External evaluation of the predictive performance of published population pharmacokinetic models of linezolid in adult patients.

OBJECTIVES: Several linezolid population pharmacokinetic (popPK) models have been established to facilitate optimal therapy; however, their extrapolated predictive performance to other clinical sites is unknown. This study aimed to externally evaluate the predictive performance of published pharmacokinetic models of linezolid in adult patients. METHODS: For the evaluation dataset, 150 samples were collected from 70 adult patients (72.9% of which were critically ill) treated with linezolid at our center. Twenty-five published popPK models were identified from PubMed and Embase. Model predictability was evaluated using prediction-based, simulation-based, and Bayesian forecasting-based approaches to assess model predictability. RESULTS: Prediction-based diagnostics found that the prediction error within ±30% (F30) was less than 40% in all models, indicating unsatisfactory predictability. The simulation-based prediction- and variability-corrected visual predictive check and normalized prediction distribution error test indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting with one or two prior observations significantly improved the models' predictive performance. CONCLUSION: The published linezolid popPK models showed insufficient predictive ability. Therefore, their sole use is not recommended, and incorporating therapeutic drug monitoring of linezolid in clinical applications is necessary.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

NOD2 induces VCAM-1 and ET-1 gene expression via NF-κB in human umbilical vein endothelial cells with muramyl dipeptide stimulation.

OBJECTIVES: Endothelial dysfunction is involved in various aspects of vascular biology and different stages of cardiovascular diseases (CVDs). Nucleotide-binding oligomerization domain-containing protein (NOD) 2, a pivotal innate immune receptor for muramyl dipeptide (MDP), has been reported to be a central regulator in CVDs. Previously, we reported that NOD2 played a leading role in MDP-triggered oxidative stress in endothelial cells (ECs). However, whether NOD2 participates in the regulatory mechanism of vascular cell adhesion molecule­1 (VCAM-1) and endothelin­1 (ET-1) expression was not elucidated. METHODS: Human umbilical vein endothelial cells (HUVECs) were stimulated with MDP for 12 h. mRNA expression of VCAM­1 and ET­1 was detected using real time polymerase chain reaction (PCR). Scrambled control small interfering RNA (siRNA) and NOD2 siRNA were transfected into HUVECs using Lipofectamine 2000 reagent (Invitrogen, Waltham, MA, USA). Furthermore, pyrrolidine dithiocarbamate was adopted to investigate the effect of nuclear factor κB (NF-κB) on NOD2-mediated VCAM­1 and ET­1 gene expression in MDP-treated HUVECs. RESULTS: Data showed that MDP significantly increased VCAM­1 and ET­1 mRNA expression, which was dependent on NOD2. In addition, NF-κB inhibition suppressed NOD2-mediated gene expression of VCAM­1 and ET­1. CONCLUSION: Collectively, we confirmed NOD2 aggravated VCAM­1 and ET­1 gene expression through NF-κB in HUVECs treated with MDP.

Brain Transport Profiles of Ginsenoside Rb1 by Glucose Transporter 1: In Vitro and in Vivo.

Ginsenoside Rb1 (Rb1) has been demonstrated its protection for central nervous system and is apparently highly distributed to the brain. The objective of this study was to characterize Rb1 transport at the blood-brain barrier (BBB) using primary cultured rat brain microvascular endothelial cells (rBMEC), an in vitro BBB model. The initial uptake velocity of Rb1 in rBMEC was temperature- and concentration-dependent, and was significantly reduced by phloretin, an inhibitor of GLUT1 transporter, but was independent of metabolic inhibitor. Furthermore, the transport of Rb1 into rBMEC was significantly diminished in the presence of natural substrate α-D-glucose, suggesting a facilitated transport of Rb1 via GLUT1 transporter. The impact of GLUT1 on the distribution of Rb1 between brain and plasma was studied experimentally in rats. Administration of phloretin (5 mg/kg, i.v.) to normal rats for consecutive 1 week before Rb1 (10 mg/kg, i.v.) at 0.5, 2, and 6 h did not alter Rb1 concentrations in plasma, but resulted in significant decreased brain concentrations of Rb1 compared to in the phloretin-untreated normal rats (489.6 ± 58.3 versus 105.1 ± 15.1 ng/g, 193.8 ± 11.1 versus 84.8 ± 4.1 ng/g, and 114.2 ± 24.0 versus 39.9 ± 4.9 ng/g, respectively). The expression of GLUT1 in the phloretin-treated group by western blotting analysis in vitro and in vivo experiments was significantly decreased, indicating that the decreased transport of Rb1 in brain was well related to the down-regulated function and level of GLUT1. Therefore, our in vitro and in vivo results indicate that the transport of Rb1 at the BBB is at least partly mediated by GLUT1 transporter.

Vancomycin-induced acute kidney injury in elderly Chinese patients: a single-centre cross-sectional study.

AIMS: The objective of the present study was to investigate the current situation concerning, and risk factors for, vancomycin (VAN)-induced acute kidney injury (VI-AKI) in elderly Chinese patients, to assess outcomes and risk factors in patients who have developed VI-AKI, in order to provide suggestions for improving the prevention and treatment of this condition in these patients. METHOD: We retrospectively identified elderly older inpatients who had received four or more doses of VAN treatment. We compared patients with VI-AKI with those who received VAN treatment and had not developed AKI (NO-AKI). We defined VI-AKI as developing AKI during VAN therapy or within 3 days after withdrawal of VAN. RESULTS: A total of 647 out of 862 elderly inpatients were included in the study. Among those excluded, in 89.3% of cases (192/215) this was because of lack of data on serum creatinine (SCr). Among included patients, 32.5% (210/647) of patients received therapeutic drug monitoring (TDM) during VAN therapy. In 66.9% of cases (424/634), there was insufficient TDM, and in 3.9% (25/634) this was appropriate. A total of 102 patients had confirmed VI-AKI, with an incidence of 15.8% (102/647). Multiple logistic regression analysis revealed that hyperuricaemia [odds ratio (OR) = 3.045; P = 0.000)], mechanical ventilation (OR = 1.906; P = 0.022) and concomitant vasopressor therapy (OR = 1.919; P = 0.027) were independent risk factors for VI-AKI; higher serum albumin (OR = 0.885; P = 0.000) was determined to be an independent protective factor for VI-AKI. CONCLUSIONS: For the elderly Chinese patients treated with VAN, there was insufficient monitoring of SCr, too little use of VAN TDM, and lower rate of patients whose VAN though serum concentrations were not obtained at the correct time. We recommend that hospital managers increase investment in clinical pharmacists, to strengthen professional management. Patients with concomitant hyperuricaemia and on mechanical ventilation and vasopressor therapy should be paid more attention, and a higher serum albumin was determined to be an independent protective factor for VI-AKI.

Muramyl Dipeptide Induces Reactive Oxygen Species Generation Through the NOD2/COX-2/NOX4 Signaling Pathway in Human Umbilical Vein Endothelial Cells.

Vascular endothelium dysfunction caused by oxidative stress accelerates the pathologic process of cardiovascular diseases. NOD2, an essential receptor of innate immune system, has been demonstrated to play a critical role in atherosclerosis. Here, the aim of our study was to investigate the effect and underlying molecular mechanism of muramyl dipeptide (MDP) on NOX4-mediated reactive oxygen species (ROS) generation in human umbilical vein endothelial cells (HUVECs). The 2,7-dichlorofluorescein diacetate staining was to measure the intracellular ROS level and showed MDP-promoted ROS production in a time- and dose-dependent manner. The mRNA and protein levels of NOX4 and COX-2 were detected by real-time polymerase chain reaction and western blot. Small interfering RNA (siRNA) was used to silence NOD2 or COX-2 gene expression and investigate the mechanism of NOD2-mediated signaling pathway in HUVECs. Data showed that MDP induced NOX4 and COX-2 expression in a time- and dose-dependent manner. NOD2 knock-down suppressed upregulation of COX-2 and NOX4 in HUVECs treated with MDP. Furthermore, silence of COX-2 in HUVECs downregulated the NOX4 expression after MDP stimulation. Collectively, we indicated that NOD2 played a leading role in MDP-induced COX-2/NOX4/ROS signaling pathway in HUVECs, which was a novel regulatory mechanism in the progress of ROS generation.

The efficacy of parenteral fish oil in critical illness patients with sepsis: a prospective, non-randomized, observational study.

BACKGROUND AND OBJECTIVES: To investigate the clinical outcomes in septic patients receiving parenteral fish oil. METHODS AND STUDY DESIGN: A prospective, non-randomized, observational clinical study was carried out in 112 patients with sepsis from March, 2013 to May, 2015 in the surgical intensive care unit (SICU) of a tertiaryreferral hospital. The patients were put into one of two groups; either the control or the study group. Patients received the standard treatment of sepsis based on guidelines in the control group. In the study group, patients received parenteral nutrition (PN) containing fish oil. The Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the length of ICU and hospital stay, duration of mechanical ventilation, mortality, and readmission into the ICU were recorded. Tumor necrosis factor (TNF)-α and procalcitonin (PCT) levels were also evaluated. RESULTS: The study group showed a significant reduction for all-cause mortality (20.0% vs 10.0% in study and control groups, p=0.034) and APACHE II score on day 5 (p=0.015), day 7 (p=0.036) and day out of SICU (p=0.045) compared with the control group. The study group tended to show a shortened length of stay in the ICU compared to the control group. However, TNF-α and PCT level, 28 d mortality, the length of hospital stay and the duration of mechanical ventilation did not show statistical differences between the two groups. There were no drug-related adverse effects shown during the study. CONCLUSIONS: PN with fish oil is probably safe and may improve clinical outcome in critical ill patients with sepsis.

The efficacy and safety of cilostazol as an alternative to aspirin in Chinese patients with aspirin intolerance after coronary stent implantation: a combined clinical study and computational system pharmacology analysis.

Dual antiplatelet therapy (DAT) with aspirin and clopidogrel is the standard regimen to achieve rapid platelet inhibition and prevent thrombotic events. Currently, little information is available regarding alternative antiplatelet therapy in patients with an allergy or intolerance to aspirin. Although cilostazol is already a common alternative to aspirin in clinical practice in China, its efficacy and safety remain to be determined. We retrospectively analyzed 613 Chinese patients who had undergone primary percutaneous coronary intervention (PCI). Among them, 405 patients received standard DAT (aspirin plus clopidogrel) and 205 patients were identified with intolerance to aspirin and received alternative DAT (cilostazol plus clopidogrel). There were no significant differences between the two groups in their baseline clinical characteristics. The main outcomes of the study included major adverse cardiac events (MACEs) and bleeding events during 12 months of follow-up. The MACEs endpoint was reached in 10 of 205 patients treated with cilostazol (4.9%) and in 34 of 408 patients treated with aspirin (8.3%). No statistically significant difference was observed in MACEs between the two groups. However, patients in the cilostazol group had less restenosis than did patients in the aspirin group (1.5% vs 4.9%, P=0.035). The occurrence of bleeding events tended to be lower in the cilostazol group (0.49% vs 2.7%, P=0.063). These clinical observations were further analyzed using network system pharmacology analysis, and the outcomes were consistent with clinical observations and preclinical data reports. We conclude that in Chinese patients with aspirin intolerance undergoing coronary stent implantation, the combination of clopidogrel with cilostazol may be an efficacious and safe alternative to the standard DAT regimen.

Potential Nexus of Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Insulin Resistance Between Hepatic and Peripheral Tissues.

The liver is the central metabolic organ and plays a pivotal role in regulating homeostasis of glucose and lipid metabolism. Aberrant liver metabolism promotes insulin resistance, which is reported to be a common characteristic of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). There is a complex and bidirectional relationship between NAFLD and T2DM. NAFLD patients with hepatic insulin resistance generally share a high risk of impaired fasting glucose associated with early diabetes; most patients with T2DM experience non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and other more severe liver complications such as cirrhosis and hepatocellular carcinoma (HCC). Additionally, hepatic insulin resistance, which is caused by diacylglycerol-mediated activation of protein kinase C epsilon (PKC𝜀), may be the critical pathological link between NAFLD and T2DM. Therefore, this review aims to illuminate current insights regarding the complex and strong association between NAFLD and T2DM and summarize novel and emerging targets for the treatment of hepatic insulin resistance based on established mechanistic knowledge.

Effect of iloprost on biomarkers in patients with congenital heart disease-pulmonary arterial hypertension.

Some biomarkers play important roles in the endothelial dysfunction of patients with pulmonary arterial hypertension (PAH), including nitric oxide (NO), endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), galectin-3 (Gal-3), B-type natriuretic peptide (BNP), and uric acid (UA). However, studies on these biomarkers in pulmonary artery blood in congenital heart disease-PAH (CHD-PAH) and the effect of iloprost on the regulation of biomarkers are lacking. This study investigated potential CHD-PAH biomarkers and their association with the severity of disease. The effect of iloprost on the regulation of these biomarkers was also studied. A total of 31 patients with CHD-PAH were enrolled. Seven with positive effects of iloprost (the average reduction in mPAP 11.13±1.73 mm Hg) and 19 with negative effects of iloprost (the average reduction in mPAP 4.21±4.87 mm Hg; iloprost positive group [IPG] vs iloprost negative group [ING], P<.01) and five age-matched controls were studied. The pulmonary artery blood sample was collected before and after inhaling iloprost, and the plasma concentrations of Gal-3, ADMA, ET-1, and NO were measured. A significant positive linear relationship was observed between mPAP and plasma ET-1, BNP, ADMA, and UA levels in all patients with CHD-PAH. ET-1, ADMA, BNP, and UA levels had a significant linear relationship with mean pulmonary arterial pressure, which could be used to predict the severity of CHD-PAH. ET-1 might be a potential biomarker to pre-evaluate the effect of iloprost on CHD-PAH. Iloprost could affect the expression of Gal-3 and, therefore, the process of fibrosis could be influenced by iloprost.

H2S Donor NaHS Changes the Production of Endogenous H2S and NO in D-Galactose-Induced Accelerated Ageing.

Aims. The study was designed to explore whether hydrogen sulphide (H2S) and nitric oxide (NO) generation changed in D-galactose- (D-gal-) induced ageing, the possible effects of exogenous H2S supplementation, and related mechanisms. Results. In D-gal-induced senescent mice, both H2S and NO levels in the heart, liver, and kidney tissues were decreased significantly. A similar trend was observed in D-gal-challenged human umbilical vein endothelial cells (HUVECs). Sustained H2S donor (NaHS) treatment for 2 months elevated H2S and NO levels in these mice, and during this period, the D-gal-induced senescent phenotype was reversed. The protective effect of NaHS is associated with a decrease in reactive oxygen species levels and an increase in antioxidants, such as glutathione, and superoxide dismutase and glutathione peroxidase activities. Increased expression of the H2S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine-ß-synthase (CBS) in the heart, liver, and kidney tissues was observed in the NaHS-treated groups. NaHS supplementation also significantly postponed D-gal-induced HUVEC senescence. Conclusions. Endogenous hydrogen sulphide production in both ageing mice and endothelial cells is insufficient. Exogenous H2S can partially rescue ageing-related dysfunction by inducing endogenous H2S and NO production and reducing oxidative stress. Restoring endogenous H2S production may contribute to healthy ageing, and H2S may have antiageing effects.

Dysregulation of TMPRSS3 and TNFRSF11B correlates with tumorigenesis and poor prognosis in patients with breast cancer.

The present study was carried out to investigate the clinical significance of TMPRSS3 and TNFRSF11B in breast cancer. Thus, the expression levels of TMPRSS3 and TNFRSF11B and the correlation with prognosis in patients with breast cancer were analyzed in silico using gene microarray and hierarchical clustering analysis. Then, the differential expression in breast cancer vs. normal breast tissue was explored in the Oncomine platform and verified in our independent samples using IHC technique. Our results indicated that TMPRSS3 was upregulated and TNFRSF11B was downregulated in breast cancer tissues compared with the levels in the human normal breast tissues. TMPRSS3 and TNFRSF11B were confirmed to be correlated with distant organ metastasis of breast cancer. Moreover, upregulation of TMPRSS3 accompanied by downregulation of TNFRSF11B was found to be associated with a shorter median overall survival and indicated a poor prognosis. In conclusion, TMPRSS3 and TNFRSF11B may have potential prognostic value to be used as tumor biomarkers in breast cancer patients.

Drug Effects and Clinical Investigations for Contrast-Induced Nephropathy After Coronary Angiography or Percutaneous Coronary Intervention in Patients With Diabetes.

The aim of the study was to investigate the risk factors of preprocedural laboratory investigations and drug effects to the incidence of contrast-induced nephropathy (CIN) in patients with diabetes who underwent coronary angiography or percutaneous coronary intervention and to assess the short-term safety. We retrospectively studied a total of 568 patients with diabetes who underwent coronary angiography or percutaneous coronary intervention from January, 2013 to January, 2014 in our hospital and compared the baseline clinical characteristics, especially the laboratory investigations and preprocedural drugs of those 2 groups (with CIN group and without CIN group), and half year follow-up. Overall, 53 (9.33%) patients were developed into CIN according to the definition of an increase of 25% from the baseline of serum creatinine concentration, supposing that on the basis of an increase of 44.2 µmol/L, the incidence would be 0.88% (5/568). No significant differences were found between the 2 groups with respect to age, diabetes mellitus duration, operation type, contrast type and volume, left ventricular ejection fraction, and combined diseases including hypertension, myocardial infarction, Arrhythmia, etc. However, patients with CIN tended to be lighter in body weight (P = 0.027) and were more often female [odds ratio (OR) = 2.8, P < 0.01], and also had a higher prevalence with acute coronary syndrome (OR = 5.1, P < 0.01). On the contrary to most studies, the preprocedural serum creatinine in with CIN group in our study was lower than without CIN group (P < 0.001). As for the preprocedural drugs, statins seemed could decrease the incidence of CIN (OR = 0.34, P < 0.05), and the use of diuretics might increase the occurrence of CIN (OR = 2.62, P < 0.05). As regard to the follow-up results, the hospitalization days and expense of with CIN group were significantly longer and higher than the without CIN group, but no significance was found between rehospitalization rate in half year. Preprocedural preventions are essential because there is no effective treatment for CIN our findings could be considered in clinical practice. There are many risk factors for CIN; it is necessary to distinguish the high-risk patients so as to carry out corresponding protection actions.

Celecoxib enhanced the cytotoxic effect of cisplatin in chemo-resistant gastric cancer xenograft mouse models through a cyclooxygenase-2-dependent manner.

Our previous study suggested that co-administration of celecoxib increased chemo-sensitivity of multidrug-resistant human gastric cancer SGC-7901/DDP cells to cisplatin (DDP) in vitro. The present study was designed to investigate whether celecoxib had the similar activities in vivo. SGC-7901/DDP and SGC-7901 xenograft mouse models were established. At the end of the experiment, cisplatin treatment alone significantly inhibited tumor growth in SGC-7901 xenograft, as compared with that in SGC-7901/DDP xenograft, suggesting that it maintained cisplatin sensitivity. When cisplatin and celecoxib were co-administrated, their antitumor activities were augmented in SGC-7901/DDP xenograft. The levels of Ki67 and PCNA after combination therapy were significantly decreased in SGC-7901/DDP xenograft, as compared with those of cisplatin treatment alone. Moreover, examining the apoptotic index by TUNEL assay showed similar results. Further studies demonstrated the inhibitory effect of celecoxib on cyclooxygenase-2 and P-glycoprotein expression was the possible reason to increase sensitivity of SGC-7901/DDP cells to cisplatin in vivo. However, the ratio of thromboxane B2 and prostaglandin F1α was elevated after celecoxib treatment in mice. This has been proposed to increase the risk of thrombogenesis. Further studies are required to evaluate the efficacy and safety of celecoxib for reducing chemo-resistance in gastric cancer.

Celecoxib enhanced the cytotoxic effect of cisplatin in drug-resistant human gastric cancer cells by inhibition of cyclooxygenase-2.

Recently studies indicated that cyclooxygenase-2 might induce P-glycoprotein expression, and was involved in the development of drug resistance phenotype in human gastric cancer cells. The present study was to explore the correlation of celecoxib, a cyclooxygenase-2 specific inhibitor, and P-glycoprotein in drug-resistant gastric cancer cells. The results showed the over-expression of cyclooxygenase-2 and P-glycoprotein in cisplatin-resistant gastric cancer SGC-7901 cells (SGC-7901/DDP), suggesting the possible involvement of cyclooxygenase-2 in the development of P-glycoprotein-mediated drug resistance. Celecoxib was more effective in SGC-7901/DDP cells with a lower inhibitory concentration compared to that in SGC-7901 cells, supporting such a cyclooxygenase-2-dependent drug resistance in SGC-7901/DDP cells. Further studies revealed down-regulation of cyclooxygenase-2 and P-glycoprotein expression by celecoxib, and a decline in prostaglandin E2 release and protein kinase A level. Celecoxib-induced apoptosis of SGC-7901/DDP cells led to increased p53 expression, decreased Bcl-2/Bax ratio and up-regulated caspase-3 level. Also, celecoxib induced apoptosis in SGC-7901/DDP cells synergistically with cisplatin. Our study suggested that celecoxib might enhance the cytotoxic effect of chemotherapeutic agents in drug-resistant human gastric cancer cells through a cyclooxygenase-2-dependent manner.

Capecitabine plus oxaliplatin (XELOX) compared with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in advanced gastric cancer: meta-analysis of randomized controlled trials.

PURPOSE: The study aims to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in patients with advanced gastric cancer. METHODS: Five databases were searched up to June 2014, without language restrictions. The outcomes included overall response rate (ORR), clinical benefit rate (CBR), and toxicity. RESULTS: Twenty-six eligible trials were selected from 178 studies that initially were identified. All trials were published in Chinese journals between 2005 and 2014 and included 1585 patients (787 in XELOX group and 798 in FOLFOXs group). The pooled results failed to show statistical significance of XELOX regimen on ORR (OR 1.18, 95% CIs 1.00-1.41, P = 0.057) and CBR (OR 1.10, 95% CIs 0.95-1.28, P = 0.191) as compared with FOLFOXs regimen. None of the 26 clinical trials reported progression-free survival, and only one reported overall survival rate. The meta-analysis demonstrated that XELOX regimen was associated with a significant lower risk with nausea, stomatitis, diarrhea and alopecia, and a significant higher risk of hand-foot syndrome. CONCLUSIONS: The evidence is limited to suggest that XELOX may share similar efficacy as FOLFOXs and reduce toxicities of chemotherapy in advanced gastric cancer therapy. However, owing to limited data and potential bias of the included studies, further rigorously controlled trials are required.

Effect of nisoldipine and olmesartan on endothelium-dependent vasodilation in essential hypertensive patients.

AIMS: To investigate whether nisoldipine and olmesartan improve endothelial function, decrease asymmetric dimethylarginine (ADMA) and alleviate the inflammatory and oxidative process. METHODS: Fifty-five essential hypertensive patients were randomized to receive nisoldipine or olmesartan for 8 weeks according to a parallel-group, active-controlled, single blind study, and 28 matched normotensive subjects served as healthy controls. Flow-mediated dilation (FMD), and plasma levels of nitric oxide (NO), endothelin-1 (ET-1), high-sensitive C-reactive protein (hs-CRP), 8-isoprostane (also named 8-isoPGF2α), and ADMA were determined. RESULTS: At baseline, the plasma levels of ADMA, ET-1, hs-CRP, and 8-isoPGF2α were markedly higher in patients with essential hypertension than in normotensive subjects (P < 0.05). A significant positive correlation was observed between plasma levels of ET-1 and ADMA in patients with essential hypertension, but not in normotensive subjects. The NO plasma concentrations were significantly lower in patients with essential hypertension than in normotensive subjects. Furthermore, hypertensive subjects demonstrated significantly lower FMD than healthy control (P < 0.05). Nisoldipine and olmesartan significantly and similarly reduced blood pressure in patients with essential hypertension (P < 0.001). At the end of the 8-week treatment, plasma ADMA and ET-1 levels were decreased significantly (P < 0.01). FMD increased significantly in nisoldipine or olmesartan-treated patients (P < 0.05). A significant decrease in plasma hs-CRP contents was observed in patients receiving nisoldipine (P < 0.05). CONCLUSION: The findings demonstrate that nisoldipine and olmesartan both improve FMD in patients with essential hypertension. This may be associated with decreased circulating levels of CRP, ET-1, and ADMA.