Explore the vast range of titles available.

目的 研究抗乳增片对大鼠乳腺增生病的治疗作用及其机制。方法 采用手术摘除卵巢后腹腔注射苯甲酸雌二醇造成大鼠乳腺增生模型。结果 与模型组比较，抗乳增片治疗组的大鼠乳头红肿、增大均较轻；血清雌二醇水平较低，孕酮水平较高；凝血时间延长；血流变各项指标明显改善。结论 抗乳增片对大鼠乳腺增生病有治疗作用，其机制可能是通过调节大鼠的激素水平和改善血液流变性来实现的。

在抗抑郁药的使用频度中，三环抗抑郁药（TCAs）之所以日渐向后排，不是因为它疗效不好，而是因为它不良反应大，不易耐受，过量时危险性大，故医生在使用TCAs期间，不但要掌握TCAs药效学，而且要熟悉TCAs的药物相互作用，这里将专门讨论TCAs的药物相互作用。

Single-target drugs have not achieved satisfactory therapeutic effects for complex diseases involving multiple factors. Instead, innovations in recent drug research and development have revealed the emergence of compound drugs, such as cocktail therapies and ＂polypills＂, as the frontier in new drug development. A traditional Chinese medicine （TCM） prescription that is usually composed of several medicinal herbs can serve a typical representative of compound medicines. Although the traditional compatibility theory of TCM cannot be well expressed using modern scientific language nowadays, the fundamental purpose of TCM compatibility can be understood as promoting efficacy and reducing toxicity. This paper introduces the theory and methods of efficacy-oriented compatibility for developing component-based Chinese medicines.

Aim： To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. Methods：Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 pg.kg^1.min 1, each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject＇s heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. Results： Peak concentrations （Cmax） of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h （range, 0.107-0.166 h）, while the area under concentration-time curve （AUC）, extrapolated to infinity, was 5.39 ng-h.mL1 （range, 3.2-6.8 ng.h.mLl）. The volume of distribution （V） was 48 L （range, 30.8-80.6 L）. The total clearance （CL） was 249 L/h （range, 199-336 L/h）. Within 8 h, 9.3% （range, 4.6%-12.4%） of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The Eo, Emax, and EC5o were 68 bpm, 73 bpm and 8.1 pg/L, respectively. Conclusion： Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important informa tion for future clinical studies on higenamine.

Aim： The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor （EGFR-TKI）. Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods： Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 （50 or 150 mg.kg-l.d-1, ig） or vehicle for 18 d. The pharmacokinetics （PK） and pharmacodynamics （PD） of TM208 were evaluated. Results： The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC5o （55.9 pg/L）, as well as three parameters （＇a＇ of 27.2%, ＇b＇ of 2730%, ＇c＇ of 0.58 h1） denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics kog （0.282 day-1）, drug potency kTM208 （0.0499 cm3/day） and the kinetics of tumor cell death k1 （0.141 day-1）, which provided insight into drug mechanisms and behaviors. Conclusion： The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.

Aim： SCT800 is a new third-generation recombinant FVill agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods： After hemophilia A mice were intravenously injected with single dose of SCT800 （80, 180, and 280 IU/kg） or the commercially available product Xyntha （280 IU/kg）, pharmacokinetics profiles were evaluated based on measuring plasma FVIIh C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha （1-200 IU/kg） were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results： Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model： 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion： In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties.

Aim： To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats. Methods： Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutane- ous administration of a single dose of exenatide （4.2, 42, or 210 pg/kg）, serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insu lin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin （in effect compartment） stimulating glucose disposition and insulin （in insulin compart- ment） inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model pro- gram. Visual predictive check and model evaluation were used to make assessments. Results： Exenatide exhibited rapid absorption with ka=4.45 h 1, and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated Sin1 of 0.822 and SCso of 4.02 pg/L. It was demonstrated that insulin stimulated giucose diSsipation （Sm2=0.0513） and inhibited the production of glucose （Im=0.0381）. Visual predictive check and model evaluation study indicated that a credible model was developed. Conclusion： The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect com- partment/indirect response model.

Aim： Erlotinib is used to treat non-small-cell lung cancer （NSCLC）, which targets epidermal growth factor receptor （EGFR） tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR （pEGFR） levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods： Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib （4, 12.5, or 50 mg/kg）. Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration, The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results： The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC~o value of 1.80 pg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm3/week which described the impact of pEGFR degradation on tumor growth. Conclusion： The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

Aim： To examine individual patient＇s demographic parameters and clinical variables related to return of consciousness （ROC） and the pharmacodynamic relationship between propofol effect-site concentration （Ce） and ROC from propofol-remifentanil anesthesia. Methods： Ninety-four patients received propofol-remifentanil anesthesia using the effect-site target-controlled infusion （TCl） system. AI clinical events were noted, and variables possibly related to propofol Ce at ROC were examined using linear correlation analyses. Phar-macodynamic modeling incorporating covariates was performed using NONMEM （Nonlinear Mixed Effects Modeling） VII software. Results： The Ce values of propofol at loss of consciousness （LOC） and ROC were 4.4±1.1 pg/mL and 1.1±0.3 pg/mL, respectively. Age was negatively correlated with propofol Ce at ROC （r=-0.48, P〈0.01）. including age as a covariate in Ceso （the effect-site concentration associated with 50% probability of return of consciousness）and λ （the steepness of the concentration-versus-response relationship） significantly improved the performance of the basic model based on the likelihood ratio test, with a significant decrease in the mini- mum value of the objective function. The Ce5o in 25-, 50-, and 75-year-old patients was predicted to be 1.38, 1.06, and 0.74 μg/mL, respectively. The λ in 25-, 50-, and 75-year-old patients was predicted to be 12.23, 8.70, and 5.18, respectively. Conclusion： Age significantly affects the relationship between propofol Ce and ROC, and pharmacodynamic modeling including age could lead to better predictions of ROC during emergence from propofol-remifentanil anesthesia.

Aim： To investigate the population pharmacokinetics （PK） and pharmacodynamics （PD） of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects. Methods： Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time （ACT）. Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and prediction corrected visual predictive check （pcVPC） approaches. Results： The final PK model was a two-compartment model without covariates. The typical PK population values of clearance （CL）, apparent distribution volume of the central-compartment （VI）, inter-compartmental clearance （Q） and apparent distribution volume of the peripheral compartment （V2） were 0.323 L.h^-1·kg^-1.086 L/kg, 0.0957 L-h ^-1.kg^-1, and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid Emax model without the Hill coefficient. In this model, a covariate, red blood cell count （RBC＊）, had a significant effect on the ECho value. The typical PD population values of maximum effect （Emax）, EC50, baseline ACT value leo） and the coefficient of RBC＊ on ECho were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of Emax, EC50, and Eo were 6.80%, 46.4%, and 4.10%, respectively. Conclusion： Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.