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Simultaneous determination of five nucleosides and nucleobases of Rehmannia glutinosa Libosch. by high performance liquid chromatography.

Wen-meng ZHANG ; Wen-wei FU ; Ming-yu SUN ; Li-xin SUN ; Yu-rong JIA ; Ping LIU

Acta Pharmaceutica Sinica.2011;46(11):1380-1384.

This study is to establish a method for simultaneously determination of five nucleosides and nucleobases, including hypoxanthine, uridine, adenine, guanosine and adenosine in Rehmannia glutinosa Libosch. which was collected from different regions in China. A Diamonsil C18 column (250 mm x 4.6 mm, 5 microm) was used. Acetonitrile and 0.04 mol L(-1) potassium dihydrogen phosphate solution were adopted as mobile phase with gradient elution. The flow rate was 1 mL min(-1) and column temperature was 30 degrees C. The detection wavelength was at 254 nm. The method had good linearity over the range of 1.0 - 16.0 microg mL(-1) (r2 = 0.999 8), 5.0 - 80.0 microg mL(-1) (r2 = 0.999 8), 1.0 - 16.0 microg mL(-1) (r2 = 0.999 5), 1.25 - 20.0 microg mL(-1) (r2 = 0.999 8) and 1.0 - 16.0 microg mL(-1) (r2 = 0.999 8) for hypoxanthine, uridine, adenine, guanosine and adenosine, respectively. The average recoveries were between 98.8% and 100.7%. The content of hypoxanthine, uridine, adenine, guanosine and adenosine in Rehmannia glutinosa Libosch. from different regions was significantly different. This established method was sensitive and reliable for the quantification of five chemical constituents in Rehmannia glutinosa Libosch.
Adenine ; analysis ; Adenosine ; analysis ; Chromatography, High Pressure Liquid ; Guanosine ; analysis ; Hypoxanthine ; analysis ; Nucleosides ; analysis ; Plants, Medicinal ; chemistry ; Rehmannia ; chemistry ; Uridine ; analysis

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Identification of the metabolites of Sinisan extract in rat plasma, urine, feces and bile after intragastric administration.

Lin-ling LU ; Yan SHU ; Da-wei QIAN ; Shu-lan SU ; Jin-ao DUAN ; Ye-fei QIAN ; Cai-fu XUE

Acta Pharmaceutica Sinica.2011;46(11):1374-1379.

Sinisan is a widely used traditional Chinese medicine (TCM) in treating various diseases; however, the in vivo metabolic profile of its multiple components remains unknown. In this paper, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was applied to identify the metabolites of Sinisan extract in rat plasma, urine, feces and bile after intragastric administration. Using MS(E) and mass defect filter techniques, 41 metabolites of 10 parent compounds (naringin, naringenin, hesperidin, neohesperidin, liquiritin, liquiritigenin, glycyrrhizic acid, glycyrrhetinic acid, saikosaponin a and saikosaponin d) were detected and tentatively identified. It was shown by our results that these compounds was metabolized to the forms of hydroxylation, glucuronidation, sulfation, glucuronidation with sulfation and glucuronidation with hydroxylation in vivo.
Administration, Oral ; Animals ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; metabolism ; pharmacokinetics ; Flavanones ; analysis ; metabolism ; pharmacokinetics ; Glucosides ; analysis ; metabolism ; pharmacokinetics ; Glycyrrhizic Acid ; analysis ; metabolism ; pharmacokinetics ; Hesperidin ; analogs & derivatives ; analysis ; metabolism ; pharmacokinetics ; Hydroxylation ; Male ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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Pharmacokinetics of cantide, an antisense oligonucleotide, and its metabolites in rhesus monkeys.

Xiu-zhong WANG ; Shi-hong WANG ; Hai-feng SONG ; Qing-qing WANG ; Sheng-qi WANG

Acta Pharmaceutica Sinica.2011;46(11):1370-1373.

To study the pharmacokinetics of cantide, an antisense oligonucleotide, and its metabolites after iv gtt administration in rhesus monkeys, a dual solid phase extraction pretreatment method coupling with non-gel sieving capillary electrophoresis analysis method was used for determination of cantide and its metabolites in plasma and their pharmacokinetic parameters were calculated. The pharmacokinetic behavior of cantide and its metabolites (M1 and M2) after iv gtt administration (8, 16 and 24 mg kg(-1)) in rhesus monkeys were investigated. After iv gtt administration of cantide to rhesus monkeys, cantide in plasma was eliminated rapidly and the terminal elimination half-life (t1/2) was 57.91-77.97 min, the correlation coefficients (r) to the dose of Cmax AUC(o-inf) and AUC(0-t) of the prototype was 0.9918, 0.9568 and 0.9773, respectively. The metabolites of cantide reached the Cmax following cantide immediately and the Cmax of metabolites were lower than that of the prototype. The CL(S) of cantide and its metabolites (M1 and M2) were 1.60-2.19, 5.92-8.58 and 6.07-8.78 mL min(-1) kg(-1), respectively. So, it is concluded that the Cmax of cantide and its metabolites increased with the dose, which is the same as their AUC(0-inf) and AUC(0-t). The CL(S) of metabolites were higher than that of the prototype. The MRT and t1/2 of metabolites in the high dose group increased obviously.
Animals ; Area Under Curve ; Electrophoresis, Capillary ; methods ; Female ; Half-Life ; Infusions, Intravenous ; Macaca mulatta ; Male ; Oligonucleotides, Antisense ; blood ; metabolism ; pharmacokinetics ; Phosphorothioate Oligonucleotides ; blood ; metabolism ; pharmacokinetics ; Solid Phase Extraction

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Analysis of metabolites of daphnetin in the intestinal wall of rats by liquid chromatography and quatrupole-time of flight mass spectrometry.

Jin-jun SHAN ; Hai-shan DENG ; Hong-mei WEN ; Hao WU ; Shou-chuan WANG ; Liu-qing DI

Acta Pharmaceutica Sinica.2011;46(11):1366-1369.

In this study, daphnetin and its major metabolites in the intestinal wall of rats were identified by liquid chromatography and quatrupole-time of flight mass spectrometry. Perfusion fluid of duodenum, jejunum, ileum and colon were collected separately for 2 hours from the rat intestine following perfusion with daphnetin. The metabolites of daphnetin in the perfusion fluid of different intestine segments were analyzed by the liquid chromatography and quatrupole-time of flight mass spectrometry. It is shown that the parent drug daphnetin and four metabolites were found in the perfusion fluid of duodenum, jejunum and ileum. However, no metabolites were found in the colon. Among the four metabolites, two daphnetin sulfates (m/z 257) were first discovered as the phase II metabolites of daphnetin in rats, which revealed a new way of daphnetin metabolism in rats.
Animals ; Chromatography, High Pressure Liquid ; Colon ; metabolism ; Duodenum ; metabolism ; Ileum ; metabolism ; Intestines ; metabolism ; Jejunum ; metabolism ; Male ; Perfusion ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization ; Umbelliferones ; metabolism ; pharmacokinetics

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Metabolic pathway and metabolites of pseudolaric acid B.

Peng LIU ; Man XU ; Hong-zhu GUO ; Jiang-hao SUN ; Hui GUO ; Shi-feng SUN ; De-an GUO

Acta Pharmaceutica Sinica.2011;46(11):1361-1365.

The metabolic profile of pseudolaric acid B (PB) was investigated by using in vivo and in vitro tests. Pseudolaric acid C2 (PC2) was identified as the specific metabolite of PB in plasma, urine, bile and feces using HPLC and HPLC-ESI/MS(n) after both oral and intravenous administration to rats, and almost no prototype was detected in all kinds of samples. The metabolic behaviors of PB orally administered in rats treated with antibiotics to eliminate intestinal microflora were identical with those in untreated rats, demonstrating that the metabolism of PB is independent of intestinal microflora. PB was stable in 48 h respective incubation with artificial gastric juice and artificial intestinal juice, suggesting that neither pepsin nor trypsin is in charge of metabolism of PB, and also demonstrating that PB is stable in both pH environments of gastric tract and intestinal tract. In vitro research on metabolism of PB in rat liver microsomes incubation revealed that little PB was metabolized and that the proposed metabolites were the demethoxy and demethoxydecarboxy products of the prototype. The amount of metabolites was extremely low compared with the prototype, indicating that liver microsomes are not responsible for the metabolism of PB either. PB was gradually metabolized into PC2 during 1 h in whole blood incubation in vitro, and the metabolic process showed dynamically dependent manner with incubation time. Once absorbed into blood, PB was quickly metabolized into PC2, accordingly, little prototype was detected in all kinds of samples. The metabolism was attributed to the rapid hydrolysis of C-19 ester bond by plasma esterase. These results clarified the metabolic pathway of PB for the first time, which was of great significance to identify the in vivo active form and interpret acting mechanism of the active compounds of P. kaempferi.
Administration, Intravenous ; Administration, Oral ; Animals ; Bile ; metabolism ; Diterpenes ; blood ; metabolism ; urine ; Esterases ; metabolism ; Feces ; chemistry ; Hydrolysis ; Male ; Metabolic Networks and Pathways ; Microsomes, Liver ; metabolism ; Pinaceae ; chemistry ; Plant Bark ; chemistry ; Plants, Medicinal ; chemistry ; Rats ; Rats, Sprague-Dawley

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Polymorphism of the 5R-5-hydroxytriptolide.

Rui-li LIU ; Ya-xi YANG ; Dong-ying CHEN

Acta Pharmaceutica Sinica.2011;46(11):1357-1360.

5R-5-hydroxytriptolide (LLDT-8) is a new drug candidate which is in clinical trial treating rheumatoid arthritis. Polymorph screening of the compound was carried out in this study. Polymorph of LLDT-8 was prepared by evaporative crystallization and antisolvent crystallization methods and was characterized by powder X-ray diffraction (p-XRD), infrared spectrometry (IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TG). It was found that p-XRD patterns, DSC curves, TG curves and IR spectra of the LLDT-8 samples prepared by the above recrystallization methods were all consistent. The 20 of main peaks in the p-XRD patterns appeared at 7.58 degrees, 8.14 degrees, 8.66 degrees, 15.46 degrees, 16.46 degrees, 29.54 degrees, 31.16 degrees and 38.26 degrees, while the infrared absorption peaks appeared at 3 471.3, 2 962.2, 2 887.0, 1 762.6, 1 677.8, 1 432.9, 1 365.4, 1 247.7, 1 080.0, 1 031.7 and 877.5 cm(-1). LLDT-8 was decomposed at 271.2 degrees C based on the determination from DSC and TG. It was showed in single crystal X-ray diffraction study that LLDT-8 crystal was monoclinic with the space group being P2 (1). The cell parameters were found to be: a = 11.460 1 (11), b = 6.320 5 (6), c = 13.028 1 (12), alpha = 90.00, beta = 115.557 (2) and gamma = 90.00. The crystal was a hydrogen-bonded dimmer. The slurry experiments, which were further conducted in solvents with different polarities, confirmed the stability of solid state of LLDT-8 based on the p-XRD determination. The polymorph of LLDT-8 made assurance of its efficacy consistence during its clinical trials.
Calorimetry, Differential Scanning ; Crystallization ; Diterpenes ; chemistry ; Drug Stability ; Spectrophotometry, Infrared ; Thermogravimetry ; X-Ray Diffraction

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Determination and biosynthesis of multiple salvianolic acids in hairy roots of Salvia miltiorrhiza.

Shu-juan ZHAO ; Jin-jia ZHANG ; Li YANG ; Zheng-tao WANG ; Zhi-bi HU

Acta Pharmaceutica Sinica.2011;46(11):1352-1356.

Danshen (Salvia miltiorrhiza Bunge) hairy roots were obtained by infecting Danshen leaves with Agrobacterium rhizogenes 9402. Besides rosmarinic acid (RA) and salvianolic acid B (SAB), the hairy root could also produce salvianolic acid K (SAK), salvianolic acid L, ethyl salvianolic acid B (ESAB), methyl salvianolic acid B (MSAB), and a compound with a molecular weight of 538 (compound 538) identified by using LC-MS. Effects of methyl jasmonate (MeJA) and yeast elicitor (YE) on the accumulation of these compounds had been investigated. MeJA increased the accumulation of SAB, RA, SAK, and compound 538 from 4.21%, 2.48%, 0.29%, and 0.01% of dry weight to 7.11%, 3.38%, 0.68%, and 0.04%, respectively. YE stimulated the biosynthesis of RA from 2.83% to 5.71%, but depressed the synthesis of SAB, SAK and compound 538. It was indicated in all the results that these Danshen hairy roots could be used as alternative resources to produce salvianolic acids. Analysis of the content variation of these compounds after elicitation suggested that SAK and compound 538 might be the intermediates in the biosynthesis from RA to SAB in Danshen hairy roots.
Acetates ; pharmacology ; Alkenes ; analysis ; Benzofurans ; analysis ; Cinnamates ; analysis ; Cyclopentanes ; pharmacology ; Depsides ; analysis ; Oxylipins ; pharmacology ; Phenylpropionates ; analysis ; Plant Growth Regulators ; pharmacology ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; Polyphenols ; analysis ; biosynthesis ; Salvia miltiorrhiza ; chemistry ; Yeasts ; chemistry

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Sesquiterpenoids from the whole plant of Sarcandra glabra.

Xiong LI ; Yu-feng ZHANG ; Liu YANG ; Yi FENG ; Yi-ming LIU ; Xing ZENG

Acta Pharmaceutica Sinica.2011;46(11):1349-1351.

To study the sesquiterpenoid constituents in the whole plant of Sarcandra glabra, silical column chromatography, Sephadex LH-20, reverse phase ODS column chromatography and preparative HPLC were used to isolate 70% EtOH extract of Sarcandra glabra. The structures were elucidated based on spectroscopic data (HR-ESI-MS, 1H NMR, 13C NMR, HSQC, HMBC and NOESY). Four sesquiterpenoids were obtained and identified as 4alpha-hydroxy-5alphaH-lindan-8 (9)-en-8, 12-olide (1), chloranthalactone E (2), 8beta, 9alpha-dihydroxylindan-(5), 7 (1)-ieb-8alpha, 12-olide (3) and chloranoside A (4), respectively. Compound 1 is a new sesquiterpene lacone.
Magnoliopsida ; chemistry ; Molecular Structure ; Plants, Medicinal ; chemistry ; Sesquiterpenes ; chemistry ; isolation & purification

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Design, synthesis and activity of a new type of influenza virus N1 neuraminidase inhibitors.

Fan YANG ; Lei JIN ; Nian-yu HUANG ; Feng CHEN ; Hua-jun LUO ; Jian-feng CHEN

Acta Pharmaceutica Sinica.2011;46(11):1344-1348.

In this study, the "150-cavity", next to the H5N1 influenza virus neuraminidase activity site, has been used as the target to design and synthesize a structural analogue of chlorogenic acid, N-caffeoyl-GABA, using the flexible docking simulation. The docking study showed that the N-caffeoyl-GABA could be inserted into the "150-cavity" and combined with the Arg156 side chain by hydrogen bond. The best binding free energy of H5N1 NA-N-caffeoyl-GABA complex was -7.70 kcal mol(-1), equivalent that of the NA-oseltamivir. At the same time, using the H5N1 pseudotyping virus-based NA inhibitors screening model, we determined the inhibitory effect of oseltamivir, chlorogenic acid and N-caffeoyl-GABA on the NA. Compared with chlorogenic acid, N-caffeoyl-GABA significantly enhanced the inhibitory effect on NA, but less than oseltamivir. This study showed that the "150-cavity" could possibly be used as a new neuraminidase inhibitors target, and provided a path for the development of new neuraminidase inhibitors.
Antiviral Agents ; chemical synthesis ; pharmacology ; Caffeic Acids ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Drug Design ; Enzyme Inhibitors ; chemical synthesis ; pharmacology ; HEK293 Cells ; Humans ; Influenza A Virus, H5N1 Subtype ; enzymology ; Neuraminidase ; antagonists & inhibitors ; metabolism ; gamma-Aminobutyric Acid ; analogs & derivatives ; chemical synthesis ; pharmacology

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Synthesis and biological evaluation of 3-aromatic Shiff base-5-fluoroindol-2-one derivatives.

Zheng FANG ; Zhao YANG ; Jia-feng XU ; Yong-lu WANG ; Zhi-xiang WANG ; Ping WEI

Acta Pharmaceutica Sinica.2011;46(11):1338-1343.

Based on the structure of 5-fluoroindol-2-one and fragments from thirteen multi-target tyrosine kinase inhibitors which have been marketed or in the phase of clinical research, eleven 3-aromatic Shiff base-5-fluoroindol-2-one derivatives were designed and synthesized. Their structures were identified by 1H NMR, MS and elemental analysis. In vitro antitumor bioactivities evaluation was done by MTT method. It was shown that most of synthesized compounds had antitumor activities and compounds 1b, 1g, 1i and 1h were better than or equal to the antitumor activity of positive control.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Screening Assays, Antitumor ; Humans ; Indoles ; chemical synthesis ; chemistry ; pharmacology

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