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15 June 2004, Volume 13 Issue 2

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Journal of Chinese Pharmaceutical Sciences

2004, 13(2):  1-01. 

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Chemical Constituents from Starfish Asterias rollestoni

LI Guo-qiang, DENG Zhi-wei , LI Jun, FU Hong-zheng, LIN Wen-han^*

2004, 13(2):  81-86. 

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Aim　To investigate novel bioactive and structural metabolites from marine organisms. Methods Column chromatography in association with semi-preparative HPLC were used for the isolation of compounds. 1D and 2D NMR, IR, UV, and MS were employed for structure elucidation. Results From the butanol fraction of the 95 % EtOH extract of the starfish Asterias rollestoni, a new compound N7-2’-deoxypseudoxanthosine (1), along with sixteen known compounds, 2’-O-methyl-inosine (2), 2’-deoxyinosine (3), 2’-O-methylguanosine (4), inosine (5) ; thymine (6), uracil (7), thymidine (8), deoxyuridine (9), 2’-O-methyluridine (10), (-)-(1S, 3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (11), (-)-(1R, 3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (12), (-)-(3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (13), L-tryptophan (14), L-phenylalanine (15), 3-carboxy indole (16), and p-hydroxybenzoic acid (17), have been isolated. Conclusion Compound 1 is a new natural product, and compounds 8, 9 and 10 are isolated from natural sources for the first time, and the known compounds except 14 and 15 are first reported from starfish Asterias rollestoni .

Studies on Triterpenoid Saponins of Seeds of Aesculus chinensis Bunge var. chekiangensis (Hu et Fang) Fang

GUO Jie, YANG Xiu-wei^*

2004, 13(2):  87-91. 

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Aim To study the saponin constituents of the seeds of Aesculus chinensis Bunge var. chekiangensis (Hu et Fang) Fang. Methods Compounds were separated and purified by macroreticular resin column chromatography and high-performance liquid chromatography. Their structures were elucidated by spectroscopic and hydrolysis analysis. Results Six compounds were isolated from the 70% ethanolic extracts. They were identified as escins IVc, IVd, Ia, Ib, isoescins Ia and Ib, respectively. Conclusion The above compounds were obtained from the seeds of Aesculus chinensis Bunge var. chekiangensis (Hu et Fang) Fang for the first time.

Constituents from Ranunculus sieboldii Miq.

PAN Yun-xue, ZHOU Chang-xin, ZHANG Shui-li, ZHENG Xiao-xiang, ZHAO Yu^*

2004, 13(2):  92-96. 

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Aim To investigate the chemical composition of Ranunculus sieboldii Miq.. Methods Repeated column chromatography over silica gel, polyamide and RP-18 followed by gel filtration on sophadex LH-20 were used to isolate chemical constituents, and their structures were elucidated by extensive spoctroscopic methods (UV, IR, MS, ¹H NMR, ¹³C NMR) including 2D NMR (COSY, HMQC, HMBC, NOESY) techniques and by direct comparing spectral data with those reported in literature. Results Five flavonoid glycosides named apigenin-4'-O-α-L-rhamnopyranoside (1), apigenin-7-O-β-D-glucopyranosyl-4'-O-α-L-rhamnopyranoside (2), apigenin-8-C-α-L-arabinopyranoside (3), apigenin-8-C-β-D-ga- lactopyranoside (4), tricin-7-O-β-D-glucopyranoside (5), together with tricin (6), luteolin (7), scopoletin (8), esculetin (9), scoparone (10), ferulic acid (11), protocatechuic acid (12), and tematolide (13) were isolated from the 95% ethanolic extract of its whole plant, and their cytotoxic activities were preliminarily tested. Conclusion Compounds 1-12 were obtained from this genus and compound 13 from this species for the first time. Furthermore, compound 1 was for the first time isolated from nature while the ¹³C NMR data of compounds 2 and 3 are reported for the first time. The bioassay revealed that compound 1 was active against BEL-7407 and A549 cell lines (IC50 43, 77 μg·mL^-1), 8 and 10 showed inhibitory ac- tivities on KB cell lines (IC50 78, 44 μg·mL^-1) and HL-60 cell lines (IC50 85, 85 μg· mL^-1), while 7 exerted moderate cytotoxic activities on KB, BEL-7407, A549 and HL-60 cell lines with their IC50 being 51, 55, 44 and 10 μg·mL^-1, respecfvely.

Purification and Characterization of Cytotoxins from Agkistrodon acutus Venom and Their Anticancer Activity

ZHANG Liang, LI Hong, WU Wu-tong^*

2004, 13(2):  97-102. 

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Aim To investigate the anticancer activity of two new cytotoxins from the venom of Agkistrodon acutus. Methods The venom was isolated by FPLC column chromatography consisting of DEAE Sepharose FF and Source 30S. The cytotoxic activity on tumor cells was detected by MTT method. Purity and molecular weight were determined by SDS-PAGE (silver staining). Their stabilities to temperature and pH were also detected. Results Two pure cytotoxins named ACTX-6 and ACTX-8 were obtained. Their molecular weights are 98 kDa and 27 kDa, respectively. ACTX-6 consists of two subunits bonded together by disulfide bonds. Conclusion ACTX-6 and ATCX-8 have highest inhibitory activity on lung cancer cell A549. ACTX-6 is stable to heat while ACTX-8 not. ACTX-6 is stable between pH 7-9 and ACTX-8 between pH 6-9.

Isolation and Purification of Gonyautoxins from Two Strain of Alexandrium minutum Halim

MIAO Yu-ping, CHEN Yi-min, ZHOU Hong-nong, WEN Ren^*

2004, 13(2):  103-105. 

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Aim To study isolation and purification of Gonyautoxins from two different strains of Alexandrium minutum Halim. Methods Ethanol extracts of the two culture strains of Alexandrium minutum Halim were fractionated by gel filtration and ion exchange chromatography to obtain gonyautoxins. The toxin profiles were tested by HPLC method. Results Both strains contain gonyautoxin-1, gonyautoxin-2, gonyautoxin-3 and gonyautoxin-4. The total gonyautoxin content of Amtk4 strain is almost 10 times higher than that of Amtk2 strain. Conclusion Alexandrium minutum Halim Amtk4 strain is suitable for the preparation of Gonyautoxins.

Qualitative and Quantitative Analysis of Rhizoma of Polygonum cuspidatum

ZHANG Mian^*, WANG Lei, HUANG Lan, ZHANG Zi-jia, WANG Zheng-tao

2004, 13(2):  106-111. 

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Aim To establish reliable methods for evaluating the quality of rhizoma of Polygonum cuspidatum (Huzhang in Chinese). Methods TLC and HPLC were employed for the chemical identification and content determination, respectively. Results A qualitative TLC method and a quantitative HPLC method with piceid as the reference substance were established, respectively. With piceid as the reference substance and ethyl acetate-methanol-formic acid-water (19:3:0.5:1) as the mobile phase, a TLC method for the identification of Huzhang from the commonly used crude drugs of the same family was also set up. Conclusion The established TLC method can reasonably appraise the quality of the drug and easily distinguish Huzhang from the other commonly used crude drugs of the same family. The HPLC method for determining piceid is simple, reproducible, accurate, and feasible.

An Isopropyldioxy Flavonol from Hypericum perforatum L.

DOU Yu-ling, QIN Hui-ling, ZHOU Tong-shui, OU Ling, LU Yan-hua^*, WEI Dong-zhi^**

2004, 13(2):  112-114. 

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Aim Isolation and structural elucidation of the constituents from the aerial part of Hypericum perforatum L. Methods Column chromatography and TLC were used to isolate chemical constituents. Physico-chemical characterization and spectroscopic analysis were employed for structural identification. Results Three flavonols were isolated and identified. Conclusion Compound 1 is a novel natural product and its structure has been characterized to be 3, 5, 7-trihydroxy-3’, 4’-isopropyldioxy-flavone.

First Asymmetric Synthesis of (-)Methyl 2, 2-dimethyl-3-hydroxychromanyl-6-formate

XIE Zhi-xiang, HU Yang, LI Ying^*

2004, 13(2):  115-118. 

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Aim To synthesize naturally occurring (-) methyl 2,2-dimethyl-3-hydroxychromanyl-6-formate. Methods Sharpless’ asymmetric dihydroxylation was employed to construct the 3-hydroxychroman. Results First asymmetric syn- thesis of (-) methyl 2, 2-dimethyl-3-hydroxychromanyl-6-formate (1) was accomplished starting from methyl 4-hydroxy- benzoate (2), and the absolute configuration was established. Conclusion A useful method for constructing chiral 3- hydroxychroman by employing Sharpless' asymmetric dihydroxylation is achieved.

A 3D-QSAR Study on C-3 Substituted 4,6-Dichloroindole-2- Carboxylic Acids with Comparative Molecular Field Analysis

SONG Huai-en, SHEN Jian-hua*, WEN Ren*, JIANG Hua-liang

2004, 13(2):  119-123. 

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Aim and Method Comparative molecular field analysis (CoMFA), a three dimensional quantitative struc-ture-activity relationship (3D-QSAR) method was applied to a novel series of C-3 substituted 4,6-dichloroindole-2-carboxylic acids to study the relationship between their structure and the affinity for the glycine site of the NMDA receptor. Result The coefficients of cross-validation q² and non cross-validation r² for the model established by the study are 0.744 and 0.993, respectively, the value of variance ratio F is 261.343, and standard error estimate (SE) is 0.039. Conclusion These values indicate that the CoMFA model may have a good prediction for the activity of C-3 substituted 4, 6-dichloroin- dole-2-carboxylic acids. As a consequence, the predicted activity values of new designed compoumds supports our conclusion from the model.

Effect of Chitosan-Cysteine Conjugate on Enzymatic Degradation and Hypoglycemic effect of Insulin

QI Rong, PING Qi-neng^*, XU Rui-yang, SHI Yong-ping

2004, 13(2):  124-129. 

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Aim To evaluate the inhibitory effect of chitosan-cysteine conjugate on enzymatic degradation and hypogly-cemic enhancement effect of insulin. Methods Chitosan-cysteine conjugate was synthesized. The protective effect of the conjugate against degradation of insulin by α-chymotrypsin and trypsin was evaluated in vitro. Insulin enteric-microspheres were prepared by using O1/O2 emulsion solvent evaporation method. The hypoglycemic enhancement effect of the conjugate was studied by oral administration of insulin solution or enteric-microspheres to rats. Results The thiol group content of the synthesized conjugate was about 200 μmol·g^-1 polymer, which showed a strong protective effect on insulin from enzymatic degradation in vifro. Almost all the insulin incubated in α-chymotrypsin solution or trypsin solution without chitosan-cysteine conjugate was degraded entirely within 1 h and 5 h respectively, whereas above 75% of insulin remained in the same content of the enzymatic solution containing 4 mg·mL^-1 conjugate. The drug loading of insulin enteric-microspheres was about 7%.In vivo experiment, chitesan-cysteine conjugate (85 mg·kg^-1) prolonged the hypoglycemic time of insulin solution or enter-ic-microspheres when administered simultaneously with the absorption enhancer SNAC. Conclusion Chitosan-cysteine con-jugate has a marked inhibitory effect on the enzymatic degradation of insulin in vitro, and it displays a significant hypoglyce-mic enhancement effect on insulin oral formulation in vivo.

Determination of Plasma Concentration of Cinnamic Acid by High-Performance Liquid Chromatography and Its Pharmacokinetics in Rats after Oral Administration of Zi-Shen Pill

DAI Rong-hua, SONG Zong-hua, JU Tao, BI Kai-shun*

2004, 13(2):  130-133. 

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Aim To develop a simple and sensitive high-performance liquid chromatographic method for determination of plasma concentration of cinnamic acid and pharmacokinetic study in rats after a single oral dose of traditional Chinese me-dicinal preparation Zi-Shen pill. Method Plasma samples were acidified with hydrochloric acid and extracted with ethyl ac-etate. Cinnamic acid was determined by HPLC using a C18 column. A mobile phase of methanol-acetonitrile-water-triethyl-amine (7:22:73:0.2, V/V), with the pH adjnsted to 4.0 with phosphoric acid, and with a UV detector set at 340 nm. Results The standard curve was linear over the range of 1.92-192.0 μg·mL^-1. The LLOQ was 1.92 μg·mL^-1. The RSDs of within-day and between-day precision were <8%. The mean recovery was 82.0%. Concusion After valida-tion, the method has been used to investigate the pharmacokinetic profilies of the traditional Chinese medicinal preparation Zi-Shen pill.

Stability of Baicalin Aqueous Solution by Validated RP-HPLC

QIU Feng, TANG Xing, HE Zhong-gui^*, LI Hao-zhi

2004, 13(2):  134-137. 

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Aim In the present study a RP-HPLC method was developed and validated to investigate the stability of baicalin aqueous solution. Methods The influences of temperature and pH on the stability of baicalin aqueous solution were investigated by classic homoiothermic acceleration test, and the pH for the most stable solution was determined. Results The time when baicalin suffered 10% loss was found to be 18.1 h, and the degradation activation energy of baicalin was 79.1 kJ·moL^-1. The pH at which baicalin is most stable is 4.28. Conclusion The temperature should be kept at a lower level and the pH should be adjusted to near that for the most stable solution in the production of baicalin preparations.

RP-HPLC Determination of Pinoresinol Diglucopyranoside in Qing'e Pill Extract

XIONG Zhi-li, LUO Xuan, LI Xiao-qin, LI Fa-mei^*

2004, 13(2):  138-141. 

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Aim To develop and determine pinoresinol diglucopyranoside in Qing’e Pill, a traditional Chinese com-pound preparation containing Eucommia ulmoides Oliv. as the principal drug, by a reverse-phase high-performance liquid chromatographic method (RP-HPLC). Methods The extract of Qing'e Pill was refiuxed with 75% ethanol, purified on an AB-8 macroporous adsorption resin column and then injected into HPLC system. The HPLC assay was performed on an ODS analytical column with a mixture of methanol-acetonitrile-water (24:3:78, V/V/V) as the mobile phase at a flow-rate of 1.0 mL·min^-1, and a UV detector set at 227 nm. Results Good linearity between peak area and concentration was found in the range of 5.5-170 μg·mL^-1 for pinoresinol diglucopyranoside ( r>0.9998). The average recovery was 99.3%. The intra-day assay RSD and the inter-day assay RSD were 1.3% and 2.8%, respectively (n = 5). The content of pinoresinol diglucopyranoside in Qing'ePillwasdetermined to be 0.446±0.012mg·g^-1 (n = 10). Conclusion The RP-HPLC meth-od was proved to be sensitive, specific, accurate and precise for the determination of pinoresinol diglucopyranoside in Qing’e Pill.

Meta-analysis of the Use of ACEI for Inhibiting Albuminuria in Diabetic Patients

WU Hao, ZHAI Suo-di^*, LU Rong-zhi

2004, 13(2):  142-150. 

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Aim To examine whether AER(albumin excretion rate) in normotensive diabetic patients can be effectively inhibited by ACEI. Methods Literature on randomized controlled trials of ACEI for inhibiting AER in normotensive dia-betic patients was searched. The electronic databases retrieved were Medline(1980-2003), Embase database (1980-2000), Cochrane Library, CL( 1980-2004), CBMdisc( 1980 - 2002), and IPA(1980-2002). Seven studies were chosen.Data were combined by Revman 4.2. Results The pooled effect of change in AER is -56.31 μg·min^-1 [-81.96, -30.66] (P<0.0001). According to the analysis of subgroups, the pooled effects of 1-5 years are -11.97μg·min^-1 [-22.04, -1.89](P = 0.02), -28.01 μg· min^-1[-34.50, -21.52](P<0.00001), -43.24 μg·min^-1[-57.15, -29.32] (P<0.00001), -61.65 μg·min^-1 [-77.77,-45.54] (P<0.00001), and -98.41 μg·min^-1 [-162.02,-34.79] ( P = 0.002). Regarding progression toclinincal proteinuria as end-point,the pooled Peto OR =0.27 [0.18,0.40] (95% CI), P<0.00001. According to the analysis of subgroups, the pooled effects of 2 and 5 years are Peto OR = 0.30 [0.18,0.51] (P<0.00001) and Peto OR=0.25 [0.13,0.50](P<0.0001). Publication bias is small. Conclusion In normotensive diabetic patients, ACEI inhibits AER effectively and reduces the probability of progression of microalbuminuria to clinical proteinuria.