Journal of Chinese Pharmaceutical Sciences

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2007, 16(3): 1-04.

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Preparation and characterization of 9-nitrocamptothecin self-emulsifying microemulsion injection

Juan-Li Lu, Jian-Cheng Wang^*, Xuan Zhang, Qiang Zhang^*

2007, 16(3): 157-161.

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Aim To prepare a self-emulsifying microemulsion of 9-nitrocamptothecin (9-NC ME) for intravenous injection and investigation of its pharmacokinetic profiles in normal SD rats. Methods 9-NC ME was optimized in terms of droplet size and lack of drug precipitation following aqueous dilution using a pseudo-ternary phase diagram. Physicochemical properties of 9-NC ME were evaluated. 9-NC ME was intravenously administered via tail vein in healthy rats. Results A stable microemulsion was formulated consisted of soybean oil as oil phase, EPC/Tween-80 as emulsifier, and anhydrous ethanol as co-emulsifier. The droplets of the microemulsion were spherical shape with mean diameter of 38.3 ± 4.0 nm after 1:20 dilution with 5% glucose injection. The pharmacokinetic parameters of 9-NC ME after intravenous administration in rats were t1/2 of 0.97 ± 0.14 h, AUC0-∞ of 372.77 ± 49.62 ng·h·mL^-1, and MRT of 1.40 ± 0.21 h which were 1.4-fold, 1.65-fold, and 1.4-fold more than those of 9-NC solution (P<0.01). Conclusion The results suggested that 9-NC ME was a promising drug delivery system and it was expected to provide a novel 9-NC injection for cancer patients.

In vitro characterization of two new doxorubicin liposomes modified with argine-glycine-aspartic acid tripeptide or glycine-argine-glycine-aspartic acid-serine pentapeptide

Chun-Lei Luo, Hui Zhao, Jian-Cheng Wang, Xuan Zhang, Wan-Liang Lu, Qiang Zhang^*

2007, 16(3): 162-169.

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Aim Peptides as ligands have shown the active targeting properties to the receptors like integrins, a family of receptors over-expressed in cancers. The present study was to develop and characterize two peptides modified drug-containing liposomes. Methods Argine-glycine-aspartic acid (RGD) tripeptide and glycine-argine-glycine-aspartic acid-serine (GRGDS) pentapeptide were used for modifications on the doxorubicin-loaded sterically stabilized liposomes (SSL-doxorubicin) for the liposome preparation, RGD-SSL-doxorubicin and GRGDS-SSL-doxorubicin, respectively. Characterizations were performed by measurements of the encapsulation efficiency, particle size and zeta potential, release rates in a simulated in vivo environment, and cytotoxicity to ovarian cancer cells. Cell uptake was investigated by flow cytometry and confocal microscopy methods. Results All encapsulation efficiencies of the liposomes were above 95%, and the modifications using RGD or GRGDS did not affect the final encapsulation efficiency. Average particle sizes of the liposomes were in the range between 105.7 ± 3.5 nm and 130.5 ± 3.0 nm, and zeta potential values were between –3.3 ± 0.3 and –6.1 ± 0.3 mV. Approximately 2/5 of doxorubicin was released from liposomes before 12 h in the simulated in vivo environment containing fetal bovine serum. Inhibitory rates to cancer cells of the modified liposomes were slightly lower as compared to free doxorubicin. Similar phenomena were observed in the uptake measured by flow cytometry and confocal assay. After uptake applying various formulations on the cancer cells, doxorubicin was mainly distributed in the nuclei of SKOV-3 cells. Conclusion Two new doxorubicin-contained liposomes were successfully prepared and modified with argine-glycine-aspartic acid (RGD) tripeptide and glycine-argine-glycine-aspartic acid-serine (GRGDS) pentapeptide. In vitro characterization indicated that modifications did not alter significantly the properties of the sterically stabilized liposomes.

Pharmacokinetics and bioequivalence of two pantoprazole sodium enteric-coated tablet products in healthy Chinese volunteers

Hai-Yan Xu, Peng Zhang, Xue-Ya Wang, Tao Shen, Huai-Qing Zhao^*

2007, 16(3): 170-175.

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Aim To evaluate the pharmacokinetics and bioequivalence of domestic pantoprazole sodium enteric-coated tablets as compared with imported pantoprazole enteric-coated tablets. Methods This was an open randomized, two periods cross over study on twenty healthy male volunteers. The pantoprazole concentrations in plasma after an oral dose of 40 mg pantoprzaole preparations were determined by a HPLC-UV method. Non-compartmental method was used for the calculation of pharmacokinetic parameters. Logarithm-transformed Cmax and AUC were analyzed by the analysis of variance (ANOVA) with 90% confidence intervals. Results The main pharmacokinetics parameters of domestic pantoprazole sodium enteric-coated tablets and imported pantoprazole sodium enteric-coated tablets were as following: Cmax (3610 ± 956), (3466 ± 1209) ng·mL^-1, tmax (3.00 ± 0.40), (3.00 ± 0.46) h, AUC0-t (8140 ± 5065), (8390 ± 5474) ng·h·mL^-1, AUC0-∞ (8293 ± 5094), (8625 ± 5606) ng·h·mL^-1, t1/2 (1.61 ± 0.28), (1.85 ± 0.27) h, respectively. Conclusion Domestic pantoprazole sodium enteric-coated tablets were bioequivalent with the imported pantoprazole sodium enteric-coated tablets.

Basic physical, acoustic properties, and in vitro ultrasound imaging enhancement of the lipid-coated microbubbles

Yu Xiang, Jian Sun, Xian-Rong Qi^*

2007, 16(3): 176-182.

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Aim To research on a stable microbubble with good acoustic properties and excellent imaging enhancing effect, and to make it to be a promising agent for the enhancement of ultrasound imaging in the ultrasound diagnosis of cardiovascular system diseases. Methods The morphology, size and zeta potential of lipid-coated microbubbles (LCM), the acoustic properties of backscatter, and the second harmonic scatter of LCM were determined. Furthermore, the relationship between the concentrations and the amplitude values of the second harmonic was investigated by testing the intensities of the second harmonic at different concentrations. The imaging effect of LCM was also studied in vitro. Results The mean diameter of LCM was 3.38 μm with 95% of the bubbles under 5 μm. The scatter signal generated by microbubbles was observed under different concentrations in the bistatic modes while the position of transmitting transducer and receiving transducer was orthogonal. The intensity of the second harmonic scatter fell with the decrease of microbubble concentration. The increase rate of the second harmonic amplitude values generated by the microbubbles versus that by physiological saline was linear with the natural logarithm of bubble concentrations. The LCM could enhance the ultrasound image of thrombus. Conclusion The LCM exhibited good physical state and acoustic properties, which could increase the imaging quality.

Bioequivalence of bicalutamide capsules and tablets in Chinese healthy volunteers

Bing Wang, Ben-Jie Wang, Chun-Min Wei, Xiang-Lin Kong, Rui-Chen Guo^*

2007, 16(3): 183-186.

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Aim To establish a HPLC method for the determination of bicalutamide plasma concentration and to evaluate the bioequivalence of bicalutamide capsules (test) and tablets (reference). Methods A single oral dose of 50 mg bicalutamide capsules or tablets were given to 48 Chinese healthy volunteers in a one period parallel design test. Bicalutamide in plasma was analyzed using a XB-C18 column with a mobile phase of acetonitrile-water (60:40, V/V) and the dectection wavelength of272 nm and it is pharmacokinetic parameters were calculated and evaluated using DAS2.0. Results The linear range of bicalutamide was 10 – 1200 ng·mL^-1. The main pharmacokinetic parameters of the test and reference were as the followings, t1/2 (138.36 ± 32.03) and (146.12 ± 27.04) h, Tmax (17.17 ± 4.65) and (16.92 ± 4.85) h, Cmax (910.83 ± 130.49) and (868.71 ± 115.35) ng·mL^-1, AUC0-672 (172437.08 ± 3986.07) and (176842.34 ± 35733.85) ng·mL^-1·h, and AUC0-∞ (179456.55 ± 43127.65) and (185270.39 ± 39688.63) ng·mL^-1·h, respectively. The two-one side t-test analysis showed that the confidence intervals of Cmax, AUC0-672 and AUC0-∞ were (98.9% – 100.7%), (98.8% – 100.6%) and (99.7% – 101.7%), respectively. Conclusion The relative bioavailability of bicalutamide capsules was 97.51%. The bioequivalence was demonstrated by the two-one side t-test.

Preparation and characterization of ferromagnetic fluids for hyperthermia of tumor

Yan-Fei Zhou, Tian-Yuan Fan^*, Ren-Jie Yang, Hong-Liang Sun, Qi-Sheng Xia

2007, 16(3): 187-191.

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Aim To prepare and characterize ferromagnetic fluids for hyperthermia of tumor. Methods Ferromagnetic fluids (FFs) of magnetite (Fe3O4) was prepared in the presence of polyethylene glycol (PEG-6000) by chemical precipitation method. The iron content of the FFs was determined by spectrophotometric method using o-phenanthroline. The FFs/PEG-6000 was characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), infrared spectrometry (IR), and vibrating sample magnetometer (VSM). Heating effects of the FFs was measured in an alternating magnetic field in vitro. The hyperthermia of FFs in a rabbit was performed. Results The FFs/PEG-6000 was proved to be composed of Fe3O4 by XRD and IR. TEM showed that the ferromagnetic particles appeared to be almost spherical and dispersed well. The average particle size was 13.3 ± 3.8 nm by XRD. The saturation magnetization and residual magnetization of the FFs were 23.39 A/m (1.556 emu/g) and 0.56 A/m (0.02604 emu/g), respectively. The coercive force was 12 Oe. The specific absorption rate (SAR) of FFs was 69 ± 10W/g [Fe]. After direct injection of FFs to hepatic VX2 carcinoma of a rabbit, the temperature in the core of the tumor was between 41 – 46 °C in an alternating magnetic field. Conclusion FFs/PEG-6000 was expected to be useful in hyperthermia of tumor.

Pharmacokinetics of nifedipine sustained-release tablets in healthy Chinese volunteers

Jing Wu, Ben-Jie Wang, Chun-Min Wei, Fan-Long Bu, Rui-Chen Guo^*

2007, 16(3): 192-196.

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Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 (5 μm, 4.6 mm × 150 mm) column and a mobile phase of methanol: 0.01 mol·L^-1 ammonium acetate (60:40, V/V) were used to separate nifedipine, the detections was accuracy under atmosperic pressure electronic spray ionization (AP-ESI) mode and ion mass spectrum (m/z) of 314.9[M+H]+ for nifedipine, and 320.8 [M+H]+ for lorazepam (Internal Standard, IS). Results The linear range of nifedipine was 0.3 – 80 ng·mL^-1 ( r = 0.9997), and the limit of quantitation (LOQ) was 0.3 ng·mL^-1. The nifedipine pharmacokinetic parameters after a single dose of 20 mg nifedipine sustained-release tablets test (T) or reference (R) were as the followings, t1/2 (6.73 ± 2.00) h and (7.04 ± 2.18) h, Tmax (4.28 ± 0.70) h and (4.48 ± 0.70) h, Cmax (39.66 ± 10.58) ng·mL^-1 and (40.19 ± 10.97) ng·mL^-1, AUC0-36 (391.63 ± 108.55) ng·mL^-1·h and (387.57 ± 121.51) ng·mL^-1·h, and AUC0-∞ (408.28 ± 121.16) ng·mL^-1·h and (406.15 ± 133.13) ng·mL^-1·h. The relative bioavailability of nifedipine sustained-release tablets (test) was (103.02 ± 13.93) %. Conclusion LC-MS method for the determination of concentrations of nifedipine in human plasma was sensitive and accurate, and could be used in nifedipine bioavailability and pharmacokinetic studies.

A rapid HPLC method for determination of coniferyl ferulate in Angelica sinensis and Ligusticum chuanxiong

Yue Yu, Qing-Wen Zhang, Yi-Tiao Wang, Shao-Ping Li^*

2007, 16(3): 197-201.

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Aim A reliable and rapid HPLC method was developed for quantitative determination of coniferyl ferulate, an ester of ferulic acid, with multiple pharmacological activities in Angelica sinensis and Ligusticum chuanxiong, two commonly used Chinese medicines. Methods The determination was achieved by using a Zorbax ODS C18 analytical column (250 mm × 4.6 mm ID, 5 mm) at isocratic elution of 1% aqueous acetic acid and acetonitrile (1:1) with diode-array detection (318 nm). The calibration curve of coniferyl ferulate showed good linearity (r2 = 0.9995) within the test range. Results The developed method showed good precision with intra- and inter-day variations of 0.22% – 1.16% and 0.86% – 2.62% between the levels of 0.380 – 0.038 mg·mL–1, respectively. The repeatability represented as RSD of coniferyl ferulate was less than 2.7% for three levels (0.2 – 1.0 g of Angelica sinensis), and the recovery was 105.3% with RSD of 3.2%. Conclusion The validated method was successfully applied to quantify coniferyl ferulate in 12 samples of Danggui and Chuanxiong.

Chemical and molecular characterization of Hong Dangshen, a unique medicinal material for diarrhea in Hong Kong

Yan-Bo Zhang, Ren-Wang Jiang, Song-Lin Li, Chun-Feng Qiao, Quan-Bin Han,
Hong-Xi Xu, Ka-Lok Wong, Paul Pui-Hay But^*, Pang-Chui Shaw^*

2007, 16(3): 202-207.

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Aim To investigate the plant origin and the identity of the red substance on the surface of Hong Dangshen, a unique medicinal material for diarrhea in Hong Kong. Methods The HPLC fingerprints and 5S rRNA gene spacer sequences of Hong Dangshen were obtained and compared with those of genuine species of Radix Codonopsis. The X-ray diffraction spectrum of the red substance was analyzed and compared with that of Halloysitum Rubrum. Results Hong Dangshen showed very similar HPLC fingerprints to the Codonopsis species and the highest similarity to Codonopsis pilosula var. modesta in terms of 5S rRNA gene spacer sequences. The X-ray diffraction spectrum of the red substance was consistent with that of Halloysitum Rubrum. Conclusion The source plant of Hong Dangshen was suggested to be Codonopsis pilosula var. modesta, one of the genuine original plants of Radix Codonopsis (Dangshen) in the China Pharmacopoeia (2005 edition). The red substance on the surface of Hong Dangshen was indicated to be Halloysitum Rubrum, a traditional medicinal mineral for chronic diarrhea. Our data suggest that Hong Dangshen is derived from the roots of Codonopsis pilosula var. modesta which has been processed with Halloysitum Rubrum, and the name is suggested to be Radix Codonopsis Praeparata Halloysita Rubra.

Chemical constituents from Pithecellobium clypearia and their effects on T lymphocytes proliferation

Xiao-Yu Guo, Nai-Li Wang, Li Bo, Yi-Hua Li, Qiang Xu, Xin-Sheng Yao^*

2007, 16(3): 208-213.

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Aim To investigate the chemical constituents from the twigs and leaves of Pithecellobium clypearia Benth and their immunomodulatory effects. Methods The constituents were separated and purified by various chromatographic methods and their structures were identified on the basis of spectral analysis. The immunomodulatory effects of all the compounds were examined by a Con A-induced T lymphocytes proliferation assay. Results Eight compounds were isolated and identified as (-)-epigallocatechin (1), (-)-5, 7, 3', 4', 5'-pentahydroxyflavan (2), (-)-epigallocatechin-7-gallate (3), (-)-5, 3', 4', 5'-tetrahydroxyflavan-7-gallate (4), quercitin-3-O-α-L-rhamnpyranoside (5), myricitin-3-O-α-L-rhamnpyranoside (6), gallic acid (7), and ethyl gallate (8), respectively. Conclusion Compounds 3 and 8 were isolated from this genus for the first time, and compound 1 was isolated from this species for the first time. Compound 3 exhibited a strong inhibition on the T lymphocytes proliferation induced by Con A with an IC50 of 4.4 μmol·L–1.

Chemical constituents of Ixeris sonchifolia

Yan-Qin Lu, Chao-Feng Zhang, Mian Zhang^*

2007, 16(3): 214-217.

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Aim To investigate the chemical constituents of Ixeris sonchifolia Hance. Methods The chemical constituents were isolated by various column chromatographic methods and the structures were elucidated and characterized by spectral evidences. Result Thirteen compounds were obtained and identified as 3β-acetoxy-20-taraxasten-22-one (1), bauerenyl acetate (2), 3β-acetoxy-11-oxours-12-ene (3), oleanic acid (4), oleanane (5), 8-desoxyartelin (6), aesculetin (7), ferulic acid (8), vanillic acid (9), sonchifolinin (10), hexacosanol (11), β-sitosterol (12), and daucosterol (13). Conclusion Compounds 1, 5, and 8 were isolated from this genus for the first time; compound 7 was obtained firstly from this plant.

Chemical constituents from Xylosma controversum

Zheng-Ren Xu, Ya-Nan Lu, Xing-Yun Chai, Hong-Yan Ren, Peng-Fei Tu^*

2007, 16(3): 218-222.

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Aim To study the chemical constituents from the stems of Xylosma controversum Clos. Methods The constituents were isolated by solvent extraction, repeated chromatography with silica gel, Sephadex LH-20, and RP-18 columns. The structures were elucidated by spectral analysis. Results Thirteen compounds were isolated and their structures were identified as (-)-syringaresinol (1), syringaresinol-4-O-β-D-glucopyranoside (2), syringaresinol-4,4'-bis-O-β-D-glucopyranoside (3), (±)-catechin (4), catechin-3-O-β-D-glucopyranoside (5), catechin-5-O-β-D-glucopyranoside (6), 1,3-bis-(4-hydroxy-3,5-dimethoxyphenyl)-1,3-propanediol (7), (R)-(+)-chaulmoogric acid (8), friedelin (9), uracile (10), benzoic acid (11), vanillic acid (12), and 4-hydroxybenzoic acid (13). Conclusion All the compounds described above were isolated from this genus for the first time.

Analysis of the chemical compositions of Hirudinaria manillensis

Yan-Li Miao, Fu-Yong Fang, Wen-Dong Song^*

2007, 16(3): 223-226.

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Aim To determine and analyze fatty acids, amino acids and trace elements of Hirudinaria manillensis. Methods Contents of fatty acids, amino acids and trace elements were determined by GC/MS, HPLC and ICP-AES. Results H. manillensis contained sixteen fatty acids, among which the percentage of unsaturated fatty acids is 34.05%. The eighteen amino acids were detected, which included eight essential amino acids in human body with a ratio of 33.53 %. There were eight trace elements (Ca, Cr, Cu, Fe, Mg, Mn, V and Zn) from H. manillensis, and the content of Ca, Zn and Fe were apparently higher than those of other elements. Conclusion These methods are simple and accurate. This study reports routine quantitative methods for the analysis of multiple components in H. manillensis by GC/MS, HPLC and ICP-AES.

Molecular mechanism of Radix astragali on improvement of insulin sensitivity of SD rats treated with low dose dexamethasone

Ting-Yan Yan, Xiao-Guang Wu, Ying-Tao Zhang^*

2007, 16(3): 227-232.

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Aim To reveal the main active components and the action mechanisms of Radix astragali on insulin sensitivity improvement, we have investigated the effects of polysaccharide portion and saponin portion of Radix astragali extracts on blood biochemical indices and related gene expression of dexamethasone-induced SD rats. Methods SD rats (6 per group) received 2 μg/day subcutaneous dexamethasone for 4 weeks plus same dose (10 g material/kg) of polysaccharide or saponin extracts of Radix astragali. Blood samples, kidney tissues and epididymal fat pads were taken at the end of the experiment. Serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), glucose (GLU) and insulin (INS) levels were measured, respectively. mRNA levels of angiotensinogen in kidney, adiponectin and leptin as well as TNF-α in epididymal fats were determined by RT-PCR assay using GAPDH gene as an internal control. Results Both of polysaccharide and saponin extracts of Radix astragali exhibited positive effects in reducing serum triglycerides, glucose, and insulin levels of dexamethasone-induced SD rats. The saponin group showed more improvements on quantitive insulin sensitivity check index (QUICKI) than the polysaccharide group did. Both of the extracts down-regulated kidney angiotensinogen and fat TNF-α mRNA levels while they were simultaneously up-regulating fat adiponectin and leptin mRNA levels. No significant difference was found between actions of the two extracts. Conclusion Both of polysaccharide and saponin extracts of Radix astragali can improve insulin sensitivity. This action might be closely related to down-regulation of angiotensinogen, TNF-α and up-regulation of adiponectin and leptin expression. The results partly explained the improvement of type II diabetes and diabetic nephropathy by Radix astragali. The similar actions of the two crude extracts suggest that unknown key active compounds might exist in both and remain to be discovered.

Synthesis of dutasteride

Kui-Ping Zhang, Xiao-Ping Lei^*

2007, 16(3): 233-235.

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Aim To synthesize dutasteride. Methods The target compound was synthesized from pregnenolol via eight steps, including esterification, oxidation, hydrolysis, then oxidative ring-opening, cyclization, reduction, oxidization and finally acylation. Results The structure of the target molecule was identified by 1H NMR, 13C NMR and element analysis. The overall yield was 31.5%. Conclusion The effects of different reaction conditions on the yield of product in each step have been investigated and the optimal reaction conditions have been established.

Professors and Graduates from Peking University School of Pharmaceutical Sciences Attending the 67^thFIP Congress and CPA Centennial Anniversary

Xun Wang^*

2007, 16(3): 236-240.

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