Qualification and application of liquid chromatography-quadrupole time-offlight mass spectrometric method for the determination of carisbamate in rat plasma and prediction of its human pharmacokinetics using physiologically based pharmacokinetic modeling

Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.

Qualification and application of liquid chromatography-quadrupole time-offlight mass spectrometric method for the determination of carisbamate in rat plasma and prediction of its human pharmacokinetics using physiologically based pharmacokinetic modeling

Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.

Retrospective analysis of palliative chemotherapy for the patients with bladder adenocarcinoma: Korean Cancer Study Group Genitourinary and Gynecology Cancer Committee

BACKGROUND/AIMS: Because of rarity, role of chemotherapy of bladder adenocarcinoma are still unidentified. Therefore, we performed a retrospective analysis of the clinical features and chemotherapy outcomes of bladder adenocarcinoma. METHODS: Eligible patients for this retrospective analysis were initially diagnosed with bladder adenocarcinoma and presented with a clinically no other primary site of origin. The collected data included age, gender, performance status, stage, hemoglobin, albumin, initial date of diagnosis, treatment modality utilized, response to treatment, presence of relapse, last status of patient, and last date of follow-up. RESULTS: We retrospectively reviewed 29 patients, who were treated with chemotherapy for bladder adenocarcinoma at 10 Korean medical institutions from 2004 to 2014. The median age of patients was 58 years (range, 17 to 78) and 51.7% of the patients were female. Urachal adenocarcinoma was identified in 15 patients. Of 27 symptomatic patients, 22 experienced gross hematuria. Twelve patients were treated with 5-f luorouracil based chemotherapy, five were gemcitabine based, three were taxane and others. Thirteen of them achieved complete response (10.3%) or partial response (34.5%). Median progression-free survival (PFS) and overall survival (OS) for all patients were 10.6 months (95% confidence interval [CI], 9.5 to 11.6) and 24.5 months (95% CI, 1.2 to 47.8), respectively. The cases of urachal adenocarcinoma exhibited worse tendency in PFS and OS (p = 0.024 and p = 0.046, respectively). CONCLUSIONS: Even though bladder adenocarcinoma had been observed moderate effectiveness to chemotherapy, bladder adenocarcinoma is a highly aggressive form of bladder cancer. PFS and OS were short especially in urachal carcinoma.

Modest Anti-Cancer Activity of a Bile Acid Acylated Heparin Derivative in a PC14PE6 Induced Orthotopic Lung Cancer Model / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: A novel chemically modified heparin derivative, heparin-deoxycholic acid nano-particles, has lower anticoagulant activity, and was recently reported to have significant anti-tumor effects on squamous head and neck cancer cells. Therefore, the aim of this study was to evaluate the anti-tumor effects of heparin-deoxycholic acid nano-particles in a human lung adenocarcinoma cell line. MATERIALS AND METHODS: An orthotopic lung cancer model in 16 mice was developed using intra-thoracic injections of 0.5x10(6) PC14PE6 cells. Ten days after inoculation, the mice were divided into two groups. PBS and Heparin-DOCA particles were injected once a day every 3 days in the tail vein, for a total of 5 injections. The body weight and survival of each mouse were monitored and the tumor size in the lung was measured by SPECT-CT before and after heparin-DOCA nano-particle treatment. RESULTS: IThe HD particles had no significant cytotoxicity when the PC9 cells were treated in vitro. There was no statistical difference in tumor size, body weight and survival between the HD treated and control groups in vivo. Furthermore, there was no difference in the amount of CD31 between tumor tissues in the two study groups. CONCLUSION: HD synthesized with unfractionated heparin had no apparent inhibitory effects on tumor growth in a PC14PE6 cell induced orthotopic lung cancer mouse model. The HD particles did not significantly inhibit tumor-induced angiogenesis at the tumor sites.

Preliminary Study on the Enhancement of Reconstruction Speed for Emission Computed Tomography Using Parallel Processing / 핵의학분자영상

PURPOSE: Conventional image reconstruction uses simplified physical models of projection. However, real physics, for example 3D reconstruction, takes too long time to process all the data in clinic and is unable in a common reconstruction machine because of the large memory for complex physical models. We suggest the realistic distributed memory model of fast-reconstruction using parallel processing on personal computers to enable large-scale technologies. MATERIALS AND METHODS: The preliminary tests for the possibility on virtual manchines and various performance test on commercial super computer, Tachyon were performed. Expectation maximization algorithm with common 2D projection and realistic 3D line of response were tested. Since the process time was getting slower (max 6 times) after a certain iteration, optimization for compiler was performed to maximize the efficiency of parallelization. RESULTS: Parallel processing of a program on multiple computers was available on Linux with MPICH and NFS. We verified that differences between parallel processed image and single processed image at the same iterations were under the significant digits of floating point number, about 6 bit. Double processors showed good efficiency (1.96 times) of parallel computing. Delay phenomenon was solved by vectorization method using SSE. CONCLUSION: Through the study, realistic parallel computing system in clinic was established to be able to reconstruct by plenty of memory using the realistic physical models which was impossible to simplify

A Study on GPU-based Iterative ML-EM Reconstruction Algorithm for Emission Computed Tomographic Imaging Systems / 핵의학분자영상

PURPOSE: The maximum likelihood-expectation maximization (ML-EM) is the statistical reconstruction algorithm derived from probabilistic model of the emission and detection processes. Although the ML-EM has many advantages in accuracy and utility, the use of the ML-EM is limited due to the computational burden of iterating processing on a CPU (central processing unit). In this study, we developed a parallel computing technique on GPU (graphic processing unit) for ML-EM algorithm. MATERIALS AND METHODS: Using Geforce 9800 GTX+ graphic card and CUDA (compute unified device architecture) the projection and backprojection in ML-EM algorithm were parallelized by NVIDIA's technology. The time delay on computations for projection, errors between measured and estimated data and backprojection in an iteration were measured. Total time included the latency in data transmission between RAM and GPU memory. RESULTS: The total computation time of the CPU- and GPU-based ML-EM with 32 iterations were 3.83 and 0.26 sec, respectively. In this case, the computing speed was improved about 15 times on GPU. When the number of iterations increased into 1024, the CPU- and GPU-based computing took totally 18 min and 8 sec, respectively. The improvement was about 135 times and was caused by delay on CPU-based computing after certain iterations. On the other hand, the GPU-based computation provided very small variation on time delay per iteration due to use of shared memory. CONCLUSION: The GPU-based parallel computation for ML-EM improved significantly the computing speed and stability. The developed GPU-based ML-EM algorithm could be easily modified for some other imaging geometries.

Optimization of Inpatient Management of Radioiodine Treatment in Korea / 핵의학분자영상

We established a model to calculate radioactive waste from sewage disposal tank of hospitals to optimize the number of patients receiving inpatient radioiodine therapy within the safety guideline in our country. According to this model and calculation of radioactivity concentration using the number of patients per week, the treatment dose of radioiodine, the capacity and the number of sewage tanks and the daily amount of water waste per patient, estimated concentration of radioactivity in sewage waste upon disposal from disposal tanks after longterm retention were within the safety guideline (30 Bq/L) in all the hospitals examined. In addition to the fact that we could increase the number of patients in two thirds of hospitals, we found that the daily amount of waste water was the most important variable to allow the increase of the number of patients within the safety margin of disposed radioactivity. We propose that saving the water amount be led to increase the number of patients and they allow two patients in an already furnished hospital inpatient room to meet the increasing need of inpatient radioiodine treatment for thyroid cancer.

A Case of Cholestatic Hepatitis Induced by Epstein-Barr Virus Infection / 대한간학회지

Acute viral hepatitis in human can be caused by a large number of viruses with a wide range of clinical manifestations and laboratory findings. EBV is a rare causative agent of an acute hepatitis, during the course of infectious mononucleosis. Hepatic manifestations of EBV are usually mild and resolve without serious complications. EBV is rather uncommonly confirmed as an etiologic agent in acute viral hepatitis of adults and it rarely causes cholestatic hepatitis. We report a case of EBV hepatitis with cholestatic feature that was verified through serum viral marker and liver biopsy.

The Factors Related to the Prognosis of Solitary Hepatocellular Carcinoma after Radiofrequency Ablation / 대한간학회지

BACKGROUND/AIMS: Several risk factors, such as size and location, are related to local recurrence after radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). The objectives of this study were to clarify factors related to prognosis. METHODS: From October 1999 to December 2002, we performed RFA for 107 consecutive patients with solitary HCC. We evaluated spiral computed tomography and serum alpha-fetoprotein level every 3 months after RFA. Seven possible factors for prognosis were analyzed using the Cox proportional hazards regression model: tumor size, tumor location, age, sex, etiology, platelet count, and Child-Pugh classification. Overall survival and disease free survival rate were estimated using the Kaplan- Meier method, and differences between two groups were compared using the log rank test. RESULTS: The Kaplan-Meier estimates of overall survival after radiofrequency ablation were 90.5% at 12 months, 67.4% at 24 months and 46.4% at 36 months and disease free survival were 71.4%, 46.7% and 20.9%, respectively. Using the Cox proportional hazards regression model, it was shown that with regard to overall survival and disease free survival, Child-Pugh classification (P=0.001, P=0.026) and platelet count (P<0.001, P=0.002) were statistically significant factors. The other factors did not have a statistically significant relationship to overall survival and disease free survival. CONCLUSIONS: The size and location known as local recurrence factors were not statistically significant with regard to survival and disease free survival. The Child-Pugh classification and platelet count, that reflect the liver function at the time of RFA, were significant factors for prognosis.

Predictive factors for the diagnosis of nonalcoholic steatohepatitis and the degree of liver fibrosis / 대한내과학회지

BACKGROUND: Nonalcoholic steatohepatitis (NASH), which is the most severe form of nonalcoholic fatty liver disease (NAFLD), is a disease of emerging identity and importance with increasing epidemic of obesity in Korea. Since NASH may progress to fibrosis, cirrhosis, and even hepatocellular carcinoma, the identification of patients who may progress from steatosis to NASH is important. The aim of this study was to find clinical factors discriminating NASH from steatosis, and predictive factors for the degree of liver fibrosis in NASH. METHODS: Between January 2000 and August 2003, ultrasono-guided liver biopsies were performed on 50 patients in whom NAFLD was suspected clinically. We analyzed clinical factors, laboratory variables, and histologic findings. RESULTS: All of liver biopsies showed compatible histologic findings with NAFLD. Steatosis was observed in 10 patients (20%) and NASH in 40 patients (80%). In patients with high body mass index (BMI) (p=0.027), NASH was more frequently observed than steatosis. The diagnostic specificity of NASH was high (90%) in patients with BMI over 27.2. BMI and AST/ALT ratio were significant risk factors for severe liver fibrosis in multivariate analysis (p=0.014 and 0.04, regression coefficient 0.43 and 4.484, respectively). CONCLUSION: BMI and AST/ALT ratio correlated the degree of liver fibrosis in NASH. So, high BMI (over 27.2) may discriminate NASH from steatosis, and high BMI and high AST/ALT ratio may be useful as predictive factors for severe liver fibrosis in NASH.

The Diagnostic Validity of Helicobacter pylori Stool Antigen Test in the Pre- and Post-eradication / 대한소화기학회지

BACKGROUND/AIMS: The efficacy of a new enzyme immunoassay designed to detect H. pylori antigens in stool (HpSA) was evaluated before and after the eradication therapy. METHODS: HpSA test was performed in 75 patients whose H. pylori status was defined on the basis of concordant results of the 13C-urea breath test (13C-UBT), rapid urease test and histology. Fifty-one H. pylori-positive patients were treated with a week regimen of triple therapy (amoxicillin 1.0 g b.d., clarithromycin 500 mg b.d., rabeprazole 10 mg b.d). Four weeks after the completion of therapy, previous tests including HpSA were repeated on 29 of 51 patients. Six weeks after the completion of therapy, HpSA test was repeated on 10 of 29 patients. RESULTS: Before the eradication, the sensitivity, specificity, and accuracy of HpSA test was 80.4%, 95.2% and 84.7%, respectively. When the cut-off value of 0.12 was adopted on the basis of our receiver operation characteristics (ROC) curve, the sensitivity and specificity improved as 90.0% and 95.2%. Four weeks after the completion of therapy, the sensitivity, specificity and accuracy of HpSA test was 50.0%, 88.9% and 86.2%, respectively. In 3 patients, false positive results at 4th week were converted to true negative at 6 weeks. CONCLUSIONS: The HpSA test is a useful diagnostic method for H. pylori in pre-eradication stage. The specificity of HpSA test in the post-eradication was similar to other studies. For the velue of HpSA test in the post-eradication period, further studies about the cut-off value and the guideline of optimal time after the eradication may be needed.

Clinical Analysis and Comparison of Mammotome Biopsy between 8G and 11G Probes / 한국유방암학회지

PURPOSE: We analysed the clinical data to compare the usefulness of ultrasound guided vacuum-assisted Mammotome biopsy between 8G and 11G probes. METHODS: 108 cases in this study underwent an ultrasound- guided minimally invasive excisional breast biopsy through small incision. Removal of the breast lesions was accomplished Mammotome biopsy with 8G or 11G probes. RESULTS: The 108 lesions was excised. Mean size of the lesions were 10.7 mm in 8G and 9 mm in 11G. 105 lesions (95%) had benign pathology, three lesions (2.8%) were malignant, and two lesions (1.9%) had atypical ductal hyperplasia. As procedural complications, hematoma was 23/58 (39.7%) in 8G and 10/50 (20%) in 11G, and ecchymosis was 33/58 (55%) in 8G and 11/50 (22%) in 11G. But there was no major complications which need hospitalization and surgical intervention. CONCLUSION: Breast biopsy using Mammotome with 8G probe is as safe as 11G and effective technique.

Clinical Evaluation of Recurrent Intussusception

To evaluate the clinical findings of the recurrent intussusception. 351 patients with 445 intussusceptions were reviewed. Recurrence rate, pattern of recurrence, reducibility, pathologic lead points (PLP), and operative findings and long term follow up of the multiple recurrences were analyzed. Of 351 patients, 303 had no recurrence, 26 had one recurrence, and 22 had multiple recurrences. Over all recurrence rate was 16.4% ; 18.5% were managed by air reduction, 16.2% by barium reduction and 5.9% by operation. Elven PLPs were proved operatively operatively and an additional 6 suspected PLPs were depicted radiologically. The most frequent PLP was ileal lymphoid hyperplasia. Intervals between reduction and recurrence were less than 2 weeks in 31 cases, between 2 weeks and 1 year in 55, and more than 1 year in 8. The longest interval was 2 years and 4 months.

The Clinical Usefulness of Balloon Occluded Retrograde Transvenous Obliteration in Gastric Variceal Bleeding / 대한간학회지

BACKGROUND/AIMS: Gastric variceal bleeding is difficult to treat endoscopically because the hemodynamics of the gastric varix are different from that of the esophageal varix. Transjugular intrahepatic portosystemic shunt (TIPS), which has been used widely, does not always result in the regression of gastric varix and it may aggravate the hepatic encephalopathy. Balloon occluded retrograde transvenous obliteration (BRTO) was introduced as a new procedure for gastric variceal bleeding with minimal invasiveness. The purpose of this study was to evaluate the therapeutic effects and complications on follow-up of BRTO as a new treatment option for gastric variceal bleeding. METHODS: Patients with gastric variceal bleeding, who were treated with BRTO form September, 2001 to April, 2003, were included in the study. After the definite confirmation of the shunts with abdominal CT, the sclerosing agent, 5% ethanolamine oleate, was injected into the gastric varix during occlusion through gastrorenal shunts. The procedurre was deemed a technical success when the clotting of the sclerosing agent was observed without leakage, and a clinical success when bleeding stopped and the varix decreased in size or was eradicated during the follow-up period (6-23 months, mean: 17.7). RESULTS: Technical success was achieved in 12 of 13 patients (92%) with gastric variceal bleeding. There were no significant side effects. In the one case of failure, the bleeding was controlled with TIPS. Eleven of the 12 patients who had technical success were shown to be clinically successful. The follow-up endoscopic exam showed some aggravation of pre-existing esophageal varices in four patients and a new development of esophageal varices in two patients. Endoscopic variceal ligation was done on one patient in whom esophageal variceal bleeding was present during the follow-up period. CONCLUSIONS: BRTO was proven to be a feasible, safe and less invasive procedure than TIPS and found to be an effective treatment of a gastric variceal bleeding. Considering the possible aggravation of pre-existing esophageal varices or the new development of esophageal varices, regular endoscopic examinations might be needed during the follow-up period.