Clinic blood pressure responses to two amlodipine salt formulations, adipate and besylate, in adult Korean patients with mild to moderate hypertension: a multicenter, randomized, double-blind, parallel-group, 8-week comparison.
The commercially available formulation of amlodipine is conjugated with besylate salt to increase water solubility. Recently, a new amlodipine salt formulation has been developed in which the free base of amlodipine is conjugated with a chemically different salt, adipate.



The goal of this study was to compare the antihypertensive effect and tolerability of amlodipine adipate with those of amlodipine besylate in patients with mild to moderate hypertension.



This was a multicenter, randomized, doubleblind, parallel-group study in which patients received 8 weeks of treatment with either amlodipine adipate or amlodipine besylate. The primary efficacy variable was noninferiority of the difference in mean changes from baseline in trough diastolic blood pressure (DBP) after 8 weeks of treatment. Secondary efficacy variables included mean changes in DBP, systolic blood pressure (SBP), and response rate (defined as the proportion of patients whose DBP was <90 mm Hg or whose DBP had decreased from baseline by > or =10 mm Hg). The incidence of adverse events (AEs) was also assessed.



Two hundred eleven patients were randomly assigned to receive amlodipine adipate (n = 106) or amlodipine besylate (n = 105). Study patients were primarily female (54.5%), with a mean (SD) age of 52.2 (9.6) years and a mean body weight of 67.1 (10.2) kg; there were no between-group differences in demographic profiles. After 4 weeks of randomized treatment, 58 (27.5%) patients (29 [27.4%] amlodipine adipate, 29 [27.6%] amlodipine besylate) had not achieved a mean DBP <90 mm Hg, and their dose was doubled. Mean DBP changes at 8 weeks were -15.2 (7.3) mm Hg in the amlodipine adipate group and -14.2 (7.4) mm Hg in the amlodipine besylate group (P = NS). Because the 95% CI for the difference in mean DBP changes between groups (-0.53 to 2.55) was within the prespecified lower limit (-4 mm Hg), amlodipine adipate was considered noninferior to amlodipine besylate. Mean SBP changes were -24.9 (12.1) mm Hg in the amlodipine adipate group and -22.0 (14.7) mm Hg in the amlodipine besylate group (P = NS). The response rates were 92.0% for amlodipine adipate and 95.4% for amlodipine besylate (P = NS). The overall incidence of clinical AEs was 20.8% in the amlodipine adipate group and 25.7% in the amlodipine besylate group (P = NS). Drug-related clinical AEs occurred in 5.7% and 12.4% of patients in the respective treatment groups (P = NS). Serum uric acid levels decreased significantly from base-line in both groups (P < 0.001).



Eight weeks of treatment with amlodipine adipate produced significant reductions from baseline in blood pressure in these patients with mild to moderate hypertension. The efficacy of amlodipine adipate was not inferior to that of amlodipine besylate. Tolerability was comparable between the 2 treatment groups.

title: Acute oliguric renal failure associated with angiotensin II receptor antagonists.

title: FOXO1 impairs whereas statin protects endothelial function in diabetes through reciprocal regulation of Kruppel-like factor 2.
abstract: Krüppel-like factor 2 (KLF2) is implicated as a key molecule maintaining endothelial function. This study was designed to evaluate the reciprocal regulation of KLF2 by the forkhead transcription factor FOXO1, and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin, in hyperglycaemic conditions.



Exposure of human umbilical vein endothelial cells to 30 mM glucose activated FOXO1 and suppressed KLF2. These effects were reversed by FOXO1 small interfering RNA. Adenoviral transfection of constitutively active FOXO1 suppressed KLF2 expression. Interestingly, atorvastatin inhibited FOXO1 by increasing phosphorylation and also by inhibiting nuclear localization and replenished KLF2 in high-glucose conditions. This effect of atorvastatin was attenuated by mevalonate. Chromatin immunoprecipitation analysis demonstrated that glucose increased whereas atorvastatin decreased FOXO1 binding to the promoter region of the KLF2 gene. In the vessels of Otsuka Long-Evans Tokushima Fatty rats, animal models of type 2 diabetes, FOXO1 was activated and KLF2 was suppressed, and this was reversed by atorvastatin treatment. The arteries from Otsuka Long-Evans Tokushima Fatty rats showed impairment of endothelium-dependent vasodilatation, and both atorvastatin and KLF2 gene therapies restored it.



Suppression of KLF2 by FOXO1 may be a plausible mechanism of diabetic endothelial dysfunction. High-glucose-induced, FOXO1-mediated KLF2 suppression was reversed by atorvastatin, suggesting that intensive statin treatment could be a therapeutic option in diabetic vascular dysfunction.

title: 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.
abstract: 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: Aging and arterial stiffness.
abstract: Arterial walls stiffen with age. The most consistent and well-reported changes are luminal enlargement with wall thickening and a reduction of elastic properties at the level of large elastic arteries. Longstanding arterial pulsation in the central artery causes elastin fiber fatigue and fracture. Increased vascular calcification and endothelial dysfunction are also characteristic of arterial aging. These changes lead to increased pulse wave velocity, especially along central elastic arteries, and increases in systolic blood pressure and pulse pressure. Vascular aging is accelerated by coexisting cardiovascular risk factors, such as hypertension, metabolic syndrome and diabetes. Vascular aging is an independent risk factor for cardiovascular disease, from atherosclerosis to target organ damage, including coronary artery disease, stroke and heart failure. Various strategies, especially controlling hypertension, show benefit in preventing, delaying or attenuating vascular aging.

title: Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases.
abstract: The forkhead factor, FOXO3a, is known to induce apoptosis in endothelial cells (ECs). However, its effects on extracellular matrices (ECM), which are important in EC survival, remained unknown. Here, we evaluated the role of FOXO3a on EC-ECM interaction.



Constitutively active FOXO3a was transduced to human umbilical vein endothelial cells by adenoviral vector (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection led to dehiscence of ECs from fibronectin-coated plates, resulting in anoikis, which was significantly reversed by matrix metalloproteinase (MMP) inhibitor, GM6001. FOXO3a increased the expression of MMP-3 (stromelysin-1) but decreased the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1), which was associated with increased MMP enzymatic activity in zymography. Pathophysiologic conditions such as serum starvation or heat shock also induced activation of endogenous FOXO3a, leading to activation of MMP-3 and apoptosis, which was reversed by GM6001. Delivery of Ad-TM-FOXO3a to the intraluminal surface in vivo led to EC denudation, disrupted vascular integrity, and impaired endothelium-dependent vasorelaxation.



Activation of MMPs and possible ECM disruption represent novel mechanisms of FOXO3a-mediated apoptosis in ECs.

title: A New and Simple Practical Plane Dividing Hepatic Segment 2 and 3 of the Liver: Evaluation of Its Validity
abstract: The conventional method of dividing hepatic segment 2 (S2) and 3 (S3) is subjective and CT interpretation is unclear. The purpose of our study was to test the validity of our hypothesis that the actual plane dividing S2 and S3 is a vertical plane of equal distance from the S2 and S3 portal veins in clinical situations.  We prospectively performed thin-section iodized-oil CT immediately after segmental chemoembolization of S2 or S3 in 27 consecutive patients and measured the angle of intersegmental plane on sagittal multiplanar reformation (MPR) images to verify its vertical nature. Our hypothetical plane dividing S2 and S3 is vertical and equidistant from the S2 and S3 portal veins (vertical method). To clinically validate this, we retrospectively collected 102 patients with small solitary hepatocellular carcinomas (HCC) on S2 or S3 the segmental location of which was confirmed angiographically. Two reviewers predicted the segmental location of each tumor at CT using the vertical method independently in blind trials. The agreement between CT interpretation and angiographic results was analyzed with Kappa values. We also compared the vertical method with the horizontal one.  In MPR images, the average angle of the intersegmental plane was slanted 15 degrees anteriorly from the vertical plane. In predicting the segmental location of small HCC with the vertical method, the Kappa value between CT interpretation and angiographic result was 0.838 for reviewer 1 and 0.756 for reviewer 2. Inter-observer agreement was 0.918. The vertical method was superior to the horizontal method for localization of HCC in the left lobe (p < 0.0001 for reviewers 1 and 2).  The proposed vertical plane equidistant from S2 and S3 portal vein is simple to use and useful for dividing S2 and S3 of the liver.

title: Genetic Characterization and Assessment of Authenticity of Ancient Korean Skeletal Remains
abstract: To study the maternal lineage history of Korea, we extracted DNA from the skeletal remains of 35 museum samples (some dating back to the Paleolithic Age) excavated from 11 local burial sites scattered throughout southern Korea. Mitochondrial DNA (mtDNA) control region sequences (HV1, HV2, and HV3) were successfully determined for 11 samples with no sharing of the control region polymorphisms with individuals involved in the laboratory analyses. Each of the 11 mtDNAs was assigned to the appropriate East Asian mtDNA haplogroup according to the haplogroup-specific control region mutation motif and diagnostic coding region single nucleotide polymorphism. The successful mtDNA haplogroup determination for each ancient Korean mtDNA and the confirmation of the absence of abnormal mutations based on the haplogroup-directed database comparisons indicates that there is no mosaic structure from cross-contamination or sample mix-up or other errors in our mtDNA sequences. The presence of haplogroups B, D, and G in the prehistoric age is consistent with the hypothesis that the early Korean population has a common origin in the northern regions of the Altai Mountains and Lake Baikal of southeastern Siberia. In addition, the modern Korean population, which possesses lineages from both southern and northern haplogroups, suggests additional gene flow from southern Asian haplogroups in recent times, but many more ancient samples need to be analyzed to directly tell whether there was regional continuity or replacement of early lineages by other lineages in ancient Korea.

title: Atypical Imaging Features of Epstein-Barr Virus–Positive Primary Central Nervous System Lymphomas in Patients without AIDS
abstract: Recent clinical experience with EBV-positive PCNSL in patients without acquired immune deficiency syndrome showed that they tended to have atypical features seen on conventional MR imaging. The purpose of our study was to evaluate the MR imaging features of EBV-positive PCNSL in patients without AIDS and to compare these imaging findings with those of EBV-negative PCNSL.  MR images were obtained in 55 consecutive patients with pathologically proved EBV-positive (n = 10) or EBV-negative (n = 45) PCNSL. We statistically analyzed the differences between the patient groups regarding the occurrence of tumor necrosis or hemorrhage and ADC, rCBVmax, rCBVr, and the Cho/NAA ratio in the tumor area.  Tumor necrosis and hemorrhage were observed in 9 (90%) and 7 (70%), respectively, of the patients with EBV-positive PCNSL; necrosis was observed in 8 (18%), and hemorrhage, in 3 (7%) patients with EBV-negative PCNSL (P < .0001 each). The necrotic core was hyperintense relative to contralateral white matter, as seen on DWI in 4 patients with EBV-positive PCNSL, though the ADC between the 2 patient groups did not differ significantly. rCBVmax, rCBVr, and the Cho/NAA ratios did not differ significantly between the 2 groups. The sensitivity and specificity of necrosis and hemorrhage for differentiating the 2 groups were 89.2% and 81.7% and 78.5% and 94.1%, respectively.  Our initial clinical experience with a small number of patients suggests that EBV-positive PCNSL in patients without AIDS tends to present with atypical MR imaging features.

title: Effects of 9-cis-retinoic acid on the insulin-like growth factor axis in former smokers.
abstract: Insulin-like growth factor (IGF) axis has been associated with the risk of lung cancer. 9-cis-retinoic acid (9-cis-RA) has shown potential chemopreventive activities in former smokers. This study was designed to evaluate the effects of 9-cis-RA on IGF axis in former smokers to identify any benefit the retinoid may have in preventing lung cancer.



Serum concentrations of IGF-I, IGF binding protein (IGFBP)-3, and their molar ratio (IGF-I/IGFBP-3) were measured with radioimmunoassay kits in stored blood samples from the participants of an original chemoprevention trial. The participants had ceased smoking for at least 12 months and were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg) or placebo. All statistical tests were two-sided.



A total of 111 samples from the study's baseline and 84 samples from the 3 months treatment were analyzed. The serum concentrations of IGF-I and IGF-I/IGFBP-3 at baseline were significantly lower in female than in male participants. After 3 months of treatment, the serum level of IGF-I and IGF-I/IGFBP-3 were significantly lower in the 9-cis-RA group than in the placebo group (P = .03 and P < .01, respectively), but the IGFBP-3 level was significantly higher (P = .03).



9-cis-RA treatment modulated the IGF axis in former smokers, suggesting that the IGF axis is a potential target for the chemopreventive activities of 9-cis-RA and that the serum concentrations of IGF, IGFBP-3, and IGF-I/IGFBP-3 could serve as surrogate end point biomarkers of 9-cis-RA treatment.

title: Simulation and prediction of the adaptive immune response to influenza A virus infection.
abstract: The cellular immune response to primary influenza virus infection is complex, involving multiple cell types and anatomical compartments, and is difficult to measure directly. Here we develop a two-compartment model that quantifies the interplay between viral replication and adaptive immunity. The fidelity of the model is demonstrated by accurately confirming the role of CD4 help for antibody persistence and the consequences of immune depletion experiments. The model predicts that drugs to limit viral infection and/or production must be administered within 2 days of infection, with a benefit of combination therapy when administered early, and cytotoxic CD8 T cells in the lung are as effective for viral clearance as neutralizing antibodies when present at the time of challenge. The model can be used to investigate explicit biological scenarios and generate experimentally testable hypotheses. For example, when the adaptive response depends on cellular immune cell priming, regulation of antigen presentation has greater influence on the kinetics of viral clearance than the efficiency of virus neutralization or cellular cytotoxicity. These findings suggest that the modulation of antigen presentation or the number of lung resident cytotoxic cells and the combination drug intervention are strategies to combat highly virulent influenza viruses. We further compared alternative model structures, for example, B-cell activation directly by the virus versus that through professional antigen-presenting cells or dendritic cell licensing of CD8 T cells.