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Published in last 1 year |  In last 2 years |  In last 3 years |  All Please wait a minute... For Selected: Download Citations EndNote Ris BibTeX Toggle Thumbnails Select Effects ofβ1-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy LIU Jie, LIU Zhao-qian, LIU Ying-zi, TAN Zhi-rong, HU Dong-li, LI Zhi, WANG Dan, ZHANG Wei, ZHOU Hong-hao Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1130-1137.   Abstract （87）      PDF （300KB）（97）       Knowledge map    Save BACKGROUND: Metoprolol is a selectiveβ1-Blocker commonly used in essentiaL/hypertension. It is metabolized by CYP2D6.CYP2D6 *10, which was identified to decrease activity of CYP2D6, is the main variance in Chinese population.β1-adrenergic receptor, with Ser49Gly and Gly389Arg polymorphisms, is the target of metoprolol.It was still unknown that whether the CYP2D6 andβ1-adrenergic receptor had a synergic effect on metoprolol antihypertension therapy. AIM: To clarify the genetic polymorphism associated with metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy. METHODS: 125 mild-to-med essentiaL/hypertension patients were enrolled in this study.Patients were mono-therapied with metoprolol for 12 weeks.Blood pressure was monitored every 4 weeks.PCR-RFLP method was use to identify CYP2D6 *10 andβ1-adrenergic receptor Ser49Gly and Gly389Arg polymorphisms.Plasma metoprolol concentration was measured by HPLC- fluorescence detection. RESULTS: Trough blood level (C0)of metoprolol was associated with CYP2D6 *10 variance in a gene-dose-effect manner, whereas the extent of blood pressure decrease was not significant different in CYP2D6 *1 *1, *1 *10 and CYP2D6 *10 *10 patients. After 12 weeks metoprolol therapy, Gly49 carriers had stronger decrease in systolic and diastolic blood pressure than that of Ser49 homozygotes.Similarly, subjects homozygous for Arg389 had stronger decrease in blood pressure than that of Gly389 carriers.CONCLUSION: CYP2D6 *10 variance significantly change the pharmacokinetics of metoprolol, and the genetic polymorphisms of β1-adrenergic receptorwere associated with the pharmacodynamics of metopolol in antihypertension therapy. Reference | Related Articles | Metrics Select Population pharmacokinetics of Guanxin Ⅱ prescription CHEN Wen-qian, HU Yu-hui, ZHANG Yan-qing, ZHANG Guan-min, LI Liang, ANG Wei-ning, LU Wei Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1138-1143.   Abstract （81）      PDF （270KB）（62）       Knowledge map    Save AIM: To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin and ferulic acid. METHODS: Drug concentrations of rat plasmas after intravenous injection of paronia pall (PPE) or ferulic acid (FA) extract solution, as well as oral administration of PPE and FA solution, and different kinds of decoctions based on Guanxin Ⅱ prescription were determined by an HPLC system. NONMEM (nonlinear mixed-effect modeling) method was used to analyze the population pharmacokinetics of PF and FA. RESULTS: A two-compartment model with first order degradation in absorption phase, and an ordinary twocompartment model were adequately describe PF and FA pharmacokinetic profiles, respectively.The mean of PF population parameters, CL1, V1, CL2, V2, Ka0, and Ka1, were 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135 h, and 0.0135 h, respectively, while the typical values of CL1, V1, CL2, V2, Ka1, and F in FA model were 0.295 L/h, 0.025 L, 0.0331 L/h, 0.0518 L, 0.110 h, and 0.40, respectively.Inter-individual variabilities were estimated and dose formulation (DF) was identified as a significant covariate in the model. CONCLUSION: The results indicate that the pharmacokinetic behaviors of index components in Guanxin Ⅱ prescription can be influenced by different dose formulations administrated in rats. Reference | Related Articles | Metrics Select Metabolomics approach to the biochemical differentiation of Traditional Chinese Medicine syndrome types of hypertension LU Yi-hong, HAO Hai-ping, WANG Guang-ji, CHEN Hu-xiao,ZHU Xuan-xuan, XIANG Bing-ren, HUANG Qing, A Ji-Y Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1144-1150.   Abstract （138）      PDF （252KB）（192）       Knowledge map    Save AIM: Traditional Chinese Medicine (TCM) has been practiced in China for thousands of years, providing a unique theoretical and practical approach to the treatment of diseases.In TCM theory, the notions of the “whole” and the use of “ system” rather than isolation are important concepts, which well fit to systems biology theory.In the present study, we try to discover whether GC/MS-based metabolomics approaches contribute to differentiate the TCM syndrome types of hypertension. METHODS: The three phenotypes of constitution in patients with essential hypertension, the hyperactivity of liver yang type, tan shi yong sheng type and yin xu yang kang type, were classified by TCM approach. Serum metabolomic profiles for healthy persons and hypertension patients were acquired using GC/MS global analysis. Principal components analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and Mahlanobis distance (MD) were applied to facilitate the metabolomics data differentiation and prediction. RESULTS: Using PCA and PLS-DA, it was capable of distinguishing normal blood pressure serum samples from those of the TCM syndrome types, while failed to discriminate the three TCM syndrome types of hypertension from each other. Further MD analysis contributed not only to a fine differentiation, but also to a clear exhibition of the progression, of the three syndrome types. CONCLUSION: This pilot study suggests that the metabolomics approach might be a powerful tool for exploring the scientific essence of the TCM theory. Reference | Related Articles | Metrics Select Pharmacokinetic/pharmacodynamic studies in anestheticdrug-drug interactions-a response surface model with remifentanil and sevoflurane for Chinese adult patients YANG Lu, YANG Ba-xian, ZHANG Li-ping, BI Shan-shan, LU Wei Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1151-1156.   Abstract （99）      PDF （353KB）（59）       Knowledge map    Save AIM: To determine the interactions with response -surface modeling methodologies when sevoflurane (Sevo) and remifentanil (Remi) were administered simultaneously. METHODS: (1) Patients, Study design and drug delivery :Based on parallel slices design, sixtyfive patients were randomly assigned to inhale a specific end-tidal concentration of sevoflurane (0.3 % to 3.4 %), with different level of remifentanil (0 -10 ng mL).The responses to laryngoscopy were observed for each given concentration pair.(2) Pharmacokinetic/pharmacodynamic analysis with response surface mode :The probability of no response (P) was assessed in the modeling process as below. $P=\frac{(Us+Ur)^{r}}{[U_{50}/I(Q)]^{r}+(Us+Ur)^{r}}$ RESULTS AND DISCUSSION:NONMEM estimated average values (RSE %) of the model parameters for laryngoscopy of C50,Sevo, C50,remi, U50, r, Imax and Qmax are 1.71 % (12.9), 12.4 ng/mL (19.0), 6.62 (10.6), 1.53 (8.76), 2.31 (8.23), 0.706 (2.46), respectively.The inter-individual variability (CV %) in parameter Imax and inter-occasion variability (S.D.) in this model are 12.7 and 0.0316, respectively.It is concluded that the response-surface modeling approach provided a novel method to study drug-drug interactions. Reference | Related Articles | Metrics Select Differential effects of PPARγligand rosiglitazone and selective antagonist GW9662 on adipocytokine gene expression in 3T3-L1 adipocytes LIU Ying-zi, Vural Ozdemir, OUYANG Dong-sheng, LIU Zhao-qian, LIU ie, LI Zhi,WANG Dan, ZENG Fei-yue, TAN Zhi-rong, HU Dong-li, ZHOU Hong-hao Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1157-1162.   Abstract （103）      PDF （238KB）（99）       Knowledge map    Save BACKGROUND: There is a growing recognition that the adipose tissue is an endocrine organ that secretes signaling molecules such as adiponectin and resistin.The peroxisome proliferator activated receptor γ (PPARγ)is expressed in high levels in the adipose tissue.Thiazolidinediones are selective PPARγagonists with insulin-sensitizing properties.It has been postulated that thiazolidinediones such as rosiglitazone exert their pharmacodynamic effects in part through modulation of resistin (implicated in insulin resistance)and adiponectin (an insulin- sensitizing molecule)expression subsequent to activation of PPARγ.There are conflicting data, however, on the biological direction in which resistin expression is modulated by PPARγagonists and whether an increase in adiponectin expression can occur in the face of an upregulation of resistin. METHODS: Using the murine 3T3-L1 adipocytes as a model, we evaluated the changes in resistin and adiponectin gene expression after vehicle, rosiglitazone (10 μmol/L, a PPARγagonist), GW9662 (5 μmol/L, a selective PPARγantagonist)or GW662 and rosiglitazone co-treatment. RESULTS: In comparison to vehicle treatment, rosiglitazone increased the average adiponectin and resistin mRNA expression by 1.66- and 1.55-fold, respectively (P<0.05).Importantly, GW9662 also upregulated adiponectin expression (by 1.57-fold, P<0.05)but did not influence resistin expression (P> 0.05).Co-treatment with rosiglitazone and GW9662 maintained the adiponectin upregulation (1.87-fold increase from vehicle, P<0.05)while attenuating resistin upregulation (1.31-fold increase from vehicle, P<0.05)induced by rosiglitazone alone (1.55-fold increase from vehicle, P<0.05). CONCLUSION: This study presents new evidence that adiponectin transcript is upregulated with both a PPARγagonist (rosiglitazone)and antagonist (GW9662), while GW9662 co-treatment does not block rosiglitazone-induced adiponectin upregulation.These data collectively suggest that biological mechanisms independent from PPARγmay underlie thiazolidinedione pharmacodynamics on adiponectin expression.Moreover, increased adiponectin expression by GW9662, in the absence of an upregulation of resistin expression, lends further support on the emerging clinical potential of PPARγ antagonists in treatment of insulin resistance.Decreased resistin expression may not be crucial for the insulin-sensitizing effect of rosiglitazone.These findings may serve as a foundation for future dose-ranging and time-course studies of thiazolidinedione pharmacodynamics on adipocytokine expression in human adipocytes. Reference | Related Articles | Metrics Select Stereoselective bile excretion of ibuprofen glucuronide and the transport mechanism in the biliary efflux CHEN Xi-jing, Masahiro Iwaki Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1163-1167.   Abstract （84）      PDF （204KB）（119）       Knowledge map    Save AIM: To illustrate the effects of drug transporters on the bile efflux of ibuprofen glucuronide (IBG), the difference of bile excretion and plasma concentration of ibuprofen(IB)and its glucuronides was studied in EHBR and normal SD rat(SDR).METHODS: After 20 mg/kg of IB enantiomers administrated intravenously, the bile and blood were collected from the rats and the concentration of IB and their glucuronide were measured by HPLC methods.RESULTS: The bile excretion of IBG was obviously (but no totally)suppressed in EHBR (1.7 %±1.0 %, 0.6 %±0.9 % of the dose respectively for S-IBG and R-IBG)compared with that in SDR (18.4 %±4.0 %and 3.0 %±2.4 % of the dose respectively for S-IBG and R-IBG), for both kinds of rats, there are more S-IBG excreted than that of R-IBG.As the result of reduction of IBG excreted in bile, the concentration of IBG was higher in blood in EHBRs.CONCLUSION: The results suggest that Mrp2 is the most important transporter for IBG, and other transporter(s)may participate in the process. 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