Journal of Chinese Pharmaceutical Sciences

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2007, 16(2): 1-04.

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Elsholtzia: review of traditional uses, chemistry and pharmacology

Ai-Lin Liu, Simon M.Y. Lee, Yi-Tao Wang, Guan-Hua Du^*

2007, 16(2): 73-78.

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The chemical constituents, pharmacological activity and traditional uses of 20 species attributed to the genus Elsholtzia (Labiatae) used in China are reviewed and compared. A survey of the literature available shows that these species are used mostly for the treatment of respiratory and gastrointestinal disorders. Additionally, some of these Elsholtzia species show antibacterial, anti-inflammatory, relieving fever, analgesic activities and myocardial ischemia protection. Generally, the essential oils or flavonoids from these plant extracts are assumed to be the active principles.

Simultaneous determination of five nucleosides and nucleobases in Panax notoginseng using high-performance liquid chromatography

Jing Wang, Yi-Tao Wang, Shao-Ping Li^*

2007, 16(2): 79-83.

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Aim To quantitatively determine five nucleosides and nucleobases, including cytidine, uridine, guanosine, adenosine and uracil in different parts of Panax notoginseng. Methods Separation was performed on a Zorbax SB-Aq column using a gradient elution with mobile phase of 8 mmol·L^–1 ammonium acetate aqueous solution (A) and methanol (B). The assay was carried out at a flow rate of 1 mL·min^–1 at 25 ºC with the diode-array detection at 260 nm. Results Cytidine, uridine, guanosine, adenosine and uracil had good linearity in the ranges of 1.79 – 57.40 μg·mL^–1 (r² = 1.0000), 3.30 – 105.60 μg·mL^–1 (r² = 1.0000), 3.09 – 98.80 μg·mL^–1 (r² = 0.9999), 2.77 – 88.60 μg·mL^–1 (r² = 1.0000) and 0.38 – 12.30 μg·mL^–1 (r² = 1.0000) with average recoveries of 93.9%, 96.5%, 92.7%, 93.2% and 98.8%, respectively. The content of cytidine, uridine, guanosine, adenosine and uracil in different parts of P. notoginseng were significantly different. Conclusion This is the first report on quantitative determination of nucleosides and nucleobases in P. notoginseng.

Sensitive liquid chromatography electrospray ionization ion-trap mass spectrometry for the determination of rupatadine in human plasma

Yu-Guan Wen^*, Ling-Han Yu, Jian-Ling Peng, Ri-Fang Liao, Cui Ma

2007, 16(2): 84-89.

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Aim To develop and validate a sensitive and specific liquid chromatography electrospray ionization ion-trap mass spectrometry (LC-ESI-MS/MS) method for the identification and concentration of rupatadine in human plasma. Methods After the addition of the internal standard (IS, loratadine) and 0.01 mol·L^–1 sodium hydroxide solution, plasma samples were extracted with methylene chloride: ethyl acetate mixture (20:80, V/V). The organic layer was evaporated under vacuum drying at 37 ºC. The residue was reconstituted with 200 μL mobile phase. Chromatography was performed on an Agilent Eclipse XDB-C18 (4.6 mm × 150 mm, 5 μm) column with a mobile phase consisting of acetonitrile (1% formic acid) –20 mmol·L^–1 ammonium acetate (76:24, V/V) at a flow-rate of 0.6 mL·min^–1. Detection was performed on Agilent MSD Trap XCT ion-trap mass spectrometry connected to a Agilent 1100 high performance liquid chromatography (HPLC) by selected reaction monitoring (SRM) mode via electrospray ionization (ESI) source. Rupatadine (MRM m/z 416→309) and loratadine (MRM m/z 383→337) were detected by Agilent MSD Trap XCT ion-trap mass analyser. Results The method was proved to be sensitive and specific by testing 20 different plasma batches. Linearity was established for the range of concentrations 0.05 – 14.0 ng·mL^–1 with a coefficient of determination (r) of 0.998. The intra-and inter-day precision (RSD %) were lower than 15% and accuracy ranged from 85.1% to 114.0%. The lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.05 ng·mL^–1 with a precision of 9.22% (n = 5). Conclusion The proposed method is sensitive and reproducible enough to be used in pharmacokinetic, bioavailability or bioequivalence studies of rupatadine.

Preparation and evaluation of ophthalmic thermosensitive in situ gels of penciclovir

Gui-Ling Li, Mei Li^*

2007, 16(2): 90-95.

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Aim To develop pluronic F127 (PF127) based formulations of penciclovir (PCV) aimed at enhancing its ocular bioavailability. Methods Thermosensitive in situ gels of penciclovir were prepared through combination of HPMC K4M or carbopol 934P and pluronic F127. Optimized formulations were examined through measuring gelation temperature, rheology speciality, drug release behavior, pharmacokinetics and ocular irritation. Results The gelation temperature was reduced by adding HPMC K4M or carbopol 934P, and the viscosity was enhanced slightly. Either HPMC K4M or carbopol 934P delayed the release of PCV from in situ gel. PCV was released by non-Fickian diffusion. The study of ocular irritation for different PCV formulations did not show any irritation or damage for the cornea. PCV bioavailability from combination of carbopol 934P and pluronic F127 gels was higher than that obtained from any other gels. Conclusion Pluronic F127 formulations of PCV can be used as liquid for administration by instilling into the eye. Facilitated by the appropriate eye temperature, the formulations were transformed to gel phase. On the basis of in vitro and in vivo results, PCV formulations containing HPMC K4M or carbopol 934P and low concentration of pluronic F127 (12%) showed potential for use as a drug delivery system with improved ocular bioavailability.

Stepwise multiple regressions application in liposome orthogonal experiments

Xiao-Jing Fan, Qian Liu, Peng Zhen, Yang Zhang, Xin Hu^*

2007, 16(2): 96-100.

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Aim New statistical method was applied in data analysis of orthogonal experiments to optimize the preparation of liposome. Method Particle size, zeta potential, encapsulation efficiency and physical stability of liposomes were selected by orthogonal design as evaluating indicators. Through three statistical methods (direct observation, variance analysis and stepwise multiple regression), the optimized preparing conditions were acquired and validated by experiment. Results All of the four indicators were different by these analyses. The validation experiments indicated that the optimized conditions by stepwise multiple regressions were better than that by traditional analysis. Conclusion Experiment results suggested that multiple regressions could avoid the weakness of direct observation and variance analysis, but more work should be done in preparing liposomes.

A RP-HPLC method for determination of paclitaxel in its solid dispersion

Xiang-Rui Liu, Ke-Chun Wu, Chun-Hui Zhang, Xuan Zhang^*, Qiang Zhang

2007, 16(2): 101-104.

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Aim To develop and validate a RP-HPLC method for the analysis of paclitaxel in a solid dispersion. Methods Paclitaxel and the internal standard norethisterone were separated using a Phenomenex ODS 3 column and monitored at a wavelength at 227 nm. The isocratic mobile phase consisting of methanol-acetonitrile-water (40:30:30, V/V) was pumped at a flow-rate of 1.0 mL·min^–1. The dissolution studies were performed according to published studies. Results Under these chromatographic conditions, the calibration curve was linear in the range of 4–40 μg·mL^–1 with the correlation coefficient of 0.9999. The mean recovery was 98.42 % (RSD = 1.19%). At the 60 min time point, the dissolution of paclitaxel from the solid dispersion was nearly 100 %, however, the original form of paclitaxel was about 30%. Conclusion The method was proven to be specific, accurate and precise for determining the dissolution of paclitaxel from solid dispersion.

Preparation of anti-resistant stealthy liposomes by incorporating vincristine with quinacrine and the pharmacokinetics in Sprague-Dawley rats

Gong-Wen Liang, Wan-Liang Lu^*, Jin-Wei Wu, Ji-Hui Zhao, Ting Li, Yu-Teng Zhang, Hua Zhang, Jian-Cheng Wang, Xuan Zhang, Qiang Zhang

2007, 16(2): 105-111.

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Aim The objectives of the present study were to prepare stealthy vincristine plus quinacrine liposomes and evaluate the pharmacokinetics in Sprague-Dawley rats. Methods Anti-resistant stealthy liposomes were prepared by incorporating vincristine with quinacrine together using the ammonium sulfate gradient loading procedure. For the pharmacokinetic study, Sprague-Dawley rats were divided into two groups: each rat in the Group I was administered intravenously via tail vein as stealthy liposomal vincristine plus quinacrine, and the Group II similarly given as a mixture solution of free vincristine plus free quinacrine. The concentrations of vincristine and quinacrine in plasma were measured by HPLC with diode array detection and fluorescence detection, respectively. Results The mean particle size of stealthy liposomes was 135.9 ± 7.1 nm and the encapsulation efficiencies of stealthy liposomes were > 90% for vincristine, and > 85% for quinacrine, respectively. Administered as the stealthy vincristine plus quinacrine liposomes, the plasma exposures of both vincristine and quinacrine were significantly extended, and the mean concentrations of both vincristine and quinacrine were significantly higher compared to those given as the mixture solution of free vincristine plus free quinacrine. The Cmax, t1/2, AUC0–24 h values of vincristine for stealthy liposomal group were significantly increased, but the total clearance Cl values decreased, as compared to those of free drug group, respectively. Similarly, the Cmax, t1/2 and AUC0–24 h values of quinacrine for the stealthy liposomal group were significantly increased, but the total clearance Cl values decreased, as compared to those of free quinacrine. Conclusion The anti-resistant stealthy liposomes are successfully prepared by incorporating vincristine with quinacrine, and the liposomes extend significantly the duration in blood circulation and improve evidently the plasma concentrations of both vincristine and quinacrine.

Combined effect of hydroxypropyl-β-cyclodextrin and media pH on the solubility of prostaglandin E₁

Fu-Gen Gu^*, Chun-Zhi Wu, Yong-Liang Gao

2007, 16(2): 112-115.

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Aim To investigate the combined effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) and media pH on the solubility of prostaglandin E1 (PGE1) and construct a theoretical equation for the drug solubility as a function of HP-β-CD concentration and media pH. Methods The solubility of PGE1 under different pH conditions was determined. Then, the drug solubility in different concentrations of HP-β-CD acidic or pH neutral solutions was measured, respectively. Finally, a theoretical solubility equation for the drug as a function of HP-β-CD concentration and media pH was deduced and confirmed in experiment. Results PGE1 was solubilized by HP-β-CD or by increasing media pH. The drug solubility as a function of HP-β-CD concentration was found to follow the AL-type complexation model in acidic or neutral pH media, suggesting that both the ionized and neutral drugs form 1:1 molecular ratio complexes. Conclusions The solubility of PGE1 may be improved by increasing media pH or by using HP-β-CD as a solubilizer. HP-β-CD and media pH can produce combined effect on the solubility of PGE1. The deduced equation for the drug solubility in this study effectively characterizes the roles of HP-β-CD and media pH in determining total solubility of the drug.

Preparation of liposomal fluconazole gel and in vitro transdermal delivery

Shan-Shan Zhao, Qing Du^*, De-Ying Cao

2007, 16(2): 116-118.

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Aim Liposomal fluconazole gel was prepared and its properties were studied. Methods The fluconazole liposomes were prepared by film dispersion method. Their shapes and sizes were observed by transmission electronic microscope and particle size analyzer, respectively. The skin permeation of liposomal gel was studied on rat skin by permeation cell. Results The entrapment efficiency of fluconazole liposomes was 47.68%. The fluconazole liposomes were oval or round in shape, and their average diameter was 250 ± 8 nm. The accumulative skin permeation of liposomal fluconazole gel (25.27%) was lower than that of non-liposomal fluconazole gel (36.72%), but fluconazole retained in rat skin of liposomal gel (162 ± 15 μg·cm^–2) was higher than that of nonliposomal gel (48 ± 6 μg·cm^–2). Conclusion Liposomal fluconazole gel can significantly increase the deposited amounts of fluconazole in rat skin and it may be beneficial for topical use.

Synthesis of protected aminoalkyl sulfinyl dilactones from α-amino acids

Gang Fu, Xiao-Min Zou, Yi-Qiu Fu, Ke Mou, Chao Ma, Yang Lu, Ping Xu^*

2007, 16(2): 119-124.

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Aim To synthesize protected aminoalkyl sulfinyl dilactones which were useful as the synthetic intermediates or the Cterminal pharmacophores of potential peptidomimetic proteasome inhibitors. Methods Organic reactions such as reduction, oxidation, olefination, and dihydroxylation were used. Results A convenient synthetic procedure to afford a series of aminoalkyl sulfinyl dilactones was presented, which would be useful in the synthesis of five- or six-member sulfinyl dilactones. Conclusion Four aminoalkyl sulfinyl dilactones connecting different α-amino acids were synthesized.

Study on the regioselective alkylation of 2-thiopyrimidine

Yang Xu, Hua Yang, Jin Hu, Xiao-Wei Wang, Jun-Yi Liu^*

2007, 16(2): 125-127.

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Aim To investigate the alkylation of 2-thiopyrimidine. Methods Treating the starting material 2-thiopyrimidine with chloromethyl ethers via a procedure of K2CO3 in DMF or with alkyl halide in CH3ONa-CH3OH at room temperature, to obtain the corresponding regioselective 2-S-allkyl pyrimidines. The products were determined by ¹H NMR, 2D NMR, IR and MS spectra. Results 2-S-alkyl-pyrimidines were regioselectively synthesized. Conclusion In different conditions with different alkyl halides, 2- thiouracil could be converted into the corresponding 2-S-alkylpyrimidines regioselectively.

Synthesis and anti-shock activity of divalent β-D-galactopyranosyl-(1→4)-β-D-glucopyranosides

Wan Zhang, Qing Li, Xiang-Bao Meng, Zhi-Hui Zhao, Zhong-Jun Li^*

2007, 16(2): 128-131.

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Three divalent β-D-galactopyranosyl-(1→ 4)-β-D-glucopyranosides were synthesized using acetylated lactosyl bromide as donor and polyethylene glycols with different polymeric degree (n = 4, 5, 6) as linker, and evaluated for in vivo inhibitory activity to leukocyte-endothelial cell adhesion on severe burn-shock rats. The result showed that the length of linkers had apparent influence on anti cell adhesion activity.

Chemical constituents of Salvia cavaleriei Levl. var. erythrophylla (Hemsl.) Stib

Ya-Ling Cai^*, Jin-Lan Ruan, Gui-Di Feng, Wei Fang

2007, 16(2): 132-133.

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Aim To investigate the chemical constituents of Salvia cavaleriei Levl. var. erythrophylla (Hemsl.) Stib. Methods Compounds were isolated by silica gel column chromatography and Sephadex LH-20 gel column chromatography, and the structures were identified by spectral analysis. Result Five compounds were identified as 3β, 6β, 23-trihydroxyolean-12-en-28-oic acid (1), ursolic acid (2), n-heptadecanoic acid (3), n-octadecanoic acid (4), and β-sitosterol (5). Conclusion Five compounds were isolated from the plant for the first time.

Arsenic trioxide inhibites transgenic tumor necrosis factor-α promoter activity in vascular smooth muscle cells and THP-1 monocytes in vitro

Zhuo-Qi Zhang^*, Xi-Chuan Cao, Yong-Lin Huang

2007, 16(2): 134-138.

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Aim This study was to evaluate the effect of arsenic trioxide (As2O3) on the transgenic TNF-α promoter activity in cultured vascular smooth muscle cells (VSMCs) and THP-1 monocytes. Methods Human TNF-α promoter was constructed by reporter gene system and was transiently transfected into VSMCs and THP-1 in vitro. The promoter activity was tested by luciferase activity with or without LPS and Ang II stimulation, before and after different dosage of As2O3 treatment. Results 1. TNF-α promoter effectively expressed in VSMCs and THP-1 compared with CMV promoter (58.3% and 80.9%, respectively). Both LPS and Ang II significantly up-regulated TNF-α promoter activity (P<0.05). 2. As2O3 significantly inhibited, both intact and LPS/Ang II stimulated promoter activity, in a dose dependent manner (P<0.05), and in both cell type. Conclusion These results manifested that, the inhibition effect of As2O3 on the activity of human TNF-α promoter indicated its potential inhibition on pro-inflammatory cytokine genes expression at transcriptional level and its potential anti-inflammatory property in the cardiovascular system.

Synergistic effect of pinellia total alkaloids and uncaria total alkaloids on anticonvulsant action in mice and rats

Yin-Xia Cheng, Ming-Zheng Wang^*, Jing-Jing Chen, Rong Yang, Xin-Gu He,
Yong-Gang Ma, Li-Hua Yang, Ming-Sheng Zhang

2007, 16(2): 139-145.

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Aim To investigate the synergistic effect of the combination of pinellia total alkaloid (PTA) and uncaria total alkaloid (UTA), and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic effect profiles of combinations of PTA with UTA, alone and at three fixed ratios of 1:4, 1:1, 4:1, were evaluated in maximal electroshock (MES)-induced seizures and acute toxicity test in mice. Respective ED50 and LD50 were calculated with Bliss’s method. Their synergistic effect were evaluated by isobolographic analysis and allowed the determination of benefit indices (BI) for respective combinations. The model of convulsive rats kindled by penicillin topically injected into cortex was used to investigated the content of Glu, Asp, Gly and GABA in hippocampus using high performance liquid chromatography (HPLC). Results Combinations of PTA and UTA at the ratio of 4:1 were synergistic in MES test and antagonistic in acute toxicity test, showing the best profile for combinations of PTA with UTA. In contrast, the ratios of 1:4 and 1:1, despite synergistic in MES test, were additive in acute toxicity test. The 4:1 combination and two drugs alone significantly decreased Glu level and increased GABA level in the hippocampus，but the GABA level in the 4:1 combination group was higher than that in the two drugs alone groups. They did not have significant influence on the levels of Asp and Gly. Conclusion Combinations of PTA and UTA at 4:1 ratio demonstrated synergistic effect in anticonvulsant action and antagonistic effect in toxicity. The anticonvulsant mechanism might be related to decreasing the excitability of Glutamatergic neurons and increasing the inhibition of GABAergic neurons.

Preparation and study of anti-hepatitis B virus activity in vitro of oxymatrine phospholipid complex

Lu-Jun Wang, Peng-Fei Yue, Yan-Ling Zhao, Pei-Lie Cai, Xu Zhou, Hai-Long Yuan^*

2007, 16(2): 146-152.

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Aim The oxymatrine phospholipid complexs were prepared, and its activity against hepatitis B virus in vitro were studied. Methods Using tetrahydrofuran as a reaction medium, oxymatrine and phospholipids were resolved into the medium. Oxymatrine phospholipid complexs were prepared. The toxicity measurements and inhibitory effect on HBsAg, HBeAg, and HBVDNA of oxymatrine phospholipid complex in 2.2.15 cells were studied respectively. Results The content of oxymatrine in the phospholipids complexs prepared was 24.86% (W/W). The TCO of the oxymatrine phospholipid complexs was 250 μmol×L^–1. The inhibitory effect of HBsAg, HBeAg, HBV-DNA of 2.2.15 cells treated by oxymatrine phospholipid complex were higher than those of the oxymatrine. Conclusion Oxymatrine phospholipid complex can have stronger effective activity against hepatitis B virus compared with oxymatrine. So oxymatrine phospholipid complexs were showing its potential antiviral activity in hepatitis B treatment.

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