Table of Content

15 December 1999, Volume 8 Issue 4

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Full Papers

New Alkaloids from the Roots of Stemona japonica Miq.

Zou Changying, Fu Hongzheng, Lei Haimin, Li Jun, Lin Wenhan^*

1999, 8(4):  185-190. 

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From the roots of Stemona japonica(Miq), five new alkaloids, namely tuberostemonine B(1), tuberostemonine C(2), bisdehydrotuberostemonine B(3), bisdehydrotuberostemonine C(4) and isomaistemonine(5) have been isolated. Their structures were elucidated by 2D NMR, IR andMS, in comparison with the spectral data of their analogues. Compound 1 was a C-10 isomer oftuberostemonine and compound 2 was a C-9 isomer of 1. Compounds 3 and 4 were identified as thedidehydrogenated products of tuberostemonine B and tuberostemonine C respectively due to theoxidation transformation. Compound 5 was the unsaturated lactone spiral isomer of maistemonine.

Synthesis of Analogues of Paclitaxel with 14β-Side Chain from Sinenxan A

Yin Dali, Liu Ruiwu, Wang Donghui, Guo Jiyu, Liang Xiaotian^*, Yoshinori Sekiguchi, Kazuya Kameo

1999, 8(4):  191-200. 

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Sinenxan A (2), isolated from tissue culture, possesses an A/B/C ring skeletonwithout 1,7,9,13-oxygen functionality of paclitaxel (1). Two 1,7,9,13-deoxy, C-14β side chain analogues 4 and 5 of 1 were synthesized from 2 by incorporating the 4,20-double bond into the D-ring and introducing the side chain at 14β position. Compounds 4 and 5 showed significantly decreasedactivity in the cytotoxicity assay in vitro against KB, A2780, and HCT-8. In tubulin assembly assaythey did not show any activity at 10 μmol.L^-1.

Synthesis and Antiaggregating Activity of Nonpeptide Fibrinogen Receptor Antagonists (Ⅱ): N-Substituted-O-(4-Amidinophenoxy) Ethyl-L-Tyrosine Methyl Ester

Xu Tianlin^*, Jiang Xuntian^**, Hua Weiyi, Ni Peizhou, Pei Yongmei^*

1999, 8(4):  201-206. 

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A series of nonpeptide fibrinogen receptor antagonists were designed andsynthesized by mimicking the structure of Arg-Gly-Asp (RGD) sequences in fibrinogen. In order toexplore the effect of spacer polarity on inhibitory activity, 12 N-substituted-O-(4-amidinophenoxy) ethyl-L-tyrosine methyl esters have been synthesized with the less polar dioxyethylene spacer insteadof the aminocarbonyl methyl in our previous report. The inhibitory effects of 12 target compoundscontaining tyrosine skeleton for adenosine 5-diphosphate (ADP) induced platelet aggregation inrabbit platelet-rich plasma were evaluated utilizing a turbidometric technique and 9 compoundsshowed inhibitory action at the concentration as low as 1×10^-6 mol·L^-1, of which Ii has the bestactivity.

Modeling of Sustained Drug Release from a Planar Matrix with a Super-saturation Loading

Xu Tongwen, He Binglin

1999, 8(4):  207-211. 

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This paper concerns with matrix-diffusion mechanism in slab monolithic matrixin the case that a drug loading is above its saturation level. A comprehensive model is proposed andthe general solutions are acquired by Laplace transform, from which a special case can be derived.The equations obtained are compared with Higuchi's model and tested with a 5-fluorouracil(5-Fu) loaded poly (ethylene-vinylalcohol), i. e., 5 -Fu/EVAL matrix system. The experimental data haveconfirmed the validity of the theoretical model at middle drug loadings, e.g., those between 15.5 and 123.6 mg.cm^-3. The model proposed is superior to Higuchi's for a relatively low loading system, muchas that less than 15.5 mg.cm^-3 and can theoretically support the hypotheses of Higuchi's model.Neither of these two theoretical models can describe the high drug loading systems, such as thoseloaded over 210 mg.cm^-3. This case has been discussed elsewhere.

Enzymatic Synthesis of L-Tryptophan from L-Cysteine and Indole

Wei Pinghe, Wu Wutong

1999, 8(4):  212-215. 

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Objective: L-Tryptophan was enzymatically synthesized by tryptophanase in genetic engineering strain WW-11 from L-cysteine and indole. Methods:Tryptophanase in engineeringstrain was expressed by IPTG induction. The engineering strain free cells with the highest enzymeactivity were used as enzyme source in the reaction mixture. L-Tryptophan accumulated in the reaction mixture was analysed and determined by paper chromatography and amino acid analyzer Results:An yield of 1.18g of L-tryptophan was obtained from 0.75 g of L-cysteine and 0.75g of indolein 80 mL reaction mixture shaking for 48 h at 37 ℃. The conversion rate was 93.2% for L-cysteineand 90.1% for indole. After isolation and purification, the crystals were identical with authentic Ltryptophan, in respects of melting point, optical activity and IR-spectrum. Conclusion:Tryptophanase in genetic engineering strain could effectively catalyze L-cysteine and indole tosynthesize L-tryptophan. This enzymatic synthesis method is one of the more effective methods forthe industrial production of L-tryptophan.

A Novel Sustained Release Gastric Floating Tablet Containing Nimodipine Solid Dispersion

Wu Wei, Zhou Quan, Zeng Renjie, Li Fengqian

1999, 8(4):  216-221. 

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A novel sustained release gastric floating tablet containing solid dispersion withenhanced bioavailability and prolonged gastrointestinal resident time of the model drug nimodipine,apoorly soluble drug, was manufactured. Solid dispersion of nimodipine was prepared by a solventmelting method using poloxamer 188 as carrier. The floating tablet was made up of nimodipinepoloxamer 188 solid dispersion, hydroxypropylmethylcellulose, magnesium carbonate, hexadecanol,and several other additives. Formulations were optimized using an experimental design. Optimal formulation showed immediate buoyancy after introduction into simulated gastric fluid and maintained asustained floating state for over 10 h. Noninvasive scintigraphy also showed that the dosage formfloated to the surface of the gastric fluid from the bottom of the stomach. Food had an important effect on in vivo transit. Under fed conditions, the floating dosage form seemingly left small intestineabout 5 h after ingestion, and the non-floating tablet was emptied within 3 h. Under fasted conditions,the floating dosage form remained in the stomach and small intestine for only 3 h and the non-floatingtablet disintegrated and left the absorption site within 2 h. Pharmacokinetics in healthy male volunteers indicated that the relative bioavailability of this novel dosage form was about 4 times that of aconventional nimodipine tablet, and the mean resident time was twice that of the conventional tablet.

A New Method for Evaluating Drug Dosage Forms In Vitro and In Vivo Correlation

Su Jie, Cui Yong, Zhang Junshou

1999, 8(4):  222-228. 

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A dissolution model and a dissolution-absorption model were used to describe in vitro and in vivo fates of drug dosage forms. Accordingly, two groups of equations were developed todisplay the kinetic processes of the two models. Considering that an in vitro dissolution test was usednot to simulate the absorption of drugs in vivo but to approach its in vivo dissolution behavior, the in vitro dissolution rate constant Rout, and the in vivo dissolution rate constant Rin were selected to evaluate the correlation between the in vitro and in vivo processes. Two computer programs were developed to simulate the in vitro and in vivo processes respectively, thereby providing the approximationof Rout and Rin In this simulation, an absorption rate constant Ka (obtained from conventional pharmacokinetic simulation) of drug solution was used to substitute the absolute absorption rate constant Kab(which means the absorption rate constant of a completely dissolved drug solution at the absorptionsite) of the drug to obtain Rin. Two dosage forms of tramadol hydrochloride (capsule and oral solution)were orally administered to six healthy volunteers and blood samples were assayed with a HPLC procedure with fluorescence detection. The data of oral solution were used to obtain the approximation ofKab.in vitro dissolution test was also performed with the capsule. After the computer-aided simulationon the data obtained from the capsule, the mean Rin for six volunteers was 6.27±0.52×10^-5 mL.mg^-2/3 min^-1 and the mean Rout, of six samples at 0, 25, 100 rpm stirring rate in dissolution test was9.03±2.03×10^-5, 1.63±0.90×10^-4 and 1.80±0.65×10^-4 mL.mg^-2/3.min^-1, respectively. These results mightsuggest that compared with Rin, Rout, values were higher to some extent, which means that the dissolution test method used here achieved a faster dissolution rate than that of the in vivo. The dissolutiontest at 0 rpm stirring rate provided a relatively approximate result, even though it still seemed to be alittle faster This work might introduce a method to evaluate the in vitro and in vivo correlation and todirect the improvement of an in vitro dissolution test.

Analysis of the Combination Chemotherapy Effect In Vitro Utilizing the Median-effect Principle

Lu Hongdi, Tang Weixue, Zhou Jianfang

1999, 8(4):  229-232. 

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In this paper, the median-effect principle was used to design a computer programto evaluate the combination chemotherapy effect in vitro. This program requires fewer tests and cannot only determine whether the interaction of two drugs is synergic, but also analyse the synergicefficiency with changing dosages. It can be used as a reference for the design of combination chemotherapy in clinical practice.

The Expression of Human Arrhythmic Related Gene Kv1.5 and Kv4.2 on Xenopus Oocytes

Xu Donghui, Xu Shibo, Wang Zhiguo, Stanley Nattel

1999, 8(4):  233-236. 

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By techniques of gene clone, microinjection and patch-clamp, human arrhythmicrelated gene Kv1 .5 and Kv4.2 were translated into cRNA, and then injecte4 into Xenopus oocytes, respectively. A pure and single K⁺ current of ultrarapid delayed rectifier K⁺ current (IKur) or transientoutward K⁺ current (Ito) was respectively detected on Xenopus oocytes. This is a modern pharmacological model for evaluating class III antiarrhythmic drugs. It can overcome many defects of previousmethods for evaluating antiarrhythmic drugs, such as lacking human fresh cardiac muscle cells asmaterial, and co-expression of many currents on cell membrane.

Communications

Chemical Constituents of Stelmatocrypton khasianum

Zhang Qingying, Zhao Yuying, Ma Libin, Cheng Tieming

1999, 8(4):  237-240. 

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The Analgesic and Anticancer Activity of N-(N-acetyl-L-amino acyl)-5-methoxytryptamines

Han Dongmei, Han Mei, Wang Chao, Zhao Ming, Peng Shiqi^*

1999, 8(4):  241-243. 

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Synthesis and Crystal Structure of Cis, trans-1,2-di-methyl-3,5-diphenyl-4-pyrazolidine Carboxylic Acid

Liu Ligang, Ji Min, LiuHong, Hua Weiyi

1999, 8(4):  244-247. 

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Other

CONTENTS OF VOLUME 8

1999, 8(4):  248-250. 

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