ETV2 Enhances CXCL5 Secretion from Endothelial Cells, Leading to the Promotion of Vascular Smooth Muscle Cell Migration.

Abnormal communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) promotes vascular diseases, including atherogenesis. ETS variant transcription factor 2 (ETV2) plays a substantial role in pathological angiogenesis and the reprogramming of ECs; however, the role of ETV2 in the communication between ECs and VSMCs has not been revealed. To investigate the interactive role of ETV2 in the EC to VSMC phenotype, we first showed that treatment with a conditioned medium from ETV2-overexpressed ECs (Ad-ETV2 CM) significantly increased VSMC migration. The cytokine array showed altered levels of several cytokines in Ad-ETV2 CM compared with those in normal CM. We found that C-X-C motif chemokine 5 (CXCL5) promoted VSMC migration using the Boyden chamber and wound healing assays. In addition, an inhibitor of C-X-C motif chemokine receptor 2 (CXCR2) (the receptor for CXCL5) significantly inhibited this process. Gelatin zymography showed that the activities of matrix metalloproteinase (MMP)-2 and MMP-9 increased in the media of VSMCs treated with Ad-ETV2 CM. Western blotting revealed a positive correlation between Akt/p38/c-Jun phosphorylation and CXCL5 concentration. The inhibition of Akt and p38-c-Jun effectively blocked CXCL5-induced VSMC migration. In conclusion, CXCL5 from ECs induced by ETV2 promotes VSMC migration via MMP upregulation and the activation of Akt and p38/c-Jun.

Plantamajoside Attenuates Neointima Formation via Upregulation of Tissue Inhibitor of Metalloproteinases in Balloon-Injured Rats.

The abnormal change of vascular smooth muscle cell (VSMC) behavior is an important cellular event leading to neointimal hyperplasia in atherosclerosis and restenosis. Plantamajoside (PMS), a phenylethanoid glycoside compound of the Plantago asiatica, has been reported to have anti-inflammatory, antioxidative, and anticancer activities. In this study, the protective effects of PMS against intimal hyperplasia and the mechanisms underlying the regulation of VSMC behavior were investigated. MTT and BrdU assays were performed to evaluate the cytotoxicity and cell proliferative activity of PMS, respectively. Rat aortic VSMC migrations after treatment with the determined concentration of PMS (50 and 150 µM) were evaluated using wound healing and Boyden chamber assays. The inhibitory effects of PMS on intimal hyperplasia were evaluated in balloon-injured (BI) rat carotid artery. PMS suppressed the proliferation in platelet-derived growth factor-BB-induced VSMC, as confirmed from the decrease in cyclin-dependent kinase (CDK)-2, CDK-4, cyclin D1, and proliferating cell nuclear antigen levels. PMS also inhibited VSMC migration, consistent with the downregulated expression and zymolytic activities of matrix metalloproteinase (MMP)2, MMP9, and MMP13. PMS specifically regulated MMP expression through p38 mitogen-activated protein kinase and focal adhesion kinase pathways. Tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2 levels were upregulated via Smad1. TIMPs inhibited the conversion of pro-MMPs to active MMPs. PMS significantly inhibited neointimal formation in BI rat carotid arteries. In conclusion, PMS inhibits VSMC proliferation and migration by upregulating TIMP1 and TIMP2 expression. Therefore, PMS could be a potential therapeutic agent for vascular atherosclerosis and restenosis treatment.

Oxidative stress generated by polycyclic aromatic hydrocarbons from ambient particulate matter enhance vascular smooth muscle cell migration through MMP upregulation and actin reorganization.

BACKGROUND: Epidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined. RESULTS: VSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significantly increased in ambient PM-treated VSMCs, with MMP9 levels being significantly higher in WPM-treated VSMCs than in those treated with SPM. As expected, migration was significantly increased in all tested PAHs (anthracene, ANT; benz(a)anthracene, BaA) and their oxygenated derivatives (9,10-Anthraquinone, AQ; 7,12-benz(a)anthraquinone, BAQ, respectively). The phosphorylated levels of focal adhesion kinase (FAK) and formation of the focal adhesion complex were significantly increased in ambient PM or PAH-treated VSMCs, and these effects were blocked by administration of NAC or α-NF, an inhibitor of AhR, the receptor that allows PAH uptake. Subsequently, the levels of phosphorylated Src and NRF, the downstream targets of FAK, were altered with a pattern similar to that of p-FAK. CONCLUSIONS: PAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.

Clinical Outcomes of Ticagrelor in Korean Patients with Acute Myocardial Infarction without High Bleeding Risk.

BACKGROUND: Although ticagrelor is known to increase the bleeding risk compared to clopidogrel in East Asian patients, its clinical benefits in patients with acute myocardial infarction (AMI) without high bleeding risk (HBR) remains unknown. METHODS: A total of 7,348 patients who underwent successful percutaneous coronary intervention (PCI) from the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), between November 2011 and December 2015, were divided into two groups according to the Academic Research Consortium for HBR criteria (KAMIR-HBR, 2,469 patients; KAMIR-non HBR, 4,879 patients). We compared in-hospital major adverse cardiovascular events (MACEs, defined as a composite of cardiac death, non-fatal myocardial infarction, or stroke), and the thrombolysis in myocardial infarction (TIMI) major bleeding between ticagrelor and clopidogrel in the KAMIR-HBR and the KAMIR-non HBR groups, respectively. RESULTS: After propensity score matching, ticagrelor had a higher incidence of in-hospital TIMI major bleeding than clopidogrel in all patients (odds ratio [OR], 1.683; 95% confidence interval [CI], 1.010-2.805; P = 0.046) and the KAMIR-HBR group (OR, 3.460; 95% CI, 1.374-8.714; P = 0.008). However, there was no significant difference in in-hospital TIMI major bleeding between ticagrelor and clopidogrel in the KAMIR-non HBR group (OR, 1.436; 95% CI, 0.722-2.855; P = 0.303). No differences were observed in the cumulative incidences of in-hospital and 6-month MACEs between ticagrelor and clopidogrel in both groups. CONCLUSIONS: The bleeding risk of ticagrelor was attenuated in Korean patients with AMI without HBR. Appropriate patient selection could reduce in-hospital bleeding complications associated with ticagrelor in Korean patients with AMI who underwent successful PCI.

LRP5 Regulates HIF-1α Stability via Interaction with PHD2 in Ischemic Myocardium.

Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/ß-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/ß-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment.

Guidelines for accreditation of endoscopy units: quality measures from the Korean Society of Coloproctology.

PURPOSE: Colonoscopy is an effective method of screening for colorectal cancer (CRC), and it can prevent CRC by detection and removal of precancerous lesions. The most important considerations when performing colonoscopy screening are the safety and satisfaction of the patient and the diagnostic accuracy. Accordingly, the Korean Society of Coloproctology (KSCP) herein proposes an optimal level of standard performance to be used in endoscopy units and by individual colonoscopists for screening colonoscopy. These guidelines establish specific criteria for assessment of safety and quality in screening colonoscopy. METHODS: The Colonoscopy Committee of the KSCP commissioned this Position Statement. Expert gastrointestinal surgeons representing the KSCP reviewed the published evidence to identify acceptable quality indicators and indicators that lacked sufficient evidence. RESULTS: The KSCP recommends an optimal standard list for quality control of screening colonoscopy in the following 6 categories: training and competency of the colonoscopist, procedural quality, facilities and equipment, performance indicators and auditable outcomes, disinfection of equipment, and sedation and recovery of the patient. CONCLUSION: The KSCP recommends that endoscopy units performing CRC screening evaluate 6 key performance measures during daily practice.

Low density lipoprotein receptor-related protein 1 regulates cardiac hypertrophy induced by pressure overload.

BACKGROUND: Cardiac hypertrophy is associated with functional changes in cardiomyocytes, which often results in heart failure. The low-density lipoprotein receptor-related protein 1 (LRP1) is a large multifunctional endocytic receptor involved in many physiological and pathological processes. However, its function in the development of cardiac hypertrophy remains largely unclear. METHODS: Adenoviral constructs were used for either overexpression or silencing of LRP1 in both in vitro and in vivo experiments. Cardiac function was measured using the Millar catheter. RESULTS: LRP1 expression was upregulated in both transverse aortic constriction (TAC)-induced hypertrophic myocardium and catecholamine (phenylephrine (PE) and norepinephrine (NE))- and angiotensin II (AngII)-induced hypertrophic cardiomyocytes. In addition, cell surface area, protein/DNA ratio, and the mRNA levels of hypertrophic markers were significantly increased in LRP1-overexpressing cardiomyocytes without catecholamine stimulation. Conversely, LRP1 inhibition by LRP1-specific siRNA or a specific ligand-binding antagonist (RAP) significantly rescued hypertrophic effects in PE, NE, or AngII-induced cardiomyocytes. LRP1 overexpression induced PKCα, then activated ERK, resulting in cardiac hypertrophy with the downregulation of SERCA2a and calcium accumulation, which was successfully restored in both LRP1-silenced cardiomyocytes and TAC-induced hearts. CONCLUSIONS: LRP1 regulates cardiac hypertrophy via the PKCα-ERK dependent signaling pathway resulting in the alteration of intracellular calcium levels, demonstrating that LRP1 might be a potential therapeutic target for cardiac hypertrophy.

The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation.

BACKGROUND: The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection. METHODS: Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%). RESULTS: Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection. CONCLUSIONS: A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection.

Agreement of the Resting Distal to Aortic Coronary Pressure With the Instantaneous Wave-Free Ratio.

BACKGROUND: Recently, 2 randomized controlled trials showed that the instantaneous wave-free ratio (iFR), a resting coronary physiological index, is noninferior to fractional flow reserve for guiding revascularization. The resting distal to aortic coronary pressure (Pd/Pa) measured at rest is another adenosine-free index widely available in the cardiac catheterization laboratory; however, little is known about the agreement of Pd/Pa using iFR as a reference standard. OBJECTIVES: The goal of this study was to investigate the agreement of Pd/Pa with iFR. METHODS: A total of 763 patients were prospectively enrolled from 12 institutions. iFR and Pd/Pa were measured under resting conditions. Using iFR ≤0.89 as a reference standard, the agreement of Pd/Pa and its best cutoff value were assessed. RESULTS: According to the independent core laboratory analysis, iFR and Pd/Pa were analyzable in 627 and 733 patients (82.2% vs. 96.1%; p < 0.001), respectively. The median iFR and Pd/Pa were 0.90 (interquartile range: 0.85 to 0.94) and 0.92 (interquartile range: 0.88 to 0.95), and the 2 indices were highly correlated (R2 = 0.93; p < 0.001; iFR = 1.31 * Pd/Pa -0.31). According to the receiver-operating characteristic curve analysis, Pd/Pa showed excellent agreement (area under the curve: 0.98; 95% confidence interval: 0.97 to 0.99; p < 0.001) with a best cutoff value of Pd/Pa ≤0.91. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 93.0%, 91.4%, 94.4%, 93.3%, and 92.7%, respectively. These results were similar in patients with acute coronary syndrome and stable angina. CONCLUSIONS: Pd/Pa was analyzable in a significantly higher number of patients than iFR. Pd/Pa showed excellent agreement with iFR, suggesting that it could be applied clinically in a similar fashion. (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology? [CONTRAST]; NCT02184117).

Influence of Contrast Media Dose and Osmolality on the Diagnostic Performance of Contrast Fractional Flow Reserve.

BACKGROUND: Contrast fractional flow reserve (cFFR) is a method for assessing functional significance of coronary stenoses, which is more accurate than resting indices and does not require adenosine. However, contrast media volume and osmolality may affect the degree of hyperemia and therefore diagnostic performance. METHODS AND RESULTS: cFFR, instantaneous wave-free ratio, distal pressure/aortic pressure at rest, and FFR were measured in 763 patients from 12 centers. We compared the diagnostic performance of cFFR between patients receiving low or iso-osmolality contrast (n=574 versus 189) and low or high contrast volume (n=341 versus 422) using FFR≤0.80 as a reference standard. The sensitivity, specificity, and overall accuracy of cFFR for the low versus iso-osmolality groups were 73%, 93%, and 85% versus 87%, 90%, and 89%, and for the low versus high contrast volume groups were 69%, 99%, and 83% versus 82%, 93%, and 88%. By receiver operating characteristics (ROC) analysis, cFFR provided better diagnostic performance than resting indices regardless of contrast osmolality and volume (P<0.001 for all groups). There was no significant difference between the area under the curve of cFFR in the low- and iso-osmolality groups (0.938 versus 0.957; P=0.40) and in the low- and high-volume groups (0.939 versus 0.949; P=0.61). Multivariable logistic regression analysis showed that neither contrast osmolality nor volume affected the overall accuracy of cFFR; however, both affected the sensitivity and specificity. CONCLUSIONS: The overall accuracy of cFFR is greater than instantaneous wave-free ratio and distal pressure/aortic pressure and not significantly affected by contrast volume and osmolality. However, contrast volume and osmolality do affect the sensitivity and specificity of cFFR. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02184117.

Effects of matrix metalloproteinase 13 on vascular smooth muscle cells migration via Akt-ERK dependent pathway.

Migration of vascular smooth muscle cells (VSMCs) is an early event of atherosclerosis, which is mediated mainly by matrix metalloproteinase (MMP) 2 and 9. Because MMP13 is associated with tumor cells migration, we hypothesized that MMP13 participates in VSMC migration induced by certain stimuli such as platelet-derived growth factor (PDGF) and angiotensin II (Ang II). We found that the mRNA level of MMP13 in rat aortic smooth muscle cells (RAoSMCs) was increased by both PDGF and Ang II. We observed the significant decrease of migration in PDGF- or Ang II-treated RAoSMCs by MMP13 specific inhibitor treatment. Silencing of MMP13 by a specific small interfering RNA (siRNA) significantly decreased expression of the active form of MMP13, which is followed by the decreased migration of PDGF- or Ang II-treated RAoSMCs. Interestingly, we observed synergistic inhibitory effects on migration by treatment with MMP2 and 13 or MMP9 and 13 inhibitors compared with that in single treatments. Moreover, we found that cordycepin, a known inhibitor of VSMC migration, caused significant downregulation of MMP2, 9, and 13 expression in PDGF-treated RAoSMCs. We further show that the expression level of MMP13 was significantly decreased by the treatment of Akt or ERK specific inhibitor in PDGF-treated RAoSMCs. Together, our data strongly suggest that MMP13 involves VSMCs migration via an Akt and ERK-dependent regulation [corrected].

Comparison of skin incisions used for open lateral internal sphincterotomies--radial versus circumferential incisions: a retrospective cohort study.

INTRODUCTION: Lateral internal sphincterotomy (LIS) is a safe and effective surgical treatment, commonly used in patients with chronic anal fissures (CAFs). Although LIS is a simple surgical technique, it may cause several complications. Open LIS is usually performed through an incision made in the intersphincteric groove; radial or circumferential incisions, used according to the surgeon's preference. However, differences in clinical outcomes and wound healing, based on type of skin incision, are unclear. We investigated incision site wound healing and other clinical outcomes, after open LIS, according to the type of skin incision employed. METHODS: We retrospectively reviewed the data of the electronic medical records of 602 patients who underwent open LIS for CAFs between March 2005 and February 2010 at Yang Hospital, Seoul, Korea. RESULTS: Of the 602 patients, 298 patients received radial incisions and 304 received circumferential incisions. Circumferential incisions of the anus reduced the wound healing time compared to radial incisions (19.1 vs. 24.0 days, p < 0.001). There were no significant differences between the groups in wound complications such as perianal abscess, fistula, or cellulitis. Clinical outcomes including recurrence, persistence of fissures, and continence problems were also similar between the groups. CONCLUSIONS: Our study shows that circumferential skin incisions, during LIS, are associated with shorter healing times than radial incisions.

The role of paternal drinking problems in the psychological characteristics of high school students.

BACKGROUND: It has been reported that children with parental drinking problems are at increased risk of drinking problems or psychiatric diseases in adulthood. The present study was conducted to examine the psychiatric characteristics of high school students according to paternal drinking problems. METHODS: The subjects were 950 high school students (390 male and 560 female). The paternal drinking problems were assessed by using the Father-Short Michigan Alcoholism Screening Test. The Alcohol Use Disorders Identification Test, Beck's depression inventory, and Beck's anxiety inventory were used to evaluate the drinking behavior, depression, and anxiety of high school students. RESULTS: While male students with paternal drinking problems showed significantly increased risk of anxiety (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.05 to 4.63), female students with paternal drinking problems showed significantly increased risk of depression (OR, 1.84; 95% CI, 1.24 to 2.74) according to the results of logistic regression analysis with adjustments for participants' age, whether they live together with parents, their religion, club activities, and smoking habits on the basis of students without paternal drinking problems. CONCLUSION: The above results suggest that paternal drinking problems lead to unstable mentalities in both male and female students, and that a family physician should address the mental state of teenagers with paternal drinking problems during clinical encounters.

Pure NOTES rectosigmoid resection: transgastric endoscopic IMA dissection and transanal rectal mobilization in animal models.

BACKGROUND: We report a pure natural orifice translumenal endoscopic surgery (NOTES(®); American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and the Society of American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) rectosigmoidectomy in animal models using transgastric endoscopic inferior mesenteric artery (IMA) dissection and transanal rectal mobilization. MATERIALS AND METHODS: Ten live animals (2 pigs weighing 35-40 kg each and 8 dogs weighing 25-30 kg each) were used. A gastrotomy was made using a needle-knife puncture and the balloon dilatation technique or following the creation of a submucosal tunnel. A circular stapler shaft was transanally inserted up to the sigmoid colon for spatial orientation and traction of the mesocolon. The IMA was endoscopically dissected using a Coagrasper™ (Olympus, Tokyo, Japan) and then clipped. Endoscopic division of the sigmoid mesocolon was conducted laterally toward the marginal artery. Transanal full-thickness circumferential rectal and mesorectal dissections were performed, and a colorectal anastomosis was performed using a circular stapler with a single stapling technique. During the transanal approach, the gastrotomy was closed using four endoscopic clips. RESULTS: Endoscopic dissection of the IMA was successful in all cases, but minor bleedings occurred in 3 cases. The mean time from dissection and clipping to division of the IMA was 36.7 minutes (range, 25-45 minutes). The mean operation time was 180.5 minutes (range, 145-210 minutes). There were no intraoperative complications or hemodynamic instability. The mean length of the resected specimen was 11.2 cm (range, 9-17 cm). CONCLUSIONS: A pure NOTES approach to rectosigmoid resection using transgastric endoscopic IMA dissection is technically feasible in animal models.

Effects of nifedipine on the pharmacokinetics of repaglinide in rats: possible role of CYP3A4 and P-glycoprotein inhibition by nifedipine.

BACKGROUND: The aim of this study was to investigate the effects of nifedipine on the bioavailability and pharmacokinetics of repaglinide in rats. METHODS: The effect of nifedipine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of nifedipine (1 and 3 mg/kg). RESULTS: Administration of nifedipine resulted in inhibition CYP3A4 activity with an IC50 value of 7.8 µM, and nifedipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, nifedipine significantly increased the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of repaglinide by 49.3 and 25.5%, respectively. Nifedipine significantly decreased the total body clearance (CL/F) of repaglinide by 22.0% compared to the oral control group. Nifedipine also increased the absolute bioavailability (AB) of repaglinide by 50.0% compared to the oral control group (33.6%). In addition, the relative bioavailability (RB) of repaglinide was 1.16- to 1.49-fold greater than that of the control group. Compared to the intravenous control, nifedipine significantly increased AUC0-∞ of repaglinide. Blood glucose concentrations had significant differences compared to the oral control groups. CONCLUSION: Nifedipine enhanced the oral bioavailability of repaglinide, which may be mainly attributable to inhibition of CYP3A4-mediated metabolism of repaglinide in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine and/or reduction of total body clearance by nifedipine. The current study has raised awareness of potential drug interactions by concomitant use of repaglinide with nifedipine.

Effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide: possible role of CYP3A4 and P-glycoprotein inhibition by efonidipine.

The purpose of this study was to investigate the effects of efonidipine on the pharmacokinetics and pharmacodynamics of repaglinide in rats. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of efonidipine (1 and 3 mg/kg). Efonidipine inhibited CYP3A4 activity with an IC(50) value of 0.08 µM, and efonidipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, efonidipine significantly increased the area under the plasma concentration-time curve (AUC(0-∞)) (P < 0.01 for 3 mg/kg) and the peak plasma concentration (C (max)) (P < 0.05 for 3 mg/kg) of repaglinide by 51.3 and 28.6%, respectively. Efonidipine also significantly (P < 0.01 for 3 mg/kg) increased the absolute bioavailability (AB) of repaglinide by 51.5% compared to the oral control group (33.6%). Moreover, efonidipine significantly increased (P < 0.05 for 3 mg/kg) the AUC(0-∞) of intravenously administered repaglinide. Consistent with these kinetic alterations, the hypoglycemic effect in the concurrent administration group was more pronounced than that in the control group (i.e., repaglinide alone) when the drug was given orally. A pharmacokinetic/dynamic model involving 2-compartment open model with inhibition in absorption/elimination and an indirect response model was apparently sufficient in estimating the concentration-time and effect-time profiles of repaglinide with or without efonidipine. Present study has raised the awareness of potential drug interactions by concomitant use of efonidipine with repaglinide, since efonidipine may alter the absorption and/or elimination of repaglinide by the inhibition of CYP3A4 and P-gp efflux pump. Therefore, the concurrent use of efonidipine with repaglinide may require a close monitoring for potential drug interactions.

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of losartan and its main metabolite EXP-3174 in rats: possible role of CYP3A4 and P-gp inhibition by HMG-CoA reductase inhibitors.

The present study was designed to investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, simvastatin) on the pharmacokinetics of losartan and its active metabolite EXP-3174 in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral and intravenous administration of losartan (9 mg/kg) without and with HMG-CoA reductase inhibitors (1 mg/kg). The effect of HMG-CoA reductase inhibitors on P-gp and cytochrome (CYP) 3A4 activity were also evaluated. Atorvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC50 values of 48.0, 14.1 and 3.10 µmol/l, respectively. Simvastatin (1-10 µmol/l) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner. The area under the plasma concentration-time curve (AUC0₋∞) and the peak plasma concentration of losartan were significantly (p < 0.05) increased by 59.6 and 45.8%, respectively, by simvastatin compared to those of control. The total body clearance (CL/F) of losartan after oral administration with simvastatin was significantly decreased (by 34.8%) compared to that of controls. Consequently, the absolute bioavailability (F) of losartan after oral administration with simvastatin was significantly increased by 59.4% compared to that of control. The metabolite-parent AUC ratio was significantly decreased by 25.7%, suggesting that metabolism of losartan was inhibited by simvastatin. In conclusion, the enhanced bioavailability of losartan might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of losartan in the small intestine and/or liver and to reduction of the CL/F of losartan by simvastatin.

Sirolimus- vs. paclitaxel-eluting stents for the treatment of unprotected left main coronary artery stenosis: complete 2-year follow-up of a two-center registry.

BACKGROUND: The feasibility of percutaneous coronary intervention (PCI) using drug-eluting stents and its comparability with bypass surgery in treatment of unprotected left main coronary artery (LMCA) stenosis has been shown previously. We compared the mid-to long-term outcome between sirolimus-(SES) vs. paclitaxel-eluting stents (PES) in an all-comer analysis that included all patients with unprotected LMCA stenosis who underwent PCI with SES or PES. METHODS: From March 2003 and June 2007, 196 patients underwent PCI with SES or PES for unprotected LMCA stenosis at Seoul National University Main or Bundang Hospital; SES was implanted in 141 patients and PES in 55 patients. The baseline clinical and procedural characteristics were mostly similar between the SES and PES group. RESULTS: After 2 years of follow-up, there were no differences in the rate of cardiac death (9.1% vs. 8.5%) and nonfatal MI (5.5% vs. 2.8%) between the two groups. However, the risk of repeat revascularization tended to be lower in the SES group compared with the PES group [TLR, 9.9% vs. 20.0% (P=0.06); TVR, 17.7% vs. 30.9% (P=0.05)], which did not reach statistical significance. The rate of stent thrombosis (ST) was also similar between the two groups (3.6% vs. 2.1% for definite ST, 3.6% vs. 2.8% for definite+probable ST). CONCLUSIONS: In all-comers undergoing first generation DES implantation for unprotected LMCA stenosis, PES and SES showed comparable 2-year clinical results regarding hard endpoints and major adverse cardiac events.

Risk factors for anastomotic leakage after laparoscopic rectal resection.

PURPOSE: The anastomotic leakage rate after rectal resection has been reported to be approximately 2.5-21 percent, but most results were associated with open surgery. The aim of this study was to identify risk factors and their relationship to the experience of the surgeon for anastomotic leakage after laparoscopic rectal resection. METHODS: Between March 2003 and December 2008, 156 patients underwent a laparoscopic rectal resection without a diverting ileostomy. The patients' characteristics, the details of treatment, the intraoperative results, and the postoperative results were recorded prospectively. Univariate and multivariate analyses were applied to identify risk factors for anastomotic leakage. RESULTS: The majority of operations were performed for malignant disease (n = 150; 96.2%), and 96 patients (61.5%) were males. Conversion to open surgery occurred in 1 case (0.6%). The anastomotic leak rate was 10.3% (16/156), and there were no mortalities. In the univariate analysis, tumor location, anastomotic level, intraoperative events, and operation time were associated with increased anastomotic leakage rate. In the multivariate analysis, anastomotic level (odds ratio [OR], 6.855; 95% confidence interval [CI], 1.271 to 36.964) and operation time (OR, 8.115; 95% CI, 1.982 to 33.222) were significantly associated with anastomotic leakage. CONCLUSION: The important risk factors for anastomotic leakage after laparoscopic rectal resection without a diverting ileostomy were low anastomosis and long operation time. An additional procedure, such as diverting stoma, may reduce the anastomotic leakage if it is selectively applied in cases with these risk factors.

Indications for subsequent surgery after endoscopic resection of submucosally invasive colorectal carcinomas: a prospective cohort study.

PURPOSE: This study explored predictive factors that affected oncologic outcomes after surgical resection or follow-up without surgery in patients with submucosally invasive colorectal carcinomas after endoscopic resection. METHODS: Oncologic outcomes in terms of lymph node metastasis or tumor recurrence were assessed according to resection margin, histology, and depth of invasion. RESULTS: Eighty-seven patients with submucosally invasive colorectal carcinomas after endoscopic resection were followed prospectively. Fifty-seven (65.5 percent) patients had risk factors of deep submucosal invasion and/or unfavorable histology. Among them, 30 underwent radical resection, and 6 patients had lymph node metastases. Twenty patients with risk factors were closely followed up and 3 recurrent carcinomas were detected. Ultimately, 9 of 57 high-risk patients (15.8 percent) exhibited lymph node metastasis or tumor recurrence. Among 30 patients without risk factors, none had lymph node metastasis or recurrent carcinoma. Univariate analysis showed that tumor budding (P = 0.003) and venous invasion (P = 0.021) were factors for lymph node metastasis. In multivariate analysis, only tumor budding was an independent predictor of lymph node metastasis (P = 0.026). CONCLUSIONS: Approximately 16 percent of patients with submucosally invasive colorectal carcinoma and risk factors benefited from subsequent surgery. Tumor budding was the most significant factor for lymph node metastasis. Observation would be appropriate for patients without risk factors after endoscopic resection.