Background: Both aspirin and simvastatin are prescribed as treatments or prevention of cardiovascular diseases. The aim of this study was to investigate the influence of simvastatin on pharmacokinetics and pharmacodynamics of aspirin after oral co-administration in healthy subjects. Methods: Subjects were orally administered aspirin 100 mg for 7 days followed by co-administration of aspirin 100 mg and simvastatin 40 mg for 7 days once daily. A series of blood samples were collected before and till 24hours after drug administration on Day 1 (single-dose of aspirin), Day 7 (multiple-dose of aspirin) and Day 14 (multiple-dose of aspirin and simvastatin). The effects of simvastatin on pharmacokinetics of acetylsalicylic acid and salicylic acid were assessed with the 90 % confidence intervals (CIs) of thegeometric mean ratios (GMRs) of Day 14 over Day 7 for maximum plasma concentration ($C_{max}$) and the area under the concentration-time curve ($AUC_{0-24}$). Pharmacodynamics was assessed with maximal changes of platelet aggregation from baseline. Results: Twenty-fourhealthy men aged 20 to 36 years were enrolled and 23 of them completed the study. GMRs (90 % CIs) of $C_{max}$ and $AUC_{0-24}$ for acetylsalicylic acid were 1.21 (1.04 - 1.42) and 1.28 (1.19 - 1.38), respectively. For salicylic acid, GMRs of $C_{max}$ and $AUC_{0-24}$ were 0.96 (0.91 - 1.00) and 1.00 (0.97 - 1.04), respectively. Maximal changes of platelet aggregation on Day 7 and Day 14 from baseline were not significantly different (p=0.41); $87.5{\pm}8.8$ % and $87.3{\pm}9.2$ %, respectively. Conclusion: Coadministration of simvastatin slightly increased the systemic exposure of acetylsalicylic acid with no changes of systemic exposure of salicylic acid or inhibition of platelet aggregation.

Background: Eplerenone is a selective mineralocorticoid receptor antagonist which effectively blocks mineralocorticoid receptors in various tissues throughout the body. The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients post acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The aim of this study was to evaluate pharmacokinetic characteristics and tolerability after multiple oral administration of eplerenone 100 mg for 7 days in healthy Korean volunteers. Methods: A double-blind, randomized, placebo-controlled, parallel study was conducted in 22 healthy Korean subjects. Healthy males and females between age of 20 and 55 years were enrolled. Each subject received 100 mg eplerenone (N=16) or placebo (N=6) for 7 days. Blood samples for pharmacokinetic parameter determination on day 7 were collected pre-dose and up to 36 hours after last drug administration. Adverse events were reported throughout the treatment period. Results: The steady-state concentration of eplerenone reached after multiple administration of eplerenone 100 mg for 7 days. The mean eplerenone Cmax of 1620.1 ng/mL was obtained at 1.0 hour (range 0.5 to 2 hours). The mean $AUC_{0-24h,ss}$ at day 7 was 8763.6 ng/mL*h. The mean oral clearance and mean terminal half-life of eplerenone were 13.0 L/h and 3.4 hours. There were some drug-related mild adverse events after eplerenone administration, but all adverse events recovered without any treatment. Conclusion: In this study, the pharmacokinetic parameters after multiple oral doses of eplerenone 100 mg for 7 days were evaluated and eplerenone at these doses were well tolerated in healthy Korean subjects.

Background: Fudosteine, (-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid, is a cysteine derivative that was approved in Japan, as a new mucoactive agent. The aim of this study was to evaluate the tolerability and pharmacokinetics (PK) of fudosteine in healthy Korean subjects. Methods: A randomized, open-label, parallel, escalating single-dose study was conducted in 16 healthy Korean male subjects. The subjects were allocated to single-dose groups of 400 or 800 mg. Serial blood samples for PK analysis were collected immediately prior and after dosing up to 24 hours, and plasma concentrations were determined by high performance liquid chromatography (HPLC). Safety profiles were evaluated by monitoring adverse events and clinical evaluations throughout the study. Results: Median time to peak concentration ($T_{max}$) of both dosing group were around 0.5 hours and half-life ($t_{1/2}$) were around 3 hours. Mean peak concentration ($C_{max}$) of 400 mg and 800 mg dosing group were 10.8 and 21.5 ${\mu}g/mL$ and the mean area under the plasma concentration versus time curve from the dosing time to infinity ($AUC_{inf}$) were 26.8 and 55.0 ${\mu}g{\cdot}h/mL$, respectively. Mean dose-normalized $C_{max}$ were 0.0271 and 0.0269 ${\mu}g/mL/mg$ (P=0.923), respectively and dose-normalized $AUC_{inf}$ were 0.0669 and 0.0688 ${\mu}g{\cdot}hr/mL/mg$ (P=0.093), respectively. Fudosteine was well tolerated without any serious adverse events or clinical laboratory abnormalities. Conclusion: This study showed that fudosteine has a linear PK property and is well tolerated within 800 mg in healthy Korean volunteers.

Background: This research is to identify the difficulties occuring in the course of managing the adverse events and the adverse event related standard operating procedure in the regulation of each institutional review board. Methods: In order to identify the issues of the management of adverse events of each institution, this research surveyed the IRB administrators in fifty two university hospitals nation-wide. This survey is conducted among one chairman and one IRB member from the IRB members per each IRB who have experience in reviewing adverse events. The survey also includes investigators and sponsors who engage in reporting adverse events. Results: The result of this survey demonstrates that the objects and the terms of adverse event reports provided by the Standard Operating Procedure and the KGCP of each institution are not very different from each other. However, according to the survey, any cases reported to the IRBs, although they are not specified as the object of reports in the institution, have been reviewed by the IRB members. To sum up the results of the survey, the major issues include ambiguous regulations on adverse event reports and reviews, the use of different report formats for each institution, and the difficulty with evaluating the causal relationship with Investigational Product. Conclusion: It is necessary to develop concrete and specified guidelines on the objects and the terms of reports, the standard for the causal relationship and the adequate measures for adverse events after review and to standardize the format of adverse event reporting.

Background: Calcineurin-inhibitors have wide inter-individual variation in drug response. Although therapeutic drug monitoring has been conducted to optimize personalized regimen, toxicity or rejection may occur. In this study, pharmacologic effect was evaluated by measuring calcineurin activity in peripheral blood after administration of a single dose of cyclosporine in healthy volunteers. Methods: 7 healthy Korean male subjects received cyclosporine 200 mg and blood samples were drawn immediately before and at 1, 1.5, 4, 6, 12 h after dosing to measure calcineurin activity. The blood concentrations of cyclosporine were determined for 24 hours. Calcineurin activity assay was done with Calcineurin cellular activity assay kit (Calbiochem, USA). Frozen whole blood samples in liquid $N_2$ were thawed and lysed with lysis buffer. 50 ${\mu}L$ of phosphate standard curve samples were added to each well of a 96-well plate and 10 ${\mu}L$ of diluted lysate were added to the well with RII phosphopeptide substrate. After incubating for 30 min, reaction was terminated by adding 100 ${\mu}L$ $GREEN^{TM}$ reagent. Absorbance was read at 620 nm using spectrophotometer. We evaluated percent change in calcineurin activity from baseline level in relation to the lowest level. Results: Decrease of calcineurin activity was confirmed after cyclosporine administration ($mean{\pm}SD$: $58.9{\pm}48.6$ (%)). Significant correlation was shown between calcineurin activity change and pharmacokinetic parameters ($AUC_{last}$: r = 0.834, p value = 0.01, $C_{max}$: r = 0.774, p value = 0.02). Conclusion: In this study, we confirmed the pharmacologic effect and its correlation with pharmacokinetics after administration of a single dose of cyclosporine by measuring calcineurin activity in peripheral blood in healthy volunteers.

Background: This study was aimed to investigate current tasks done by clinical research coordinators (CRCs) and appropriate tasks of CRCs perceived by investigators, and to classify tasks for CRCs into four categories such as standard, recommended, considered and limited tasks. Methods: The participants were 533 CRCs and 114 investigators who have employed CRCs. Data were collected with self-administrated questionnaire including general characteristics and 32 possible tasks of CRCs from August to November, 2010. Data was analyzed using SPSS win (version 18.0) with descriptive statistics. Results: There were 24 tasks being done by more than half of CRCs, and 15 tasks by more than 75 % of CRCs among 32 possible tasks. The most common task done by CRCs was 'collecting data based on the protocol' and the next was 'scheduling of subjects'. More than half of investigators perceived that all tasks but budgeting appropriate to be done by CRCs, and 18 tasks by more than 75 % of investigators. 13 tasks were classified as standard tasks, 14 as recommended tasks, four as considered tasks, and one as limited task. Conclusion: Standard and recommended tasks for CRCs in Korea have been drawn based on the current tasks done by CRCs and appropriate tasks of CRCs perceived by investigators. It is recommended that investigators utilize this results when they delegate tasks to CRCs and appropriate educational programs could be provided so that CRCs perform standard and recommended tasks proficiently.

Background: The aim of the current study is to investigate perspectives on the quality and validity of the current clinical research associate (CRA) education program. The trainee program of other healthcare professions including medical doctors, registered nurses, and pharmacists, has been already reviewed as an advance research. Thus, the current study evaluates the CRA education system to assist in building a more suitable CRA education infrastructure in the future. Methods: A questionnaire was handed out to CRAs with at least 3 months working experience among 30 pharmaceutical corporations, and 10 Contract Research Organizations (CROs) affiliated with the Korean Pharmaceutical Association and the Korean Clinical Research Committee. A total of 118 questionnaires were utilized for data analysis. Results: The poll shows that 93.2 % of the survey participants consider the role of a CRA as a specialized healthcare profession and 58.6 % of those respondents reason that becoming a CRA requires specialized knowledge. 95.9 % of survey participants attend a CRA trainee program for the maintenance of CRA professionalism. The respondents are inclined to attend the Government hosted CRA education program. 59.3 % of survey participants answered that implementing a CRA qualification system is necessary to establish a CRA specialty validation. Conclusion: The current study demonstrates the importance of qualification and what is necessary for being a CRA. The study result will provide a guideline for those who wish to become a CRA as part of their career. In addition, the result will also be used in developing an improved CRA education program in the future.

Background: $GreenGene^{TM}$ (Green Cross Corp.) is a recombinant clotting factor VIII which is used for hemophilia A. This study aimed to investigate the pharmacokinetics and safety profiles of 25 IU/kg and 50 IU/kg of $GreenGene^{TM}$ in Korean hemophilia A patients. Methods: A dose-block randomized, single-blind, active drug-controlled, single and multiple dose, parallel-group study was conducted with 16 hemophilia A patients (25 IU/kg: 50 IU/kg = 8:8). They received $GreenGene^{TM}$ or $GreenMono^{TM}$(active control) intravenously on day 1 and every other day from day 4 to 10. FVIII:C (Factor VIII procoagulant activity) was measured to determine the pharmacokinetics (PK) at baseline and up to 48 hours for single and multiple administration. PK parameters were determined using noncompartmental methods. Results: The maximum concentration ($C_{max}$) and the area under the concentration-time curve ($AUC_{0-48}$) of the $GreenGene^{TM}$ 25 IU/kg ($mean{\pm}SD$) were $59.00{\pm}19.26$ % and $774.40{\pm}380.13%{\cdot}h$ respectively, while those of 50 IU/kg were $131.50{\pm}39.81$ % and $1462.44{\pm}397.09%{\cdot}h$ after single administration. The $C_{max}$ and $AUC_{0-48}$ in steady state of the $GreenGene^{TM}$ 25 IU/kg were $68.17{\pm}22.75$ % and $863.30{\pm}334.40%{\cdot}h$, while those of 50 IU/kg were $147.17{\pm}18.47$ % and $1820.08{\pm}704.42%{\cdot}h$. No serious adverse event was observed. Conclusion: The $GreenGene^{TM}$ to hemophilia A patients appeared to be well tolerated within range of 25-50 IU/kg. The PK parameters of factor VIII showed dose-independent manner with 25 IU/kg and 50 IU/kg dose ranges.

Background: The use of Cooperative Institutional Review Board (Co-IRB) has become subject to continuous discussion. As a result, leading mainly by the Korea Association of Institutional Review Boards (KAIRB), "IRB mutual recognition program (MR-IRB)" was proposed. However operational methods of the program are still controversial. The object of this research is to examine domestically feasible scope and operation methods of MR-IRB by conducting survey. Methods: 71 survey data was collected from chairman or specialist of each IRB and 29 IRB members of one institution running Central IRB was included. Results: 76.5 % of respondents selected phase 3 multi-national, multi-center clinical Sponsor Initiated Trial as a suitable subject of MR-IRB, but only 50 % supported Investigator initiated trials, and answered early-stage clinical trials such as phase 1 clinical trials or biological agent trials are unsuitable due to relatively insufficient knowledge on risk level. In order to operate MR-IRB, standardized review criteria and agreement of institutions in building mutual trust is essential. Also it was learned from the survey that the most desirable way to adopt MR-IRB is to be initiated by the representing organization such as KAIRB based on mutual trust from institutional agreement. Conclusion: MR-IRB was recognized as one of Co-IRB. A suitable subjects of MR-IRB were preferred the phase 3 multi-national, multi-center clinical sponsor initiated trials to all kinds of clinical trials. This study suggests that based on real operation experience from MR-IRB pilot study, further study should be conducted to analyze pros and cons of MR-IRB and identify domestically eligible model to facilitate MR-IRB.

Background: Numerous studies have suggested that polyunsaturated fatty acids (PUFAs)-supplemented diets may decrease cardiovascular morbidity and mortality. Especially, ${\omega}$-3 PUFAs may exert beneficial effects to the treatment and prevention of dyslipidemias, arrhythmias, atherosclerosis, and hypertension. Methods: This study investigated plasma lipid profiles including total cholesterol, triglycerides (TG), LDL, HDL, and antioxidant status indicative of vitamin A, vitamin E, malondialdehyde (MDA) and distribution of plasma long-chain fatty acids (C12-C24) in 28 normal subjects and 24 hypertensive patients. Also, the correlation among PUFAs, levels of antioxidant status, and lipid profiles of the subjects were estimated. Results: The distribution of ${\omega}$-3 PUFAs, saturated fatty acids, and monounsaturated fatty acids showed significant differences (P<0.05), but that of ${\omega}$-6 PUFAs did not exhibit significant differences. The ${\omega}-6/{\omega}-3$ ratio exhibited 36.96 in normal group and 14.29 in the hypertensive patient group. The levels of vitamin A, vitamin E, and MDA were increased significantly in the hypertensive patient group. Conclusion: PUFA levels were estimated in the hypertensive patients and normal group. The results suggest that dietary intake of proper ${\omega}-6/{\omega}-3$ ratio is needed for prevention and treatment of hypertension.

Background: To investigate the safety and effectiveness of adefovir in Korean patients with chronic hepatitis B, an observational study was carried out. Methods: A total of 4,393 patients with chronic hepatitis B were enrolled from February 2004 to February 2010. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events (AEs) throughout the course of treatment. Antiviral effectiveness was assessed by measuring the degree of symptom improvement and the reduction of HBV DNA after 12 weeks of treatment. Results: Of the 4,393 patients, 4,158 patients were evaluated for safety and 3,867 patients for effectiveness assessment. A total of 118 AEs were reported in 4,158 patients (1.8 %). The most frequent AE was hepatic failure (0.2 %) followed by coughing (0.2 %), hepatic neoplasm (0.2 %), abdominal pain (0.1 %), dyspepsia (0.1 %), nausea (0.1 %), flatulence (0.1 %), hepatic cirrhosis (0.1 %), asthenia (0.1 %), increase in sputum production (0.1 %), and varicose vein (0.1 %). The incidence of unexpected AEs was 0.9 %. Forty-nine cases of serious AE were reported in 32 patients but all of those were thought to be unrelated to adefovir according to physician's evaluations. The rate of subjects with well effectiveness was 96.2 %. Conclusion: Adefovir was clinically well tolerated and effective in treatment of chronic hepatitis B patients.