Phase IV, 8-week, multicenter, randomized, active treatment-controlled, parallel group, efficacy, and tolerability study of high-dose candesartan cilexetil combined with hydrochlorothiazide in Korean adults with stage II hypertension.
The objective of this study was to evaluate the efficacy and tolerability of high-dose (32 mg) candesartan in Asians.



In Korean adult patients with stage II hypertension, we evaluated the efficacy and tolerability of candesartan 16 mg/hydrochlorothiazide (HCT) 12.5 mg and candesartan 32 mg/HCT 12.5 mg compared with candesartan 16-mg and 32-mg monotherapy, respectively. This Phase IV, 8-week, multicenter, randomized, active treatment-controlled, parallel group, efficacy, and tolerability study, named CAESAR (Candesartan Effect in Second Stage Arterial Hypertension), enrolled 253 patients with stage II hypertension. Treatment started with either candesartan 16 mg or candesartan 16 mg/HCT 12.5 mg. After 4 weeks, the candesartan dose was forced titrated to 32 mg in both groups. The primary and secondary objectives were to compare the blood pressure (BP) changes after 4 weeks and 8 weeks between candesartan-HCT combination therapy and candesartan monotherapy. The proportion of patients achieving target BP (systolic blood pressure [SBP] <140 mm Hg, but <130 mm Hg for patients with diabetes mellitus or chronic kidney disease; diastolic blood pressure (DBP) <90 mm Hg, but <80 mm Hg for those with diabetes mellitus or chronic kidney disease) after 4 and 8 weeks of therapy was also evaluated. Adverse events were investigated both by spontaneous report by the patient and by the investigators' evaluations in each visit. Laboratory tests were performed at the end of the study to evaluate drug tolerability.



Study patients were all Asians, mostly male (65.7%), with a mean (SD) age of 49.4 (10.6) years and a mean body weight of 68.9 (12.1) kg; there were no between-group variances in demographic profiles except that the mean age in the candesartan-HCT group (51.0 [10.2] years) was about 3.2 years higher than that in the candesartan monotherapy group (47.8 [10.7] years; P = 0.02) despite random allocation. A total of 80.4% of the study patients had not been treated before, whereas 19.6% were previously treated and enrolled after 2 weeks of washout period. Baseline sitting systolic/diastolic BPs (SBP/DBP) were 160.7 (13.0)/104.6 (9.5) mm Hg. After 4 weeks, patients treated with candesartan 16 mg/HCT 12.5 mg showed significant decreases in SBP/DBP of 28.7 (17.5)/17.8 (10.2) mm Hg, and those in the candesartan 16 mg monotherapy group showed decreases of 20.5 (14.5)/14.1 (10.1) mm Hg (P < 0.01 between treatments for both SBP and DBP). After forced titration of candesartan from 16 mg to 32 mg at week 8, there was an additional reduction in SBP/DBP of 4.1 (12.7)/3.8 (8.3) mm Hg in the candesartan-HCT combination therapy group and 4.0 (11.6)/2.0 (8.5) mm Hg in the candesartan monotherapy group (P < 0.001 for SBP and DBP in both groups compared with values at week 4). A greater proportion of patients (70.6%) attained the target BP in the candesartan-HCT combination therapy group than in the candesartan monotherapy group (53.2%, P = 0.014). A total of 32 mg of candesartan was well tolerated both in combination therapy with HCT and in monotherapy. Dizziness was the most common adverse event in both groups (5 and 2 patients, respectively).



The candesartan-HCT combination was associated with a statistically significant lowering of BP compared with candesartan monotherapy.

title: Differential effects of homocysteine on porcine endothelial and vascular smooth muscle cells.
abstract: High concentrations of homocysteine damage endothelial cells and lower concentrations increase vascular smooth muscle cell (VSMC) growth. This study investigated the effects of various concentrations of homocysteine on endothelial cells (VECs) and VSMCs in terms of cell survival, proliferation, and function. VECs and VSMCs from porcine thoracic aorta were studied. These cells were exposed to homocysteine in concentrations of 20 microM, 400 microM, and 1 mM every 8 h for 24 h, and its effect on cell survival, proliferation, and function were studied using methylthiazoletetrazolium assay, [3H]-thymidine incorporation test, and 6-keto-prostaglandin F1alpha enzyme-linked immunosorbent assay for VECs, and platelet-derived growth factor (PDGF) enzyme-linked immunosorbent assay for VSMCs, respectively. In VECs, 20 microM of homocysteine reduced the viable cell count to 95 +/- 31%, 400 microM reduced it to 89 +/- 35%, 1,000 microM reduced it to *58 +/- 29% (control = 100 +/- 30%, n = 18, *p < 0.05). In VSMCs, 20 microM of homocysteine slightly increased the viable cell count to 106 +/- 30%, but there was no statistical significance; 400 microM of homocysteine reduced the viable cell count to *74 +/- 29%, 1,000 microM to *50 +/- 24% (control = 100 +/- 28%, n = 18, *p < 0.05). In VECs, 20 microM of homocysteine reduced [3H]-thymidine uptake by 98 +/- 14%, 400 microM reduced it by *82 +/- 17%, 1,000 microM reduced it by *66 +/- 17% (control = 100 +/- 12, n = 6, *p < 0.05), respectively. But in VSMCs, 20 microM of homocysteine significantly increased [3H]-thymidine uptake (*131 +/- 16%), and thereafter, homocysteine decreased VSMCs [3H]-thymidine uptake, 400 microM by *24 +/- 7%, 1,000 microM by *29 +/- 10% (control = 100 +/- 16, n = 6, *p < 0.05), respectively. Homocysteine decreased VEC prostacyclin secretion in a dose-dependent manner, 20 microM by 105 +/- 0.65 pg/100 microl, 400 microM by *100 +/- 2.37 pg/100 microl, 1,000 microM by *93 +/- 2.54 pg/100 microl (control = 107 +/- 1.26 pg/100 microl, n = 6, *p = 0.007). In VSMCs, 20 microM of homocysteine slightly increased PDGF secretion by 62.2 +/- 20.7 pg/100 microl, but there was little statistical significance (p = 0.13); 400 microM of homocysteine reduced PDGF secretion by *28.9 +/- 10.7 pg/100 microl, and 1,000 microM reduced it by *21.3 +/- 4.7 pg/100 microl (control = 54.5 +/- 9.3 pg/100 microl, n = 6, *p < 0.05). High concentrations of homocysteine damaged both VECs and VSMCs with respect to cell survival, proliferation, and function. By increasing exposure to homocysteine, it was shown that physiologic high concentrations of homocysteine enhanced VSMC proliferation.

title: Cardio–renal protection with aliskiren, a direct renin inhibitor, in the ASPIRE HIGHER program
abstract: Aliskiren is the first in a new class of orally effective direct renin inhibitors. Initial results of clinical efficacy studies have demonstrated at least equivalent or superior blood pressure-lowering efficacy when compared with existing drugs, and a favorable side-effect profile either as monotherapy or as a component of combination therapy. This report aims to introduce and provide a critical appraisal of the initial results of the ASPIRE HIGHER program, evaluating the potential cardio–renal protective effects of aliskiren.

title: Prevalence and risk factors of masked hypertension identified by multiple self-blood pressure measurement.
abstract: With great interest we read the article by O'Brien,1 comprehensively reviewing implementation of out-of-office blood pressure (BP) measurement, ie, ambulatory BP measurement and self-BP measurement (SBPM), for more precise evaluation and management of hypertension. Clearly, ambulatory BP measurement provides a greater amount of BP information and, thus, can be more sensitive than SBPM. However, ambulatory BP measurement is more expensive and may cause discomfort, interfering with subjects’ normal activity, which limit its routine use.2 Here, we introduce our investigation of the diurnal BP pattern and its determining factors by implementing a multiple SBPM strategy.

A total of 5009 hypertension patients in 500 primary care clinics in Korea, whose recent BP during the last 2 visits was stable without change in medication, were enrolled. This study was performed by multicenter, prospective, observational design. To minimize possible confounding factors and to compare the differential effect of various classes of antihypertensive agents, 2 strategies were used. First, enrolled patients were …

title: Effects of interscalene brachial plexus block to intra-operative hemodynamics and postoperative pain for arthroscopic shoulder surgery
abstract: Although arthroscopic shoulder surgery is less invasive and painful than open shoulder surgery, it can often cause intra-operative hemodynamic instability and severe post-operative pain. This study was conducted to investigate the efficacy of the interscalene brachial plexus block (IBPB) on intra-operative hemodynamic changes and post-operative pain during arthroscopic shoulder surgery.  After institutional review board approval, 50 consecutive patients that had undergone arthroscopic shoulder surgery under general anesthesia were randomly assigned to one of two groups to evaluate intra-operative hemodynamic changes and post-operative pain control. Group 1 patients received an IBPB with 10 ml of normal saline guided by a nerve stimulator before induction, and Group 2 patients received 10 ml of 0.5% ropivacaine hydrochloride with the same technique. The heart rate and systolic and diastolic blood pressures were recorded before the incision and 1, 3, 5, 10, and 20 minutes after the incision. Pre-operative and post-operative pain was evaluated with a visual analog scale 1, 3, 6, 12, and 24 hours after surgery. The patients were given tramadol as a rescue medication option. The total volume of tramadol that was injected was also evaluated over the same intervals.  Group 2 showed significantly lower systolic and diastolic blood pressures and heart rates intra-operatively compared to Group 1 (P < 0.05). The visual analog scale pain scores, except at 24 hours after surgery, were significantly lower in Group 2 (P < 0.05). The total tramadol consumption significantly reduced in Group 2 (P < 0.05).  IBPB effectively controlled the hemodynamic changes that occurred during arthroscopic shoulder surgery as well as post-operative pain.

title: New CT response criteria in non-small cell lung cancer: proposal and application in EGFR tyrosine kinase inhibitor therapy.
abstract: We aimed to devise new CT response criteria (new response criteria, NRC) in patients with non-small cell lung cancer (NSCLC) and to evaluate the efficacy of the criteria for stratifying patient responses and predicting patient survival compared to that of the traditional size-based criteria RECIST version 1.1. Our institutional review board approved this study with a waiver of informed consent. We enrolled 80 NSCLC patients as an experimental arm and treated them with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). Two blinded, independent radiologists assessed CT images for tumor response using the NRC, which were also validated in a separate arm (75 NSCLC patients). Tumor responses evaluated by RECIST 1.1 and the new criteria were compared from each other and correlated with patient survival. For statistical analyses, Kaplan-Meier method and kappa statistics were used. In the experimental arm (n=80), interobserver agreements for the assessment of patient response were excellent for both RECIST and NRC. Sixteen RECIST nonresponding patients achieved a designation of partial response according to NRC. In the validation arm (n=75), patients of optimal response (partial response) with the new criteria had median overall survival of 18.4 months compared with 8.5 months in patients with poor response (P=.04). However, RECIST failed to show survival difference between the two response groups. In NSCLC patients treated with EGFR-TKIs, new CT criteria reflecting additional morphological characteristics of target lesions are reproducible and have statistically significant association with overall survival.

title: Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis.
abstract: Tobacco carcinogens induce Akt activation and lung carcinogenesis. We previously demonstrated that deguelin, a natural plant product, specifically inhibits the proliferation of premalignant and malignant human bronchial epithelial cells by blocking Akt activation. To evaluate the ability of deguelin to block tobacco carcinogen-induced lung tumorigenesis, we evaluated the in vivo effects of deguelin on Akt activation and lung tumorigenesis in transgenic mice in which Akt expression was induced by tamoxifen and in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Deguelin suppressed Akt activation in vivo, as measured by immunohistochemistry and immunoblotting, and statistically significantly reduced NNK/BaP-induced lung tumor multiplicity, volume, and load in A/J mice, as monitored by microcomputed tomography image analysis, with no detectable toxicity. These results indicate that deguelin warrants consideration as a chemopreventive agent for early-stage lung carcinogenesis in a clinical lung cancer chemoprevention trial.

title: Wide spread of Tn2006 in an AbaR4-type resistance island among carbapenem-resistant Acinetobacter baumannii clinical isolates in Taiwan.
abstract: Carbapenem resistance in Acinetobacter baumannii is a global problem. The purpose of this study was to elucidate current resistance mechanisms of imipenem-resistant A. baumannii (IRAB) in Taiwan and their correlation with patient outcomes. Acinetobacter baumannii clinical isolates from two teaching hospitals in Taiwan were collected in 2009 and were examined by Etest for determination of the minimum inhibitory concentrations (MICs) of imipenem, ceftazidime and ceftriaxone. Primers specific for carbapenemase genes and upstream regions were designed for PCR amplification. Bacterial isolates were genotyped by pulsed-field gel electrophoresis (PFGE). Clinical presentations of patients were analysed retrospectively. Upstream insertion sequence ISAba1 was found in 34 isolates that carried bla(OXA-23), including 28 with transposon Tn2006 (ISAba1-bla(OXA-23)-ISAba1) in an AbaR4-type resistance island and 6 with Tn2008 (ISAba1-bla(OXA-23)), as well as in 8 isolates carrying ISAba1-bla(OXA-51-like). All of these isolates expressed full resistance to imipenem (MIC>32 mg/L). Forty-one different PFGE genotypes were found among 62 isolates. Tn2006 was found in 19 genotypes (46.3%), which is more common than ISAba1-bla(OXA-51-like) (12.2%) (P=0.001). Prior use of carbapenems or extended-spectrum cephalosporins for ≥5 days was the only independent risk factor significantly associated with IRAB infection (odds ratio=361.175). Higher mortality was significantly associated with infection caused by IRAB and ISAba1-bla(OXA-23)-carrying strains compared with infection caused by imipenem-susceptible A. baumannii and ISAba1-bla(OXA-51-like)-carrying strains (P=0.009 and 0.027, respectively). Tn2006 is currently the most common imipenem resistance determinant, which showed a higher ability to spread among A. baumannii and was associated with a higher mortality in IRAB-infected patients.

title: Modeling T Cell Proliferation and Death in Vitro Based on Labeling Data: Generalizations of the Smith–Martin Cell Cycle Model
abstract: The fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) classifies proliferating cell populations into groups according to the number of divisions each cell has undergone (i.e., its division class). The pulse labeling of cells with radioactive thymidine provides a means to determine the distribution of times of entry into the first cell division. We derive in analytic form the number of cells in each division class as a function of time based on the distribution of times to the first division. Choosing the distribution of time to the first division to fit thymidine labeling data for T cells stimulated in vitro under different concentrations of IL-2, we fit CFSE data to determine the dependence of T cell kinetic parameters on the concentration of IL-2. As the concentration of IL-2 increases, the average cell cycle time is shortened, the death rate of cells is decreased, and a higher fraction of cells is recruited into division. We also find that if the average cell cycle time increases with division class then the qualify of our fit to the data improves.