PURPOSE: Idoxifene is currently entering phase II clinical trials for the treatment of advanced breast cancer. The radiolabeled idoxifene using 123I provides an opportunity for clinical pharmacology with single photon emission computed tomography (SPECT). The purpose of this study was to prepare radiolabeled idoxifene using 123I and to determine its cell uptake of breast cancer cell line. MATERIALS AND METHODS: With a view to evaluating new anticancer drugs, we are investigating the novel antiestrogen pyrrolidino- 4-iodotamoxifen (idoxifene). [123I]Idoxifene has been prepared in no-carrier-added form using a tributyl stannylated precursor which has been synthesized by means of (2-chloroethoxy)benzene with (+/-)-2- phenylbutanoic acid on the basis of previously reported standard methods. The biodistribution and dynamic behavior of the compound were investigated using the comparative breast cancer cell line, MCF-7 (estrogen receptor-positive) and MDA-MB-468 (non-estrogen receptor). RESULTS AND CONCLUSION: Acylation of (2-chloroethoxy)benzene with (+/-)-2-phenylbutanoic acid gave the versatile ketone (81%) which reacted with 1,4-diiodobenzene to give triphenylethylene as a mixture of E and Z geometric isomers, which were separated by the recrystallization in ethanol. The E-isomer was treated with pyrrolidine to give idoxifene (67%). In order to incorporate radioactive iodine into the 4-position, the 4-stannylated precursor was prepared (30%). The yield of radioiodination was 90-92% with a high radiochemical purity greater than 98%. The ratio of tumor uptake of the breast cancer cell line between MCF-7 and MDA-MB-468 was about 1.7.
Acylation ; Breast Neoplasms* ; Breast* ; Cell Line ; Estrogen Receptor Modulators ; Ethanol ; Iodine ; Pharmacology, Clinical ; Tomography, Emission-Computed, Single-Photon

Compared with ST elevation myocardial infarction (STEMI), long-term outcomes are known to be worse in patients with unstable angina/non-STEMI (UA/NSTEMI), which might be related to the worse health status of patients with UA/STEMI. In patients with UA/NSTEMI and STEMI underwent percutaneous coronary intervention (PCI), angina-specific and general health-related quality-of-life (HRQOL) was investigated at baseline and at 30 days after PCI. Patients with UA/NSTEMI were older and had higher frequencies in female, diabetes and hypertension. After PCI, both angina-specific and general HRQOL scores were improved, but improvement was much more frequent in angina-related HRQOL of patients with UA/NSTEMI than those with STEMI (44.2% vs 36.8%, P < 0.001). Improvement was less common in general HRQOL. At 30-days after PCI, angina-specific HRQOL of the patients with UA/NSTEMI was comparable to those with STEMI (56.1 +/- 18.6 vs 56.6 +/- 18.7, P = 0.521), but general HRQOL was significantly lower (0.86 +/- 0.21 vs 0.89 +/- 0.17, P = 0.001) after adjusting baseline characteristics (P < 0.001). In conclusion, the general health status of those with UA/NSTEMI was not good even after optimal PCI. In addition to angina-specific therapy, comprehensive supportive care would be needed to improve the general health status of acute coronary syndrome survivors.
Aged ; Angina, Unstable/physiopathology/*therapy ; Asian Continental Ancestry Group ; Female ; Health Status ; Humans ; Male ; Middle Aged ; Myocardial Infarction/physiopathology/*therapy ; Odds Ratio ; *Percutaneous Coronary Intervention ; *Quality of Life ; Registries ; Republic of Korea

OBJECTIVES: Due to the heterogeneous receptor distribution and changes of receptor status over time, the biochemical measurement of estrogen receptor status of biopsy specimens is not sufficient to diagnose breast cancer. As a result, I-123 labeled estradiols have been applied for the diagnosis. The purpose of this study was to develop a suitable radioligand for imaging estrogen receptor-positive human breast tumors. METHODS: Among the various estradiol derivatives, 17alpha-[123I]iodovinyl estradiol ([123I]IVE) has been prepared from 17alpha-ethynyl estradiol. Labeling of E-17alpha-[123I]iodovinyl estradiol (E-[123I]IVE) was carried out using peracetic acid with [123I]NaI and Z-[123I]IVE labelling was archived using chloamine- T/HCl solution with [123I]NaI. Labeling yield was determined by silica thin-layer chromatography (TLC) and radiochemical purity was measured by high performance liquid chromatography (HPLC). The biodistribution of E-[123I]IVE was measured in immature female rats at 60 min, 120 min and 300 min after injection. RESULTS: The labeling yield of two isomers was 92% and 94% (E-[123I]IVE and Z-[123I]IVE, respectively). The radiochemical purity was more than 98% after purification. The highest uptake was observed at 120 min in uterus (3.11% ID/g for E-[123I]IVE). CONCLUSION: These results suggest the possibility of using E-[123I]IVE as an imaging agent for the evaluation of the presence of estrogen receptor in patients with breast cancer.
Animals ; Biopsy ; Breast Neoplasms ; Chromatography, Liquid ; Chromatography, Thin Layer ; Diagnosis ; Estradiol* ; Estrogens ; Female ; Humans ; Peracetic Acid ; Rats ; Silicon Dioxide ; Uterus

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. METHODS: Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis. RESULTS: Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation. CONCLUSION: Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.
Animals ; Blood Glucose ; Blotting, Western ; Collagen Type I ; Diabetes Mellitus, Type 1 ; Diabetic Nephropathies ; Down-Regulation ; Extracellular Matrix ; Fibronectins ; Fibrosis ; Glomerular Basement Membrane ; Humans ; Mice* ; Microscopy, Electron ; Phosphorylation ; Polymerase Chain Reaction ; Rats ; Reverse Transcription ; RNA, Messenger ; Streptozocin ; Transforming Growth Factors

BACKGROUND: Renal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice. METHODS: We examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study. RESULTS: Through hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway. CONCLUSION: The present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.
Actins ; Animals ; Atrophy ; Blotting, Western ; Collagen Type I ; Diabetic Nephropathies ; Fibroblasts ; Fibrosis* ; In Vitro Techniques ; Mesangial Cells ; Mice* ; Peroxisomes* ; Phosphorylation ; Plasminogen Activator Inhibitor 1 ; Polymerase Chain Reaction ; Rats ; Renal Insufficiency, Chronic ; Reverse Transcription ; Transforming Growth Factor beta ; Transforming Growth Factors ; Up-Regulation ; Ureter* ; Ureteral Obstruction*

BACKGROUND: Darbepoetin alfa is a new erythropoietic agent with a three fold longer terminal half-life than recombinant human erythropoietin (r- HuEPO). The aim of this randomized, open-label study is to determine whether darbepoetin alfa is as effective as r-HuEPO for the treatment of anemia in hemodialysis patients when administered at a reduced dosing frequency. METHODS: A total 74 Korean hemodialysis patients receiving r-HuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized to continue r-HuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dosing frequency. Patients receiving r-HuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving r-HuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The initial dose of darbepoetin alfa was based on the r-HuEPO dose at the time of entry into the study, using a formula equating the peptide mass of the two molecules (200 IU r-HuEPO=1 microgram darbepoetin alfa). The doses of r-HuEPO and darbepoetin alfa were titrated to maintain hemoglobin concentrations within -1.0 to +1.5 g/dL of patients' baseline values and within a range of 8.0 to 13.0 g/ dL for up to 20 weeks (16-week dose-titration period followed by a 4-week evaluation period). The primary end point was change in hemoglobin level between baseline and the evaluation period. RESULTS: The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03+/-0.19 g/dL) and r-HuEPO (0.27+/-0.20 g/dL) groups, and the difference between the two treatments was -0.30 g/dL (95% CI, -0.84 to 0.23). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. The safety profiles of darbepoetin alfa and r-HuEPO were similar. CONCLUSION: This study suggests that darbepoetin alfa maintains hemoglobin as effectively as r- HuEPO, but with reduced dose frequency.
Anemia* ; Erythropoietin ; Half-Life ; Hemoglobin A ; Humans ; Renal Dialysis* ; Darbepoetin alfa

BACKGROUND: Transplantation of cardiac myocytes (CMs) into the injured heart emerges as a potential alternative for the treatment of heart failure. Genetic modification of CMs could enhance and/or modify its therapeutic effects. The characteristics of retroviral gene delivery, which is most commonly used in human trial, has been minimally studied in CMs due to its low efficiency in non-dividing cells. In this study, using newly developed high-titer retrovirus, we evaluated 1) the efficiency of gene transfer into CMs, 2) whether S phase during infection is necessary for the transduction, and 3) characteristics of gene delivery to mononucleated vs binucleated CMs. METHODS: Enriched CMs were cultured from the ventricles of 1 day-old rat hearts. The cells were transduced by MFG-nls-LacZ retroviruses (5x107 IU/ml) in the presence or absence of polybrene. 3H-thymidine was added to label cells in S phase. The cells were stained for b-galactosidase activity and then immunostained using MF20Ab to identify CMs. The cells were subsequently processed for in vitro autoradiography. RESULTS: 1)With 3 rounds of infection, 5.9% of total cultured cells were LacZ-positive. The efficiency of transduction reached upto 7.4% in the presence of polybrene 8 microgram/ml. 2)Nuclear morphology of LacZ-positive CMs was pleomorphic from mononucleated to multinucleated, mostly binucleated. 3)Among mononucleated CMs, 17% of cells were labelled with thymidine. Transduction efficiency (TDE) of thymidine-positive and -negative mononucleated CMs were 37.9% and 3.1%, respectively. Among binucleated cells, 28.9% of cells were labelled with thymidine. TDE of thymidine-positive and -negative binucleated CMs were 75.4% and 13.6%, respectively. 4)In total, TDE of binucleated cells were 3.5 times compared to the one of mononucleated cells (31.5% vs 9.0%). CONCLUSION: TDE of CMs using high-titer retrovirus is relatively low. S phase of cells during retroviral infection is not mandatory for the retroviral transduction. Binucleated CMs are susceptible to retroviral gene delivery and their TDE is higher than the one of mononucleated CMs.
Animals ; Autoradiography ; Cells, Cultured ; Dichlorodiphenyldichloroethane ; Genetic Therapy ; Heart ; Heart Failure ; Hexadimethrine Bromide ; Humans ; Myocytes, Cardiac* ; Rats ; Retroviridae* ; S Phase ; Thymidine ; Zidovudine

BACKGROUND AND OBJECTIVES: Coronary artery perforation is a rare, but potentially deadly, complication of percutaneous coronary intervention (PCI). The purpose of this study was to analyze the clinical characteristics, and outcome, of coronary artery perforation. SUBJECTS AND METHODS: We retrospectively reviewed 3,782 consecutive PCIs, performed between January, 1994 and May, 2002 at the Samsung Medical Center, from the database records. The medical records and angiograms of the patients were also reviewed. The coronary artery perforations were classified according to Ellis' classification. RESULTS: A coronary artery perforation was noted in 24 patients (0.6%). It was most commonly observed during PCI of the right coronary artery (46%) and a chronic total occlusion intervention (42%). The number of the patients with Ellis'classes I, II and III were 11, 8 and 5, respectively. The most frequent causes of the perforation were guidewire, followed by balloon (11 and 8 cases, respectively). The interventional modality with the highest risk of perforation in this study was rotational atherectomy, (4 out of 157, 2.6%). Five patients had cardiac tamponade, of which four occurred during a rotablator procedure. Pericardiocentesis was performed in 5 patients, while 3 patients with class III perforations received emergent coronary artery bypass surgery. There were no in-hospital mortalities, although the duration of the hospital stay for the class III patients was longer than those with classes I or II perforations. CONCLUSION: A coronary artery perforation during percutaneous coronary intervention is a potentially serious complication. However, the immediate and adequate management results in a fairly good prognosis.
Atherectomy, Coronary ; Cardiac Tamponade ; Classification ; Coronary Artery Bypass ; Coronary Disease ; Coronary Vessels* ; Hospital Mortality ; Humans ; Length of Stay ; Medical Records ; Percutaneous Coronary Intervention* ; Pericardiocentesis ; Prognosis ; Retrospective Studies

BACKGROUND: Recent advances of percutaneous coronary intervention (PCI) and transradial coronary intervention (TRI) have made it possible to reduce the local complication rate and the time until a return to ambulation. The aim of this study is to assess the safety and the patient satisfaction of the TRI-based one-day admission program for PCI. METHODS: Total 230 consecutive patients underwent TRI on the day of admission, according to pre-determined inclusion criteria, from May 2001 to October 2003. The subjects were examined for clinical and angiographic characteristics. The patients having a same-day discharge were telephone-interviewed one day and seven days after discharge to assess late complications and the patients' satisfaction. RESULTS: The mean age of the subjects was 59+/-9 years and 77.4% were male patients. 169 (73.4%) had stable angina and 37 (16.1%) had unstable angina. Stents were implanted in 178 cases (69.3%). Of the 230 patients who underwent TRI, 206 patients (89.6%) could discharge on the same day after the procedure. The procedure was successful in 98.5%. The average hospital stay for them was 9.4+/-1.4 hours. Two subjects reported hematoma near the puncture site within 24 hours after discharge, and one reported this problem 7 days after discharge. During the follow-up, there were no cases reporting chest pain needing rehospitalization or such complications as subacute vessel closure. No deaths, myocardial infarctions or revascularization were noted during the follow-up period. The majority of the patients (n=197, 95.6%) were satisfied with the same-day admission and discharge. CONCLUSIONS: Same day admission and discharge after TRI seems to be safe as well as satisfactory for not low-risk patients.
Angina, Stable ; Angina, Unstable ; Angioplasty ; Chest Pain ; Coronary Disease ; Follow-Up Studies ; Hematoma ; Humans ; Length of Stay ; Male ; Myocardial Infarction ; Patient Satisfaction ; Percutaneous Coronary Intervention ; Punctures ; Radial Artery ; Stents ; Walking

BACKGROUND AND OBJECTIVES: Although several multicenter registries have evaluated percutaneous coronary intervention (PCI) procedures in Korea, those databases have been limited by non-standardized data collection and lack of uniform reporting methods. We aimed to collect and report data from a standardized database to analyze PCI procedures throughout the country. MATERIALS AND METHODS: Both clinical and procedural data, as well as clinical outcomes data during hospital stay, were collected based on case report forms that used a standard set of 54 data elements. This report is based on 2014 Korean PCI registry cohort data. RESULTS: A total of 92 hospitals offered data on 44967 PCI procedures. The median age was 66.0 interquartile range 57.0-74.0 years, and 70.3% were men. Thirty-eight percent of patients presented with acute myocardial infarction and one-third of all PCI procedures were performed in an urgent or emergency setting. Non-invasive stress tests were performed in 13.9% of cases, while coronary computed tomography angiography was used in 13.7% of cases prior to PCI. Radial artery access was used in 56.1% of all PCI procedures. Devices that used PCI included drug-eluting stent, plain old balloon angioplasty, drug-eluting balloon, and bare-metal stent (around 91%, 19%, 6%, and 1% of all procedures, respectively). The incidences of in-hospital death, non-fatal myocardial infarction, and stroke were 2.3%, 1.6%, and 0.2%, respectively. CONCLUSION: These data may provide an overview of the current PCI practices and in-hospital outcomes in Korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research.
Angiography ; Angioplasty, Balloon ; Cohort Studies* ; Data Collection ; Drug-Eluting Stents ; Emergencies ; Exercise Test ; Humans ; Incidence ; Korea* ; Length of Stay ; Male ; Myocardial Infarction ; Percutaneous Coronary Intervention* ; Radial Artery ; Registries ; Stents ; Stroke