IS). Rat plasma was extracted with ethyl acetate after addition of phosphoric solution and the organic layer was evaporated and reconstituted with mobile phase for LC-MS analysis. The proposed method was validated with a linear range of 1.05-525.5 ng/mL for IA with limit of quantitation (LOQ) at 1.05 ng/mL. Intra- and inter-day precision expressed as relative standard deviation (RSD) were less than 10% at LOQ level and overall recovery was over 80%. This validated method was used successfully for the pharmacokinetic study of IA in rats after oral dosing of IA (100 mg/kg) and some main pharmacokinetic parameters of IA in rats were obtained.

In vivo bioassay to determine the potency of a new erythropoiesis stimulating protein

Dong-Mei Su, Hui-Lin Zhao^*, Huan-Zhang Xia

2010, 19(1): 43-46.

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A simple in vivo bioassay suitable for the routine quality control testing of a new erythropoiesis stimulating protein was developed. Subcutaneous administration of the new erythropoiesis stimulating protein to Balb/c mice in a single dose resulted in a dose-dependent increase in the number of circulating reticulocytes. Within the erythropoiesis stimulating protein dose range of 3.125 to 200 ng per mouse, there is a strong linear relationship between the dose and reticulocyte counts in the treated mice. This linear relationship allows us to determine the biological potency of the testing erythropoiesis stimulating protein preparation relative to a reference standard using parallel line assay. Accuracy, precision, dose variation and blood collection time of this method were analyzed in order to choose doses in the linear range that are suitable for setting up a useful, precise, and economical bioassay.

Bio-distributions of [¹²⁵I]Spiro-I liposomes in mice

He-Xiang Zhou, Rui-Qin Chen, Hui Sun, Pei-Ran Zhang, Hong-Mei Jia^*, Ying Xie^*

2010, 19(1): 47-51.

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We investigated the bio-distributions of [¹²⁵I]Spiro-I formulated in sterically stabilized liposomes (SSL) or targeted liposomes (SSTL) in mice, especially their brain uptake. The [¹²⁵I]Spiro-I liposomes were prepared by film-ultrasound dispersion method. Cereport (RMP-7) was covalently conjugated with DSPE-PEG, which was attached to the surface of SSL to form SSTL. The encapsulation efficiencies (ee%) of [¹²⁵I]Spiro-I-SSL and [¹²⁵I]Spiro-I-SSTL were 97.47%±4.01% and 93.02%±2.98%, respectively. The average particle sizes were (66.47±0.76) nm and (71.40±0.45) nm, respectively. After intravenous administration, [¹²⁵I]Spiro-I was quickly eliminated from blood. SSL could prolong the retention time of [¹²⁵I]Spiro-I in blood and SSTL improved its brain uptake. The AUC of [¹²⁵I]Spiro-I-SSTL in brain was increased by 1.52 times as compared to [¹²⁵I]Spiro-I, indicating that SSTL could be used for the formulation of [¹²⁵I]Spiro-I for the imaging of central nervous system (CNS).

Pharmacokinetics of Eb and its hydroxypropyl-β-cyclodextrin inclusion complex in rats

Han-Ming Cui^*, Feng-Lan Wu

2010, 19(1): 52-58.

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In our previous study, a novel organic selenium compound Eb was synthesized and found to have significant antitumor activity with much less toxicity compared with the leading compound Ebselen. Unfortunately, Eb was practically insoluble in water (2.57 μg/mL) and had very low oral bioavailability, thus its clinical application was greatly limited. In the present study, the inclusion complex of Eb with 2-hydroxypropyl-β-cyclodextrin (HP-βCD) was prepared and pharmacokinetics of Eb and the inclusion complex were investigated. The water solubility of Eb was dramatically enhanced by inclusion with HP-βCD, which reached 8.4 mg/mL. The pharmacokinetic study showed that the elimination half-life (t1/2β) of Eb was between 22 h and 30 h and the distribution half-life (t1/2α) of Eb was 1 h. The results indicated that Eb was rapidly distributed to tissues but slowly eliminated in rats. The absolute bioavailability of Eb/HP-βCD inclusion complex solution through the oral route was 28.3%, and it was 1552% that of Eb in its pure form. In summary, the absorption of Eb in the Eb/HP-βCD inclusion complex was better and faster than that of Eb in its pure form.

Efficacy and safety of fluoxetine for the treatment of post-stroke depression:
a meta-analysis

Zhan-Miao Yi, Fang Liu^*, Suo-Di Zhai

2010, 19(1): 59-66.

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Although depression may affect patients’ recovery and even their survival rate after stroke, it is often overlooked or inadequately managed. And data regarding the treatment efficacy and safety of fluoxetine in this setting are inconsistent. We aimed to systematically assess those two indices in patients with post-stroke depression (PSD). Through a systematic literature search in 10 biomedical databases, 244 articles were first identified, through which we collected and evaluated a total of 600 patients identified from 11 RCTs. The meta-analysis with Revman software indicated that fluoxetine was more effective than placebo, the combined results of 9 RCTs showed that fluoxetine decreased the depression rating scale scores significantly compared with placebo, and the pooled weighted mean difference (WMD) was 0.44 (95% CI -0.03 to 0.92). Moreover, time-dependent effects were also observed. No consistent evidence was found for its positive effects on the recovery of neurological impairments and improvements in activities of daily living (ADL). Six studies reported rate of adverse effects in both fluoxetine groups and control groups and showed no significant difference between them (OR = 0.03, 95% CI -0.00 to 0.07). This meta-analysis suggested that fluoxetine may be effective and safe for patients with PSD and it may have time-dependent effects.

Comparative analysis of essential oil components in Ephedra and its processed products by GC-MS

Ling-Yun Zhong^*, Qian-Feng Gong, Jing Zhu, Fang Chen

2010, 19(1): 67-73.

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The similarities and differences of essential oil components in the raw ingredients of Ephedra (RIE) and processed products of Ephedra obtained by stir-baking with honey or stir-baking without any supplements were analyzed by GC-MS. Wet distillation (WD) and supercritical fluid extraction (SFE) were used to extract essential oil components from the samples. Total 48, 57 and 48 compounds were found in the extracted essential oils using WD from RIE, the products obtained by stir-baking with honey from Ephedra (SBHE) and the products obtained by stir-baking without any supplements from Ephedra (SBE), respectively; whereas total 22, 36 and 28 compounds were identified in the extracted essential oils using SPE from these three samples, respectively. In addition, 14 and 9 new compounds were found in the essential oils extracted using WD from SBHE and SBE, whereas 15 and 23 new compounds were found in the essential oils extracted by SFE from SBHE and SBE, respectively. The composition and concentration of the essential oil components in the processed products were significantly different from RIE. Such changes in essential oil components might affect drug actions, which is dependent on the manner in which the sample is processed. The findings in this study may shed some lights on the understanding and further exploration of Ephedra processing.

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Journal of Chinese Pharmaceutical Sciences

2010, 19(1): 74-81.

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