Journal of Chinese Pharmaceutical Sciences

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2006, 15(3): 1-01.

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Tissue Penetration of Capecitabine and Its Tumor-Selective Delivery of 5-FU in Advanced Breast Cancer Patients

YE Min^*, ZHU Zhu, FU Qiang, SUN Qiang, MAO Feng

2006, 15(3): 131-138.

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Aim To measure the penetration of capecitabine from the plasma into tissue and to investigate the pharmacokinetics of its metabolizing into fluorouracil (5-FU) in patients with advanced breast cancer. Methods Twenty-seven patients with breast cancer received repeated doses of 1255 mg·m^-2 of capecitabine twice daily for 7 d. Blood, tumor, and adjacent healthy tissue samples were collected. The concentrations of capecitabine and its metabolite 5-FU were determined by HPLC. The concentration-time profiles of capecitabine and 5-FU were fitted by pharmacokinetic model. The tissue distribution factors for capecitabine and 5-FU, and the AUC ratios of 5-FU to capecitabine in plasma, tumor or adjacent healthy tissue, were calculated with pharmacokinetic parameters, respectively. Results The Ka of capecitabine was 1.17 h^-1 in plasma, 0.46 h^-1 in tumor tissue, and 0.61 h^-1 in healthy tissue. The AUCs of capecitabine were 2.5571 μg·mL^-1·h, 1.6292 μg·g^-1·h and 2.0850 μg·g^-1·h, and T_1/2 was 0.7823 h, 1.5281 h and 1.2896 h in plasma, tumor, and healthy tissue, respectively. The AUCs of 5-FU were 0.4187 μg·mL^-1·h, 1.6717 μg·g^-1 ·h and 1.0208 μg·g^-1 ·h; the T_1/2 was 0.6313 h , 1.2041 h and 1.0312 h in plasma, tumor, and healthy tissue, respectively. The tissue distribution factors of capecitabine were 0.6371 in tumor (AUC_cap-Tumor/AUC_cap-plasma) and 0.8514 in healthy tissue (AUC_cap-HT/AUC_cap-plasma). The tissue distribution factors of 5-FU were 3.992 6 in tumor (AUC_5-FU-tumor/AUC_5-FU-plasma) and 2.4380 in healthy tissue (AUC_5-FU-HT/AUC_5-FU-plasma). The AUC ratios of 5-FU to capecitabine were 0.1637, 1.0261, and 0.4895 in plasma, tumor, and healthy tissue, respectively. Conclusion The simulation curves for the disposition of capecitabine and its metabolite 5-FU in plasma and tissue basically describe the activation process of capecitabine metabolizing to 5-FU and 5-FU elimination. There are similar distributions for capecitabine in plasma, tumor, and healthy tissue. The exposure of 5-FU in tumor was found to be 3.992 6 times greater than that in plasma and 2.438 0 times greater than that in healthy tissue. Capecitabine may metabolize preferentially to 5-FU in tumor tissue after oral administration.

Effect of Liposome Double-Coated with Chitosan and Chitosan-EDTA Conjugates on Oral Absorption of Insulin

WU Zheng-hong, PING Qi-neng^*, LI Jian-ying, Cai Peng

2006, 15(3): 139-146.

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Aim To evaluate the gastrointestinal uptake of the insulin liposomes double-coated with chitosan (Ch) and chitosan-EDTA conjugates (CEC), and verify their efficiencies. Methods Insulin-liposomes were prepared by reversed-phase evaporation. The hypoglycemic effects of the insulin liposomes coated with Ch or/and CEC were investigated using the glucose oxidase method after oral administration in diabetic rats, normal rats, and beagle dogs. Serum insulin concentrations in beagle dogs were determined by radioimmunoassay and were assessed by Pkanalyst computer program. Results The animals fed the insulin liposomes coated with Ch or/and CEC were able to regulate better the glucose load than the animals receiving PBS or uncoated insulin liposome, and the regulative effects of the insulin liposomes double-coated with Ch and CEC were better than those of the insulin liposomes coated with Ch or CEC alone. After oral administration of the insulin-liposomes double-coated with Ch and CEC to animals, a significant (P<0.05) blood glucose reduction was observed. Their relative pharmacological bioavailability was higherthan 9 % in comparison with subcutaneous injection of insulin. In addition, incomparison with subcutaneous injection of insulin, the relative bioavailability was 12.67 % calculated by area under the curve of serum insulin concentration versustime profile after oral administration of the insulin-liposomes double-coated with Ch and CEC to beagle dogs. Conclusion The insulin-liposomes double-coated with Ch and CEC were conducive toimproving oral bioavailability of insulin.

Development of a New Azithromycin Glutamate for Parenteral Preparation, the Toxicity in Sprague-Dawley Rats and Pharmacokinetics in Human Healthy Volunteers

HE Qi-ying, LU Wan-liang^*, ZHANG Qiang^*^*

2006, 15(3): 147-154.

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Aim In order to improve the solubility of azithromycin, the objectives of the present study were to screen an appropriate salt for azithromycin by comparing acute hepatic and renal toxicities in animals, and study the pharmacokinetics of final chosen azithromycin salt. Methods Various salts of azithromycin, such as glutamate, citrate, hydrochloride, sulphate, dihydrogen phosphate, lactobionate, tartrate, and aspartate were given intravenously to Sprague Dawley rats at a dose of 10 mg once daily for 14 consecutive days via tail vein. The acute hepatic and renal indicators were measured before and after administration. A pharmacokinetic study was performed on 12 healthy human volunteers. The subjects were equally divided into two groups by a randomized crossover design. Azithromycin glutamate injection was administered by intravenous infusion or intramuscular injection at a single dose of 500 mg, respectively. Azithromycin concentrations in plasma were determined by microbial inhibition zone assay, and the pharmacokinetic parameters were calculated using a practical pharmacokinetic software 3P87 program. Results Azithromycin glutamate was least toxic to the liver and kidney of the rats, thus being selected as a final salt for parenteral preparation of azithromycin. Pharmacokinetic results showed that the area under the plasma concentration-time curves (AUC_{0-120 h}) were 21.47 ± 1.57 h·μg·mL^-1 for intravenous infusion, and 19.36 ± 2.44 h·μg·mL^-1 for intramuscular injection. The absolute bioavailability of intramuscular injection was 92.59%. Conclusion Azithromycin glutamate is suitable for the future clinical application, and its pharmacokinetics is characterized in human volunteers in the present study.

Development of Prolonged Release Microspheres of Metformin Hydrochloride Using Ion Exchange Resins

LIU Hong-fei, SU Xian-ying, LI Xiang, ZHAO Xin, ZANG Lei, PAN Wei-san^*

2006, 15(3): 155-161.

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Aim To prepare the prolonged-released microspheres of metformin hydrochloride. Methods Ion-exchange resin-drug metformin hydrochloride complexes were prepared as core materials, and followed by coating using ethylcellulose (EC) by the emulsion solvent diffusion technique. The release rate of metformin from the microcapsules was highly dependent on the encapsulating formulation, thus being used as an index for formulation screening. Orthogonal experiments were performed to optimize the coating formulation. Results The final chosen formulation for coating of metformin microcapsules were as follows: (1) the ratio of EC (20cps) to EC (45cps) was 50:50; (2) the ratio of plasticizer to coating materials was 20%; and (3) the ratio of resin-metformin complexes to coating materials was 5:1. Conclusion The prolonged release microspheres of metformin hydrochloride were successfully prepared.

Bioequivalent Evaluation of Two Brands of Losartan/Hydrochlorothiazide Compound Tablets in Healthy Chinese Male Volunteers

YANG Ping, LI Lin, SUN Jin, HE Zhong-gui^*

2006, 15(3): 162-167.

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Aim To evaluate the bioequivalence of two brands of losartan/hydrochlorothiazide (50 mg/12.5 mg) compound tablets in healthy Chinese male volunteers. Methods An open, randomized, single-dose, two-period cross-over studywith a wash-out period of 7 d was conducted. Twenty healthy male volunteers were givena single dose 50 mg losartan/12.5 mg hydrochlorothiazide of either test (T) or reference (R) compound tablets,respectively. Blood samples were collected up to 48 h after oral administration. The concentrations of losartan and hydrochlorothiazide in plasma were determined by a validated HPLC-ESI-MS method. Results In the case of losartan, the 90% confidence intervals of two one-side test for percent ratios with a significant level (α) of 0.05 were 86% – 112% for AUC_0-120 and 89% – 134% for C_max, respectively, which were within the interval proposed in the Chinese Pharmacopoeia, 80% – 125% of AUC and 70% – 143% of C_max, respectively. Similarly, the 90% confidence intervals for percent ratios were 85% – 100% and 75% – 102% for hydrochlorothiazide, both of which fell into the accepted interval. Conclusion Two immediate-release compound tablets of losartan/hydrochlorothiazideare bioequivalent from a statistical standpoint in the extent and rate of absorption from the single-dose study in healthy Chinese male volunteers.

Determination of Griffonilide in Roots of Semiaquilegia adoxoides by RP-HPLC

NIU Feng, XIE Guang-bo, CUI Zheng, CHEN Fa-kui, TU Peng-fei^*

2006, 15(3): 168-171.

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Aim To establish the method for determination of benzofuranones derivative, griffon-ilide, in the roots of Semiaquilegia adoxoides (DC.) Makino by RP- HPLC. Methods Kromasil C₁₈column was used with a mobile phase of methanol-water (containing 0.01% trifluoroacetic acid and 0.05% tetrahydrofuran) (3:97). The detecting wavelength was 260 nm. Results The calibration curve was linear over the range of 0.004 – 0.4 mg·mL^-1 with the correlation coefficient of 1.00 000. The average recovery was 98.77% with RSD 2.77%. Determinations of ten samples from different areas showed that the contents of griffonilide in the roots of S.adoxoides are 0.17 – 0.49 mg·g^-1. Conclusion The method provides an accurate and sensitive way to detect griffonilide in the roots of S.adoxoides.

GC-MS Analysis of Essential Oil Constituents from Rhizome and Root of Notopterygium incisum

YANG Xiu-wei^*, ZHANG Peng, TAO Hai-yan, JIANG Shun-yuan, ZHOU Yi

2006, 15(3): 172-177.

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Aim To analyse the chemical constituents of the essential oil extracted from the rhizome and root of Notopterygium incisum Ting ex H.T. Chang,providingscientific basis for quality control. Methods The total essential oil was extracted by water-steam distillation and separated by capillary gas chromatography (GC). The components were determined bynormalization method, and identified by GC-MS. Results GC-MS exhibited 242 peaks and 83 compounds were identified, accounting for 75.77% of the total essential oil. Conclusion In the total essential oil of the rhizome and root of N. incisum, monoterpenes and sesquiterpenes accountedfor 13.63% and 67.93%, respectively, in which (1S)-β-pinene (1.67%), 3-carene (1.05%), limonene (1.22%), and 1S-endo-bornyl acetate (1.68%) as the monoterpenes and its derivatives, and (+)-β-elemene(6.78%), sativene(1.54%), α-caryophyllene (2.64%), germacrene D (1.67%), eudesma-4 (14),11-diene(2.36%), α-selinene(2.42%), δ-cadinene(1.55%), 3,7,11-trimethyl-2,6,10-dodecatrien-1-ol (1.03%), (±)-elemol (5.18%), (-)-spathulenol (1.40%), guaiol (3.81%), dehydroxy-isocalamendiol (1.06%), γ-eudesmol (1.05%), α-eudesmol (7.97%), bulnesol (3.09%),and carotol (2.30%) as the sesquiterpenes and its derivatives were main components. In addition, isopropyl trans-cinnamatewas the maximum compound (11.3%) of the total essential oil.

Flavonoids from Millettia nitita var. hirsutissima

FENG Jie, LIANG Hong^*, ZHAO Yu-ying, WU Zeng-bao

2006, 15(3): 178-181.

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Aim To investigate the chemical constituents of Millettia nitita var. hirsutissima. Methods The constituents were isolated and purified by chromatographic techniques, and the structures were identified by spectral evidences. Results Four flavonoids were isolated from the plant, including liquiritigenin (1), naringenin (2), maackiain (3), and 3R-vestitol (4). Conclusion Compounds 1 and 2 were obtained from the genus Millettia for the first time; 3 and 4 were obtained from the plant for the first time.

Effect of Berberine Chloride on Experimental Murine Colitis Induced by Dextran Sulfate Sodium

SHU De-zhong, WAN Xian-hui, LIU Hua-rong, YANG Jun-qing, ZHOU Qi-xin^*

2006, 15(3): 182-187.

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Aim To investigate the effect in berberine chloride (BER) on experimental ulcerative colitis in mice. Methods BALB/C mice in 6 groups were allowed to drink either 4% dextran sulfate sodium (DSS) solution or distilled water freely with different doses of BER (15 mg·kg^-1, 45 mg·kg^-1, 150 mg·kg^-1) or salicylazosulfapyridine (SASP, 520 mg·kg^-1), and solvent (0.2 mL/10 mg Wt) once a day for 7 d, respectively. The symptom of ulcerative colitis was evaluated by disease activity index (DAI). Myeloperoxidase (MPO) and superoxide dismutase (SOD) activities and malondialdehyde (MDA) content were determined by HE staining and immunohistochemistry of expressions of NF-κB p65 and intercellular adhesion molecule 1(ICAM-1) proteins to observe the damage to colon tissues and possible mechanisms. Results DAI, MPO activity, MDA content and expressions of ICAM-1 and NF-κB p65 were markedly increased, while SOD activity decreased in DSS-treated mice. Treatment of mice with different doses of BER or SASP significantly decreased DAI, MPO activity and MDA content, improved histological changes of colon tissues, blunted the expressions of NF-κB p65 and ICAM-1 proteins, and enhanced SOD activity. Conclusion Berberine chloride has excellent therapeutic effect on ulcerative colitis caused by DSS in mice. The possible mechanism may be related to its antioxidant and anti-inflammatory activities associated with inhibiting the NF-κB activation and ICAM-1 expression.

Protective Effects of Oral Fructose-1, 6-diphosphate on Liver Injury in Animal Models

LIUXiao-yan, LI Feng-yun , CHI Zhi-hong, WANG Yin-ye^*

2006, 15(3): 188-193.

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Aim To investigate the effects of FDP on different liver injury models to explore the possibility of FDP used as an oral liver protective agent. Methods Chronic liver injury model in ratswas induced by carbon tetrachloride (CCl4); Acuteliver injury model in micewas induced by aminogalactose (GaIN) or lipopolysaccharide (LPS). Results In CCl4 -induced chronic liver injury model, FDP (1 – 4 g·kg^-1·d^-1, q.d., for 10 weeks) significantly lowered ALT, AST, γ-glutamyl transpeptidase(γ-GT), alkaline phosphatase (ALP), and total bilirubin (T-BIL)in serum compared with vehicle; simultaneously it evidently elevated abnormal total protein (TP), albumin (ALB) and total cholesterol ( T-CHO ) levels in serum; italso dose-dependently reduced hydroxyproline contentsin hepatic tissue. 4 g·kg^-1·d^-1 of FDP apparently decreased incidence of hepatic cirrhosis,and alleviated pathological changes of liver tissue. In GaIN-induced model, 1.0 – 4.0 g·kg^-1·d^-1 of FDP (bid, for 3 d) significantly lowered alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) levels in serum; it also decreased liver coefficient.4.0 g·kg^-1·d^-1 of FDPsignificantly alleviated pathological changes of cell ultra-structures. In LPS-induced model, only high dose of FDP(4.0 g·kg^-1·d^-1, bid, for 12 d) significantly decreased ALT level in serum. Conclusion This study first demonstrated the protective effectof oral FDP on chronic liver injury caused by CCl4 , and confirmed its effect on acute liver injury at the same time, suggesting thatLong-term oral FDPis efficacious against liver injuryinduced by different factorsand can be used as an oral liver protective agent in clinic.

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