External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients.

AIMS: Several population pharmacokinetic (popPK) models for ciclosporin (CsA) in adult renal transplant recipients have been constructed to optimize the therapeutic regimen of CsA. However, little is known about their predictabilities when extrapolated to different clinical centres. Therefore, this study aimed to externally evaluate the predictive ability of CsA popPK models and determine the potential influencing factors. METHODS: A literature search was conducted and the predictive performance was determined for each selected model using an independent data set of 62 patients (471 predose and 500 2-h postdose concentrations) from our hospital. Prediction-based diagnostics and simulation-based normalized prediction distribution error were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Additionally, potential factors influencing model predictability were investigated. RESULTS: Seventeen models extracted from 17 published popPK studies were assessed. Prediction-based diagnostics showed that ethnicity potentially influenced model transferability. Simulation-based normalized prediction distribution error analyses indicated misspecification in most of the models, especially regarding variance. Bayesian forecasting demonstrated that the predictive performance of the models substantially improved with 2-3 prior observations. The predictability of nonlinear Michaelis-Menten models was superior to that of linear compartmental models when evaluating the impact of structural models, indicating the underlying nonlinear kinetics of CsA. Structural model, ethnicity, covariates and prior observations potentially affected model predictability. CONCLUSIONS: Structural model is the predominant factor influencing model predictability. Incorporation of nonlinear kinetics in CsA popPK modelling should be considered. Moreover, Bayesian forecasting substantially improved model predictability.

External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients.

AIM: Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors. METHODS: Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. RESULTS: Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within ±30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used. CONCLUSIONS: The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability.

Rosiglitazone inhibits angiotensin II-induced C-reactive protein production in human aortic endothelial cells through regulating AT(1)-ROS-MAPK signal pathway.

OBJECTIVE: Atherosclerosis is an inflammatory disease. As an inflammatory molecule, C-reactive protein (CRP) plays a direct role in atherogenesis. Our previous study confirmed that angiotensin II (Ang II) is capable of inducing CRP generation in human aortic endothelial cells (HAECs). The present study observed the effect of rosiglitazone on Ang II-induced CRP expression in HAECs and molecular mechanisms. METHODS: HAECs were cultured, and Ang II (10(-6) M) was used as a stimulant for the generation of CRP and reactive oxygen species (ROS). HAECs were preincubated with rosiglitazone at 1, 10, 100 µM for 18 h prior to the stimulation. mRNA and protein expressions were identified by reverse transcription polymerase chain reaction and Western blot, respectively. ROS production was observed by a fluorescence microscope. RESULTS: Pretreatment of HAECs with rosiglitazone prior to Ang II stimulation markedly downregulated Ang II-induced mRNA and protein expressions of CRP (maximal inhibition of 55.2 and 99.1 %, P < 0.001 vs. Ang II alone) and AT(1) (maximal inhibition of 66.4 and 90.5 %, P < 0.001 vs. Ang II alone) in a concentration-dependent manner, inhibited Ang II-stimulated ROS production (P < 0.01 vs. Ang II alone), and attenuated Ang II-induced phosphorylation of ERK1/2 and JNK (P < 0.001 vs. Ang II alone). Meanwhile, AT(1) receptor blocker losartan also reduced Ang II-stimulated ROS generation in HAECs (P < 0.001 vs. Ang II alone). CONCLUSIONS: Rosiglitazone at the concentrations used in the present experiment is able to inhibit Ang II-induced CRP generation in HAECs by regulating AT(1)-ROS-MAPK signal pathway. These results strengthen our understanding of the anti-inflammatory and anti-atherosclerotic effects of rosiglitazone.

[Mechanism of Dahuang Zhechong pill against atherosclerosis induced by balloon angioplasty in rabbits].

OBJECTIVE: To study the mechanism of Dahuang Zhechong pill (DHZCP) against atherosclerosis induced by balloon angioplasty in rabbits. METHODS: Atherosclerosis model was established by the combination of balloon angioplasty-induced endothelial injury and high cholesterol feeding in rabbit. Male New Zealand rabbits were divided into six groups randomly: normal control, sham, model, positive control and two doses of DHZCP-treated groups. Rabbits in DHZCP-treated groups were intragastrically administered 0.9 and 1.8 g/kg DHZCP for 60 days respectively,and rabbits in positive control group were given 0.5 g/kg Danshen. MDA, NO levels and SOD activity in serum, and MPO activity in the vascular wall were determined with spectrophotometry. Expressions of proliferating cell nuclear antigen (PCNA) and BCL-2 in the vascular wall were detected by SP immuohistochemical technique. RESULTS: Compared with the model group, DHZCP significantly reduced serum MDA level and MPO activity in the vascular wall, increased serum NO level and SOD activity,and inhibited PCNA and BCL-2 expressions in the vascular wall. CONCLUSION: DHZCP inhibits the formation and development of atherosclerosis through anti-oxidative action, protecting endothelium from injury,inhibiting proliferation and promoting apoptosis of vascular smooth muscle cells.

[Study on in vitro release and transdermal behaviors of mumps cataplasm of complex prescription].

OBJECTIVE: To investigate the in vitro release and transdermal behaviors of mumps cataplasm of complex prescription. METHODS: The improved Franz difficusion was used and the concentration of drugs was detected. DCS was determined by HPLC and flavanoid contents were determined by UV. RESULTS: The accumulation skin permeation percentage of DCS and flavanoid was 32% and 21%, respectively, the in vitro release percentage of DCS and flavanoid was 47% and 42%, respectively. CONCLUSION: The transdermal behavior of mumps cataplasm of complex prescription is an zero-order kinetics progress. The in vitro release behavior is in accordance with the Higuchi equation.

Epigallocatechin-3-gallate inhibits angiotensin II and interleukin-6-induced C-reactive protein production in macrophages.

BACKGROUND: Consumption of green tea has been associated with health benefits against multiple diseases including cardiovascular diseases. However, the action mechanisms of green tea and its major ingredient epigallocatechin-3-gallate (EGCG) against cardiovascular diseases are still unclear. Emerging evidence has suggested a common role for C-reactive protein (CRP) in the pathogenesis of inflammation and atherosclerosis. Therefore, the effect of EGCG on angiotensin II (Ang II)- and interleukin-6 (IL-6)-induced CRP production in U937 macrophages and the possible mechanisms were observed. METHODS: U937 macrophages were cultured, and Ang II and IL-6 were used as stimulants for generation of CRP. U937 macrophages were preincubated with EGCG at 1, 3, 10 µM for 1 h prior to the stimulation. mRNA expression and protein level were determined by RT-PCR and ELISA, respectively. ROS production was observed by a fluorescence microscope. RESULTS: Pretreatment of macrophages with EGCG prior to the stimulation concentration-dependently inhibited Ang II- and IL-6-induced expression of CRP both in protein and mRNA levels. Meanwhile, EGCG reduced Ang II- and IL-6-stimulated generation of ROS in macrophages. CONCLUSION: EGCG is able to inhibit Ang II- and IL-6-stimulated CRP expression in macrophages to produce an anti-inflammation by interfering with ROS generation. The finding is helpful to update understanding of anti-atherosclerotic effects of EGCG.