Table of Content

Volume 13 Issue 12
26 December 2008

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Premarketing clinical safety assessment for drugs intended for longterm treatment

YANG Huan

2008, 13(12):  1321-1324. 

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With the increasing demand for drugs intended for broad, long-term treatment of non-life threatening diseases, safety is of special concern in the research and development of new drugs in these areas. This article raise the main points to consider for clinical safety evaluation in referring to the relevant ICH and FDA pre-market risk assessment guidelines.

Establishment of diabetic obese rat model and the therapeutic effects of sibutramine on it

CUI Ming-xia, WANG Lei, ZHANG Bao-lai, LU Li, WANG Li, ZHENG Rong-liang, WUYong-jie

2008, 13(12):  1325-1329. 

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AIM: To study the characteristics of diabetic obese rats induced by streptozotocin (STZ) combined with hyperalimentation animal feeds and the therapeutic effect of sibutramine on diabetes obese rats.METHODS: Rats were intravenously injected with low dose (25 mg/kg) of STZ and fed with hyperalimentation animal feeds for 4 months to establish diabetic obese rat model.The diabetic obese rats were treated with sibutramine 4 mg/kg for 17 days and the body weight and food intake daily were measured.The glucose tolerance was measured at the 15th day.At the end of the treatment, the body weight, abdominal viscera fat and right soleus muscle, the levels of blood lipid, blood sugar, insulinum demeshed in serum were measured and the insulin resistance index (FIRI) were calculated.RESULTS: The body weight, abdominal viscera fat weight and the coefficient in model rats increased significantly, but thelinea obliqua tibiae coefficient decreased significantly.The blood-fasting glocose, insulin level increased significantly, and the carbohydrate tolerance abnormality and insulin resistance occurred.The serum triglyceride (TG) level increased and the high-density lipoprotein cholesterol (HDL-C) decreased significantly.Sibutramine reduced the body weight, visceral fat mass and coefficient, ameliorated hyperinsulinemia and insulin resistant, and decreased the serum TG level and increased HDL-C level as well. But it had not obviously affected the soleus muscle coefficient, blood glucose, cholesterol and LDL-C level, and carbohydrate tolerance.CONCLUSION: The diabetic obese rat model could be induced by STZ and hyperalimentation animal feeds and sibutramine has therapeutic effect on obese diabetes rats.

Simultaneous determination of quercetin, kaempferol and isorhamnetin in dog plasma by HPLC-MS/MS

HUANG Min-wen, WANG Guang-ji, LI Hao, SUN Jian-guo

2008, 13(12):  1330-1338. 

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AIM: A rapid, sensitive and highly selective liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of quercetin, kaempferol and isorhamnetin in dog plasma.METHODS: Quercetin, kaempferol and isorhamnetin conjugates were hydrolysed chemically.The analytes were extracted from plasma samples by liquid-liquid extraction, separated on a Luna ODS-2 column (150 mm ×2.1 mm I.D., 5 μm particle size), and detected by tandem mass spectrometry with a Finnigan IonSpray ionization interface. The mobile phase consisted of 0.1 % aqueous formic acid (A)and gradient-grade acetonitrile (B).RESULTS: The calibration curves for quercetin, kaempferol and isorhamnetin were linear in concentration ranges of 0.5-100.0 ng/mL in dog plasma.The method has a lower limit of quantification (LLOQ)of 0.5 ng/mL for all the three flavonols.The intra-and inter-day precisions, expressed as the R.S.D., were less than 7.3 %, 6.2 % and 6.4 % for quercetin, kaempferol and isorhamnetin, respectively, and the recovery was more than 70 %, 66 %and 70 %, respectively.The application of this assay was examined in a preliminary pharmacokinetic study of quercetin, kaempferol and isorhamnetin in beagle dogs after oral administration of 6 Ginkgo biloba tablets.CONCLUSION: The present method was suitable for determining quetcetin, kaempferol and isorhamnetin in dog plasma.

Effects of strontium fructose 1, 6-diphosphate (FDP-Sr) on didymus lesion and the mRNA expressions of prepro ET-1(PPET-1) and endothelin converting enzyme(ECE) in diabetic rats

ZHANG Qi, TANG Xiao-yun, DAI De-Zai, YING Han-jie, DAI Yin

2008, 13(12):  1339-1343. 

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AIM: To determine the benefits of FDP-Sr on streptozotocin (STZ) induced diabetic testopathy in rats, compared with testosterone propionate, and explore its likely mechanisms.METHODS: Male SD rats were given streptozotocin to induce strontium fructose 1, 6-diphosphate (EDP-sr) diabetes for 8 weeks and in the second 4 weeks rats were treated with FDP-Sr (50, 100, 200 mg/kg, i.g.) and testosterone propionate(4 mg/kg, s.c.).GSH-px, mRNA expression of perpro ET-1 (ppET-1), endothelin coverting enzyme(ECE) in testicular tissues, morphological changes and blood testosterone were investigated.RESULTS: Seminiferous tubules in diabetic rats were significantly atrophied relative to the normal.The expressions of ppET-1 and ECE were upregulated significantly in association with decreased serum testosterone and decreased GSH-px significantly.FDP-Sr attenuated these alterations significantly, but testosterone propionate was less effective.CONCLUSION: FDP-Sr relieves diabetes induced male hypogonadism in rats in superior to that of testosterone propionate.It is likely to be related by suppressing over-active endothelin system in the testis.

Effects of probenecid on intestinal absorption of cefaclor in rats

ZHANG Xiu-hong, MA Zhang-qing, GUI Chang-qing, SONG Jian-guo

2008, 13(12):  1344-1349. 

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AIM: To investigate the effect of probenecid on intestinal absorption of cefaclor and possible mechanisms involved.METHODS: Pharmacokinetic experiments:cefaclor (100 mg/kg, i.v.) was given alone or in the presence of probenecid (300, 600 and 900 mg/kg, i.g.) to rats.Plasma concentrations of cefaclor were determined by HPLC and the corresponding parameters were calculated with DAS software.Intestinal absorption experiment:cefaclor (30μg/mL) was co-administered with different dosages of probenecid (0, 90, 180 and 270μg/mL) using an in vivo perfusion technique in rats.The effect of probenecid on intestinal absorption of cefaclor was investigated by the way of perfusion in the intestine from proximal 2 cm duodenum distal to 10 cm from ligament of Treitz.RESULTS: The plasma cefaclor concentration-time curves after i.v.administration were fitted to a two-compartment open model.Within the range of experimental dosages, the plasma concentrations of cefaclor increased in a dose-proportional manner with probenecid dosage increasing.AUC of cefaclor was positively correlated with probenecid dosage(r=0.997).In contrast, Cl, Vd and V1 of cefaclor were negatively correlated with probenecid dosage(r=-0.837,-0.817 and-0.888, respectively).Meanwhile, the mean residual percentage of cefaclor in perfusate increased dramatically only when probenecid dosage increased to 270μg/mL.CONCLUSION: Proper dosage of probenecid co-administration may result in a decrease in Vd and Cl of cefaclor and an increase in plasma cefaclor concentration. While high dosage of probenecid may decrease the cefaclor plasma concentration.The mechanism underlying may be related to the hindrance effect on cefaclor intestinal absorption with high dosage of pobenecid co-administration, mechanism in detail remains to be clarified.

Therapeutic effects of shark hepatic regenerative factor on chronic liver injury in rats

LI Qian, DOU Chang-gui, JIANG Jie, HUANG Fang, WU Wu-tong

2008, 13(12):  1350-1354. 

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AIM: The purpose of this study was to evaluate the therapeutic effects of shark hepatic regenerative factor (sHRF) on chronic liver injury in rats.METHODS: Chronic hepatic injury model in rats was induced by Carbon tetrachloride (CCl₄).The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the content of albumin and total protein in the serum and Hydroxyproline in the liver were measured.RESULTS: Statistics indicated that chronic liver-injured rats with administration for 8 weeks, sHRF could suppress the elevation of ALT, AST in serum andHydroxyproline in liver of liver injury rats induced by CCl₄.There were no significant differences at the dosage of 0.8, 1.6 mg/kg.Moreover, sHRF could increase albumin level and the ratio of albumin and globulin in serum.Hepatic histological findings indicated that sHRF could alleviate liver fibrosis and liver steatosis.CONCLUSION: sHRF had therapeutic effect on chronic liver injury in rats induced by Carbon tetrachloride.

Effects of Shenmai injection on the expression of Fas/FasL mRNA in pulmonary injury induced by ischemia-reperfusion in rabbits

WANG Jun, LIN Li-na, WANG Wan-tie, JIN Li-da, QIU Xiao-xiao, DAI Yong-yue, WANG Qin

2008, 13(12):  1355-1359. 

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AIM: To investigate the effects of Shenmai injection (SM) on the expression of Fas/FasL mRNA during pulmonary ischemia and reperfusion injury (PIRI) in rabbits.METHODS: Lung ischemia and reperfusion animal orthotopic model was established in vivo.The rabbits were randomly divided into three groups:sham operated group (sham, n=10), ischemia-reperfusion group (I-R, n=10) and I-R +Shenmai injection group (SM, n=10).The changes in several parameters, which included Fas/FasL mRNA locating expression, apoptotic index (AI), wet to dry ratio of lung tissueweight(W D) and index of quantitative assessment of histologic lung injury(IQA), and the histomorphology under light and electron microscope, were evaluated at 3 h after reperfusion in lung tissue.RESULTS: Compared with I-R group, the Fas/FasL mRNA slightly expressed in intima and extima of small pulmonary artery, pulmonary vein, and alveolar epithelium, bronchiole epithelia in SM group.The values of AI, W D and IQA were significantly lower than those in I-R group at 3 h after reperfusion in lung tissue (P <0.01 and P <0.05), and the changes of lung tissue in histomorphology were less markedly in SM group.CONCLUSION: Shenmai injection has notable protective effects on PIRI in rabbits, which may related with inhibition on Fas/FasL mRNA expression in lung tissue and decreasing apoptosis.

Effects of paroxetine on the spontaneous behavior and the c-fos expression of hypothalamus paraventricular nucleus in poststroke depression rats

NI Gui-hua, SHAO Bei, FAN Hong, HUANG Huan-jie

2008, 13(12):  1360-1364. 

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AIM: To explore the molecular action mechanism of antidepression drug on the poststroke depression (PSD) rats.METHODS: The PSD rat model of focal cerebral ischemia was established by threadtightening middle cerebral artery, followed with restraint stress and isolated breeding.The changes on rats's spontaneous behavior and the expression of c-fos in hypothalamus paraventricular nucleus (PVN), and the effects of paroxetine hydrochloride interference in the PSD rat model were evaluated.RESULTS: Compared with the control group, the consumption of sucrose water, the scores of upright and horizonal activities in the Open-Field test of PSD rats were decreased in significant differences(P <0.01).Compared with the PSD rats, the consumption of sucrose water, the scores of upright and horizonal activities in the drug treatment group increased in significant differences(P <0.01).Compared with the depression group or stroke group, the expressions of c-fos in PVN increased in PSD rats in significant differences (P <0.05).The expression of c-fos in PVN decreased in the drug treatment group, compared with the PSD group, in significant difference.CONCLUSION: The paroxetine could improve the PSD rats depression behavior, which may related with the c-fos decrease expression in the PVN.

Inhibitive and toxic effects of artesunate on murine bone marrow hematopoietic stem and progenitor cells

LI Tian-xing, YAO Lang

2008, 13(12):  1365-1369. 

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AIM: To observe the influences of artesunate (AS) on murine bone marrow hematopoietic stem and progenitor cells.METHODS: Murine bone marrow hematopoietic stem and progenitor cells were cultured in vitro with different concentration of AS. The numbers of erythrocyte colony-forming unit(CFUE) or burst-forming unit (BFU-E) in liquid or semisolid culture were counted through light microscope.Apoptosis of cultured cells and the changes of mitochondrial membrane potential were detected by flow cytometry (FCM) analysis, meanwhile, DNA ladder gel electrophoresis were conducted.RESULTS: AS could significantly inhibit the formation of CFU-E and BFU-E (P <0.05), and the inhibition effect showed a dose-dependent manner.The result showed that AS could significantly induce cell apoptosis at the concentration ranges from 0.01 mmol/L to 1.30 mmol/L by DNA fragmentation gel electrophoresis assay, and the advanced stage death rate by FCM analysis had statistical significance (P <0.05).There was a positive correlation between AS dose and the decrease of mitochondria membrane potential (r=0.546, P=0.018).CONCLUSION: AS can significantly inhibit the proliferation and differentiation of murine bone marrow hematopoietic stem and progenitor cells.AS can induce apoptosis at low dose and cause cell necrosis at high dose.

Experimental study of koali vine polysaccharides on reducing blood lipids

LI Qin, LU Hong, CHEN Ai-jun, ZHANG Xin-yue

2008, 13(12):  1370-1374. 

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AIM: To observe the effects of koali vine polysaccharides(STDT) on reducing blood lipids in hyperlipidemic animal model.METHODS: The hyperlipidemic animal model of SD rats, New Zealand rabbits and ICR mice were induced by feeding high cholesterol food and injecting intraperitoneally egg yolk, and then were administered intragastrically with different doses of STDT.The levels of TC, TG, highdensity lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) in serum were measured at different time before and after administration.RESULTS: STDT could restrain the increase of TC, TG and LDL-C in high-lipidmodel rats serum after oral administration for fourweeks at the dosages of 250, 500 and 1000 mg/kg, and degrade the blood fat level of high-lipid model, decrease the levels of TC, TG and LDL-C in rabbits serum obviously at the dosages of 100, 200 and 400 mg/kg.In addition, the high-lipid ICR mice which were administered with STDT for three days showed a decreasing tendency on blood lipids at the dosages of 400, 800, 1600 mg/kg.CONCLUSION: The results suggest that STDT has a reducing blood lipids effects on many high-lipid animal models for prevention or treatment.

Effect of estrogen on the monoamine neurotransmitter in the serum of rats with post-stroke depression

WANG Hong, SHAO Bei, Kevin O` Byrne, LI Xiao-feng, LIN Yuan-shao, YANG Jian-rong, WANG Zhi-qiang, FAN Hong

2008, 13(12):  1375-1380. 

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AIM: To study the effect of estrogen on the monoamine neurotransmitter in the serum of rats with post-stroke depression(PSD).METHODS: The female Sprague Dawley rats weighted 220-230 g were randomly divided into control group, stroke group, PSD group, antidepressant treatment group and estrogen treatment group according to the scores of Open-Field test.Rats in all groups were performed ovariectomy first.Rats in control group were feed commonly. Seven days later, rats in the stroke group, PSD group, drug treatment group and estrogen treatment group were all duplicated into focal ischemia by means of middle cerebral artery occlusion, then the rats in PSD group, drug treatment group and estrogen treatment group received isolated feed and restraint stress to duplicate PSD model.Rats in drug treatment group were received Paroxetine and in rats estrogen treatment group were received the E2-containing capsule that were embed in subcutaneous by operation.The E2-containing capsules produced circulating concentrations of E2 within the range observed during the diestrous phase of the estrous cycle.After that, the behavioral evaluations were done with Open-Field test, these rats were sacrificed and their blood were taken.The mononeurotransmitters included NE and 5-HT in serum were detected by HPLCECD.RESULTS: The spontaneous behavior and the concentration of NE and 5-HT in serum of the PSD rats decreased significantly in comparison with those in control group(P <0.05), the spontaneous behavior and the concentration of NE and 5-HT in serum of the rats in estrogen treatment group increased significantly in comparison with those in PSD group(P <0.05), the spontaneous behavior and the concentration of 5-HT in serum of the rats in estrogen treatment group increased significantly as those in drug treatment group (P > 0.05), the concentration of NE in estrogen treatment group increased non-significantly in comparison with that in drug treatment group(P <0.05).CONCLUSION: The spontaneous behavior could be improved and the 5-HT was increased by estrogen in PSD rats. That may protect the brain of PSD rats.

Effects of ganoderma liciudm ploysaccharide seleno-κ-carageenan syrup on immune function of immunosuppression mice

ZHANG Lian-long, DAI Min, MAO Zhao-xiang, WU Xin, ZHANG Chun-dong, ZHOU Dian-yun

2008, 13(12):  1381-1387. 

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AIM: To investigate the effects of ganoderma liciudm ploysaccharide (GLP) seleno-κ-carageenan syrups on nonspecific immunity, humoral immunity, cell immunity function of immune suppressed mice induced by cyclophosphamide.METHODS: Immunity hypofunction mouse models were established by intraperitoneal injection of cyclophosphamide (80 mg/kg, o.d.) for 3 days, and ganoderma liciudm ploysaccharide seleno-κ-carageenan syrups were administrated by gastric gavage for 30 days, once a day.The mononuclear phagocyte englobement function, the phagocytosis function(chicken erythrocyte) of abdominal cavity phagocyte, the number of peripheral blood leucocyte, NK cytoactive, interleukin-1 and interleukin-2 activity, TNF-αactivity, serum hemolysin, antibodyproducing cells, increment abilities of T, B lymphocyte delayed allergy were detected.RESULTS: The number of leukocytes, serum hemolysin increased in all 3 groups of ganoderma liciudm ploysaccharide seleno-κ-carageenan syrups(lower dose group:GLP 2.5 mg/kg +Se 5μg kg, medium dose group:GLP 5 mg/kg +Se 10μg kg, high dose group:GLP 15 mg/kg +Se 30μg kg).The activities of IL^-1 in lower dose group, and IL-2 in medium dose group increased.The reproductive activities of T, B lymphocytic cells, NK cytoactive, activity of TNF-αincreased in high group as well as the englobement function of peritoneal macrophage, the carbon particle clearance, antibody-producing cells, delayed allergy.The reproductive activities of T, B lymphocytic cells, NK cytoactive, activity of TNF-αincreased in medium group.CONCLUSION: Ganoderma Liciudm Ploysaccharide seleno-κ-carageenan syrups could improve the immunological function of immunosuppression mice.

Study on immunogenicity of recombinant glucagons-like peptide-1(7-36)

DENG Li-juan, LIN Fei, LIU Li-hua

2008, 13(12):  1388-1391. 

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AIM: To assess the immunogenicity of recombinant glucagons-like peptide-1 (rhGLP-1) (7-36) in Beagle dogs.METHODS: The control group and different doses rhGLP-1(7-36) group dogs were respectively administered with a subcutaneous injection of NS, 200, 100 and 50μg kg of rhGLP-1(7-36) six times weekly for 9 months.Each group had 3 male and 3 female dogs.The antibodies in serum of dog were detected by enzyme linked immunosorbent assay (ELISA) and alkaline phosphatase immunospot assay.RESULTS: The antibodies for the rhGLP-1(7-36) were not detected in all dogs in 3 months and 9 months after dosing of the rhGLP-1(7-36) and in the 1 months after the last dosing.CONCLUSION: rh-GLP-1(7-36) has no immunogenicity on Beagle dogs in the long-term run.

Research of anti-artery thrombosis mechanism of action and the effect of Xinshi injection on hemorheology in rats

XU Peng-fu, KAN Hong-wei, HUANG Shi-fu, YANG Shi-you, CHEN Han

2008, 13(12):  1392-1395. 

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AIM: To study the anti-artery thrombosis mechanism of action and the effect of Xinshi injection on hemorheological in rats.METHODS: The thrombosis model in mice induced by collagen-adrenalin and the blood stasis model in rats induced by icebath were established, then the impacts of Xinshi injection on thrombogenesis in vivo and in vitro, platelet adhesion rate and hemorheology changes were observed.RESULTS: Each dose of Xinshi injection could obviously reduce the thrombosis of mice in vivo and the platelet adhesion rate of rats.It also improved hemorheology of acute blood stasis rats, inhibited thrombosis of model rats.CONCLUSION: Xinshi injection has significant effects on anti-artery thrombosis and hemorheology of acute blood stasis rats.

Inhibitory action of momordica on non-small cell lung cancer A₅₄₉ cells and its effects on MAPK signaling pathway

HAN Yi-xiang, Xing-rong, ZHANG Sheng-hui, WU Jian-bo, LIU Xin-Hua, XIONG Shudao

2008, 13(12):  1396-1400. 

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AIM: To observe the inhibitory action and apoptotic activity of momordin to nonsmall-cell lung cancer A₅₄₉ cells and explore its effects on the expression of p42/44-MAPK and phosphorylation pp42/44-MAPK and its mechanisms of action.METHODS: A₅₄₉ cells were treated with different concentration gradient of momordinand and incubated for different time, then the cytostatic activity and apoptosis to A₅₄₉ cells were detected by CCK-8 kit and flow cytometry, respectively.The bitter melon protein were extracted for different time and the changes of signaling molecules such as p42/44-MAPK and p-p42/44-MAPK were detected by western blot.RESULTS: CCK-8 test indicated that momordin had a strong cytostatic activity to A₅₄₉ cells.TUNEL fluorescent assay indicated that momordin could markedly induce A₅₄₉ cells apoptosis. Western blot assay showed that the expression of p42/44-MAPK and p-p42/44-MAPK were partially down regulated compared with the negative control group (P <0.05).CONCLUSION: Momordin has a strong cytostatic and anti-tumor activity to non-small-cell lung cancer A₅₄₉ cells through inducing A₅₄₉ cells apoptosis.Its partial mechanisms maybe involve in inhibiting the MAPK signal pathway such as down-regulating the expression of p42/44-MAPK and phosphorylation p42/44-MAPK and driving tumor cells to apoptosis.

Effects of adenoviral vector mediated Fas ligand gene introduction on the medial layers of vascular smooth muscle cell density after rat carotid artery injury

TAO Hong, CHEN Li-xin, CEN Ming, LIN Jiang

2008, 13(12):  1401-1403. 

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AIM: To investigate the effects of Fas ligand (FasL) gene transduction mediated by adenoviral vector on the density of medial layer vascular smooth muscle cell after rat carotid artery injury.METHODS: SD rats were divided into treatment group (Ad-FasL group) and normal control group(Ad-βgal group) (n=6).Ad-βgal, Ad-FasL gene were transduced into endomembrane of balloon injury of rat carotid artery using recombination adenovirus vector, the density of medial layer vascular smooth muscle cell was observed after 3, 14 days, respectively.RESULTS: Compared with the normal control group, the density of medial layer vascular smooth muscle cell decreased after injury for 3 days, and returned to normal levels after injury for 14 days.CONCLUSION: FasL gene transduction into the vessel wall could decrease the density of medial layer vascular smooth muscle cell and inhibit the endomembrane accrementition.

Experimental study on limited sampling strategy to predict metabolizing activity of hepatic CYP3A

ZHU Xue-hui, LOU Jian-shi, JIAO Jian-jie, ZHANG Cai-li, LIU Chang-xiao

2008, 13(12):  1404-1410. 

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AIM: To evaluate feasibility of a limited sampling strategy (LSS) in the prediction of inhibited hepatic CYP3A activity with systemic clearance of midazolam (MDZ), a phenotyping probe drug for hepatic CYP3A activity.METHODS: Linear regression analysis and a Jack-knife validation procedures were performed in one group of rats pretreated with a serial doses of ketoconazole, a selective inhibitor on CYP3A, as training set to establish the most informative LSS model for accurately estimating the clearance of MDZ. Another group of rats in same setting were used as validation set to estimate the individual clearance (Clest) based on predictive equations derived from the training set.RESULTS: LSS models derived from two or three sampling time points, including 60 and 90 min, 30, 60 and 90 min and 30, 60 and 120 min, exhibited best correlation and acceptable errors between Clobs and Clest were chosen to evaluate to hepatic CYP3A activity.CONCLUSION: The results indicated that limited plasma sampling for predicting systemic clearance of MDZ is a less complicated method to evaluation of CYP3A phenotyping when the activity of hepatic CYP3A was inhibited.The present study provided theoretical basis and laboratory evidence for LSS to clinically evaluate metabolizing function of liver and design rational drug regimen.

Comparison of pharmacokinetics of ginkgolide B monomer and extract of ginkgolides in rats

WANG Tao, WANG Jian-xin, HAN Li-mei

2008, 13(12):  1411-1415. 

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AIM: To investigate the pharmacokinetics of ginkgolide B monomer and extract of ginkgolides in rats.METHODS: The concentrations of ginkgolide B from rats plasma were determined by LCMS method and the pharmacokinetic parameters were calculated using compartment model simulated by 3p87 program.C_max, t_max were expressed as measured.RESULTS: The pharmacokinetic parameters of ginkgolide B and extract in rats after oral administration of monomer were as follows:t_1/2αwas (0.18 ±0.09), (0.17 ± 0.07) h, t_1/2β was (2.3 ±2.0), (2.3 ±1.5) h, AUC_0-12 h was (2701 ± 655), (2889 ± 836)μg°L^-1 °h, AUC_0-∞ was (2778 ±680), (2966 ±854)μg°L^-1 °h, respectively.The oral bioavailability of ginkgolide B in extract was slightly higher than that in monomer.CONCLUSION: There was no significant difference in the pharmacokinetic parameters between ginkgolides B and the extract after oral administration of monomer in rats, and the coexistent substances in ginkgolide extract have no effect on the pharmacokinetic parameters of ginkgolide B in rats.

Transcriptional regulation of CYP3A4 and MDR1 mediated via nuclear receptor PXR by helicid

XIE Hai-tang, WANG Guo, FAN Lan, ZHANG Li-sheng, DAI Xiao-chang, ZHOU Honghao

2008, 13(12):  1416-1421. 

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AIM: To establish nuclear receptor PXR-expressed CYP3A4 and MDR1 dual luciferase reporter gene platform, and analyze the effect of helicid on hPXR-mediated transcriptional regulation of CYP3A4 and MDR1 genes.METHODS: PXR expression plasmid and reporter gene plasmid of either CYP3A4 or MDR1 were constructed based upon the dual luciferase reporter gene platform, and co-transfected to HepG2 cells.The transfected cells were treated with helicid of various concentrations (0.004, 0.04 and 0.4 μmol/L) for 48 hours while rifampin (10 μmol/L) was included as the positive control.Cells were lysized and luciferase activity was determined using a Dual-luciferase reporter assay kit (Promega, Madison, WI).RESULTS: Helicid, at tested concentrations, did not significantly increase promoter activities of CYP3A4 and MDR1 in HepG2 cells transfected with PXR expression plasmid (P >0.05).CONCLUSION: Nuclear receptor PXR-expressed CYP3A4 and MDR1 dual luciferase reporter gene platforms were successfully established, and helicid does not significantly induce the transcription of CYP3A4 and MDR1.

Development and validation of a liquid chromatographic electrospray ionization mass spectrometric method for the determination of digoxin in human plasma

JIA Yuan-wei, XIE Hai-tang, WANG Guang-ji

2008, 13(12):  1422-1425. 

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AIM: To develop a sensitive and selective liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS)method for clinical identification and quantification of digoxin in human plasma.METHODS: The method was based on simple liquid-liquid extraction (LLE).A Kromasil C₁₈ column (150 mm ×2.00 mm, 3.5 μm)was used as the analytical column, while a mixture of acetonitrile and 500 μmol/L ammonium chloride was used as the mobile phase.MS detection was performed using a single quadrupole mass spectrometer in a negative selected ion monitoring (SIM)mode.The deprotonated molecules [M +Cl] (-)at m z 815.40 and 819.00 were used to quantify digoxin and RgC₂(internal standard, I. S.), respectively.RESULTS: The method was linear in the concentration range of 0.05-10.0 ng/mL.The determination of digoxin was not interfered by internal material.The method recovery of digoxin was higher than 75 %.The intra-day and inter-day precisions (RSD %)were within 15.0 %for the analyte, and the freeze-thaw stability of digoxin was excellent.CONCLUSION: While requiring less human plasma, the method was proved to be simple, accurate, sensitive, and had very good reproducibility.Thus, the proposed method enables unambiguous identification and quantification for the therapeutic drug monitoring and pharmacokinetic studies of digoxin.

Comparison on anesthetic effects of remifentanil and fentanyl for posterior scoliosis correction

JIN Yan-qing, MA Zheng-liang, GU Xiao-ping, ZHONG Yu

2008, 13(12):  1426-1429. 

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AIM: To compare the effects of remifentanil and fentanyl for posterior scoliosis correction and the influences on postoperative pain.METHODS: Forty patients scheduled for posterior scoliosis correction (ASA Ⅰ-Ⅱ, aged 11-18 years) were randomly divided into group remifentanil (group R) and group fentanyl (group F).Anesthesia was maintained with propofol, vecuronium bromide and sevoflurane. Intravenous remifentanil (0.2μg°kg^-1°min^-1) and fentanyl (1μg°kg^-1°h^-1) were continuously administered for analgesia.Vecuronium bromide and analgesics were discontinued around 30 min before the wake-up test.The wake up time from propofol and sevoflurane discontinuation to movement of the patient's toe were recorded.In group R, once remifentanil infusion was stopped before surgery ended, the patients were injected with fentanyl 2μg kg.All of the patients received intravenous fentanyl (10μg°kg^-1°min^-1) for postoperative analgesia and were interviewed for pain degree during the first 24 h after surgery.RESULTS: The wake-up time were (12.3 ±5.7) min in group R and (21.6 ±6.5) min in group F(P <0.01).The analgesia efficacies in two groups were satisfactory.There was no significant difference in VAS (visual analog scale) score between the two groups during the first 24 h after surgery.CONCLUSION: Compared with group F, the wake-up time was shorted obviously in group R in posterior scoliosis correction.Remifentanil (0.2μg°kg^-1°min^-1) did not trigger postoperative hyperalgesia when fentanyl was applied after discontinuation of remifentanil during the surgery.

Clinical observation on azasetron in different juncture injection for preventing postoperative nausea and vomiting

HOU Cheng-lin, CHEN Yong-quan, JIN Xiao-ju

2008, 13(12):  1430-1433. 

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AIM: To evaluate the prophylactic effect of azasetron in different juncture injection on postoperative nausea and vomiting (PONV) during patients controlled intravenous ananlgesia (PCIA).METHODS: One hundred and twenty patients, scheduled for selective abdominal operations, were randomly divided into four groups:patients received an preoperative intravenous injection of 10 mg azasetron (Group A, n= 30), patients received an intravenous injection of 10 mg azasetron during abdominal cavity (Group B, n=30), patients received an intravenous injection of 10 mg azasetron when the operation were finished (Group C, n=30), patients with no azasetron as control (Group D, n=30).The incidence rate and score of PONV, the visual analogue scales (VAS) and Ramsay scores were recorded at 4, 8, 12, 24, 48 h postoperatively.RESULTS: There was significant difference between the postoperative VAS during 12 to 48 h and that of 4 h postoperatively(Ρ<0.01 or Ρ<0.05).There was no somnolence and deep calm happening.The incidence of PONV in Group A was significantly lower than that in Group D(Ρ<0.01 or Ρ<0.05).The incidences of PONV in Group C in postoperative 0 to 4 h and 4 to 24 h were significantly lower than that in Group D(Ρ <0.05).There was no significant difference between Group B and D(Ρ>0.05).CONCLUSION: A preoperative intravenous injection of 10 mg azasetron can be used effectively to prevent PONV during PCIA.

Advances in study of CYP2B6 gene polymorphisms and its functional significances

QIN Wen-jie, ZHOU Hong-hao

2008, 13(12):  1434-1440. 

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CYP2B6 is an important cytochrome P450 enzymes and contributes to metabolism of about 7 % of therapeutically usual drugs, including somewith narrow therapeutic index.The human CYP2B6 gene is highly polymorphic, having many single nucleotide polymorphisms in promoters and coding regions.To date, at least 29 CYP2B6 alleles have been identified. This review summarizes recent advances in the study of CYP2B6 about gene polymorphism, the frequency of CYP2B6 alleles among different populations, and their clincal significance.