Studies on Amikacin Pharmacokinetics in Neonates and Warfarin Pharmacogenomics in Mechanical Cardiac Valve Patients

Part 1. Outcomes of a new dosage regimen of amikacin based on pharmacokinetic parameters of Korean neonates Objective: The purpose of this study was to determine the outcomes of a new dosing regimen of amikacin based on pharmacokinetic analysis in Korean neonates. Methods: This study was conducted in the Neonatal Intensive Care Unit at Asan Medical Center in Seoul, Korea, between February 2003 and December 2009. Data were collected from 181 patients of 24 to 41 weeks of gestational age treated with amikacin and had two concentrations (peak and trough). Pharmacokinetic analysis was performed and a new dosing regimen based on the pharmacokinetic parameters of Korean neonates was designed according to postconceptional age, postnatal age, and weight. ‘Group 1’ patients (n=107) received amikacin under the previous dosing regimen based on the published guideline, and ‘Group 2’ patients (n=74) received amikacin under the new dosing regimen. Results: The percentage of neonates within target range of peak concentration (20-30 mg/L) was significantly higher in Group 2 neonates with the new dosing regimen (81.3%) than that of Group 1 (50.7%; p < 0.001). No significant difference in the percentage of neonates within target range of trough concentration ( 5 mg/L) was found between Group 1 and Group 2 (85.1% vs. 87.5%, p = 0.621). The percentage of neonates with peak concentration < 20 mg/L was significantly lower in Group 2 (3.8%) than that of Group 1 (21.6%; p < 0.001), and the percentage of neonates with peak concentration > 30 mg/L was significantly lower in Group 2 (15.0%) compared with Group 1 (27.6%; P < 0.001). The percentage of dosing adjustment by pharmacist was significantly lower in Group 2 (31.6%) compared with Group 1 (59.7%; p = 0.056). Conclusion: The new dosing regimen of amikacin based on the pharmacokinetic parameters in Korean neonates was effective in achieving peak and trough concentrations within the defined target range. Part 2. Influence of gene polymorphisms on the risk of warfarin bleeding complications at therapeutic INR in Korean patients with mechanical cardiac valves Background: Pharmacogenetic studies focused on the genetic regulation of warfarin dose have been conducted, but few have been on the bleeding complications at therapeutic International Normalized Ratio (INR). Objective: This study aimed to evaluate the effect of gene polymorphisms of CYP2C9, VKORC1, thrombomodulin (THBD), and C-reactive protein (CRP) on the risk of bleeding complications of warfarin at therapeutic INR in Korean patients with mechanical cardiac valves. Methods: A retrospective warfarin pharmacogenetic association study was performed. One hundred forty-two patients with mechanical cardiac valves who were on warfarin anticoagulation therapy and maintained INR levels of 2.0-3.0 for 3 consecutive times were followed up retrospectively. CYP2C9 rs1057910, VKORC1 rs9934438, CRP rs1205, THBD rs1042580, and THBD rs3176123 were genotyped. The association between genotypes and warfarin bleeding complications was evaluated using logistic regression, adjusted for demographic and clinical factors. Results: Out of 142 eligible patients, 21 patients (14.8%) had bleeding complications at therapeutic INR. Patients with the G allele in THBD rs1042580 (AG or GG) had a lower risk of bleeding than patients with the AA genotype (Adjusted OR 0.210, 95% CI 0.050-0.875, p = 0.032). The THBD rs3176123 polymorphism did not show any association with bleeding. For CRP rs1205, patients with the A allele (GA or AA genotype) had a higher risk of bleeding than patients with the GG genotype (Adjusted OR 5.575, 95% CI 1.409-22.058, p=0.014). Variant VKORC1 and CYP2C9 genotypes did not confer a significant increase in the risk for bleeding complications. Conclusions: In Korean patients with mechanical heart valves, THBD rs1042580 and CRP rs1205 were associated with bleeding complications after stabilization of warfarin anticoagulation. This study could be of much help in the process of establishing the medication safety of warfarin treatment.;Part 1. 한국 신생아에서 amikacin의 약동학 분석에 근거한 새로운 투여 지침의 적용 효과 본 연구에서는 한국 신생아의 amikacin에 대한 약동학적 분석에 근거한 amikacin의 새로운 투여지침을 적용하고, 그 효과를 평가하고자 하였다. 2003년부터 2009년까지 서울아산병원 신생아중환자실에 입원하여 amikacin을 투여 받고, 정상상태에서 혈중 최고 농도(serum peak concentration)와 혈중 최저 농도(serum trough concentration)를 모두 측정한 경우가 연구 대상이 되었다. 그룹 1의 환자 (n=107)에게는 2003년 2월부터 2005년 2월까지 기존에 사용하던 amikacin 용량 지침에 따라 투여하였다. 이 지침은 Neofax®와 1999년에 서울아산병원에서 시행한 약동학 연구에 기초한 것이었다. 그룹 1 환자의 약동학 파라미터에 근거하여 새로운 용량 지침을 개발하였고, 이 용량은 환자의 postconceptional age, postnatal age, 체중에 따라 결정되었다. 2007년 7월부터 서울아산병원 신생아중환자실의 환자들에게 amikacin의 새로운 투여 지침을 적용하였다. 2007년 7월부터 2009년 12월까지 그룹 2 환자(n = 74)의 자료를 수집하여 치료혈중농도 (therapeutic range)에 도달한 비율을 그룹 1 환자(n = 107)들의 결과와 비교하였다. 혈중 최고 농도가 목표 범위 (20-30 mg/L)에 도달한 비율이 그룹 1의 환자 (50.7%) 보다 그룹 2의 환자 (81.3%)에서 유의하게 높았다 (p < 0.001). 혈중 최저 농도가 목표 범위 (< 5 mg/L)에서 유지되는 비율은 그룹 1 (85.1%)과 그룹 2 (87.5%) 사이에 유의한 차이를 보이지 않았다 (p=0.621). 혈중 최고 농도가 치료혈중농도 미만(< 20 mg/L)으로 유지되는 비율이 그룹 2에서는 3.8%로 그룹 1의 결과 (21.6%)와 비교하여 유의하게 감소하였다 (p < 0.001). 혈중 최고 농도가 30 mg/L 이상으로 치료혈중농도의 목표치를 초과하는 비율도 그룹 2는 15%로 그룹1의 결과(27.6%) 보다 유의하게 감소하였다 (p < 0.001). 약사의 치료적 혈중 약물농도 모니터링 (therapeutic drug monitoring)에 의하여 용량을 조정한 경우도 새로운 용량 지침을 적용한 그룹 2에서는 31%로 기존 용량 지침을 적용했던 그룹 1의 결과 (57%) 보다 감소하였다 (p = 0.056). 한국 신생아의 약동학 연구에 근거한 amikacin의 새로운 투여 지침은 혈중 최고 농도와 혈중 최저 농도가 치료혈중농도의 목표 범위 내에서 유지되는 비율을 증가시켜 안전하고 효과적인 약물 치료에 기여하였다. Part 2. 한국인 인공심장판막치환 환자에서 유전적 다형성이 INR 치료범위에서 발생하는 warfarin의 출혈 위험에 미치는 영향 Warfarin에 대한 약물유전체학 연구에서 유전적 다형성이 warfarin의 유지용량에 미치는 영향에 관한 연구는 많이 수행되었으나, INR의 치료범위(2-3)에서 나타나는 출혈 부작용과 유전적 다형성의 관련 연구는 미비하다. 본 연구에서는 CYP2C9, VKORC1, thrombomodulin (THBD), C-reactive protein (CRP)의 유전적 다형성이 치료범위의 INR (2-3)에서 나타나는 출혈 부작용의 위험을 높이는지 알아보고자 하였다. 인공심장판막치환술을 시행 받고 warfarin을 복용하면서 INR 2-3을 연속하여 3회 이상 유지한 환자 142명의 자료를 후향적으로 분석하였다. 분석에 포함한 유전자들은 CYP2C9 rs1057910, VKORC1 rs9934438, CRP rs1205, THBD rs1042580, and THBD rs3176123 이었다. 총 142명의 환자 중 21명 (14.8%)이 INR 치료 범위 (2-3)에서 출혈 부작용을 경험하였다. THBD rs1042580의 G allele (AG 또는 GG)을 지닌 환자가 AA 유전형을 지닌 환자에 비하여 출혈 부작용의 위험이 0.21배로 낮게 나타났다 (Adjusted OR 0.210, 95% CI 0.050-0.875, p = 0.032). THBD rs3176123의 유전적 다형성은 warfarin의 출혈 부작용에 영향을 미치지 않았다. CRP rs1205에 대해서는 A allele (GA or AA)을 지닌 환자가 GG 유전형을 지닌 환자보다 출혈 위험이 5.575배 높았다. (Adjusted OR 5.575, 95% CI 1.409-22.058, p = 0.014). VKORC1과 CYP2C9의 유전적 변이는 warfarin의 출혈 위험을 높이는데 유의한 영향을 주지 않았다. 인공심장판막치환술을 받은 한국인 환자에서 THBD rs1042580과 CRP rs1205의 유전적 다형성이 치료범위의 INR (2-3)에서 나타나는 출혈 부작용과 관련이 있었다. 본 연구는 약물유전체학을 이용한 warfarin 치료의 안전성 확립에 도움이 될 것으로 기대한다.Introduction 1 PART 1. Outcomes of a new dosage regimen of amikacin based on pharmacokinetic parameters of Korean neonates 3 Introduction 4 Methods 8 A. Patients 8 B. Administration and monitoring 9 C. Data collection 9 D. Pharmacokinetic analysis 10 E. Statistical analysis 10 Results 12 Discussion 22 Conclusions 25 PART 2. Influence of gene polymorphisms on the risk of warfarin bleeding complications at therapeutic INR in Korean patients with mechanical cardiac valves 26 Introduction 27 Methods 30 A. Study patients and data collection 30 B. Genotyping methods 32 C. Statistical analysis 34 Results 35 A. Patient characteristics 35 B. Influence of gene polymorphisms on warfarin bleeding complications 40 1. Univariate analysis 40 2. Multivariate analysis 42 Discussion 44 Conclusions 47 References 48 Appendix, 저자 논문 목록 58 국문초록 5

Analysis on Reports of Statistical Testings for Correlation and Regression

Purpose:This study aimed to examine the accuracy and adequacy of research papers reporting statistical testings for correlation and regression. Method:Original research articles utilized correlation and regression analysis were reviewed from the Korean Journal of Women Health Nursing published from the year 2004 to 2006. Thirty-six papers were evaluated in accordance with formatted criteria in respect to an inclusiveness of research title, accuracy of statistical methods and presentation styles, and errors in reporting statistical outcomes. Result:Thirty articles (83.3%) utilized Pearsons correlational analysis, and ten articles did regression analysis. Lack of accurate understanding and interpretation of the statistical method was a main fault. Basic assumptions and diagnostic testings for each statistical method were not performed or described in most of the studies. Some points like consistency of research questions with statistical methods and criteria for sample size were still left out in part. Details of the presentation in the reporting of outcomes were not complied with the guidelines, which need careful concerns of the writers. Errors in English of result tables were found in more than one third of the tables. Conclusion:The outcome would be reflected in the submission guidelines for future writers. To reach the level comparable with internationally recognized nursing journals, concrete knowledge to apply statistical methods should be ensured in the processes of submission, reviews, and editing

Analysis on Reports of Statistical Testings for Mean Differences

Purpose: This study aimed to evaluate the accuracy and adequacy of research papers reporting statistical testings for mean differences. Methods: Original research articles utilized t-test, Chi-square test, and ANOVA were reviewed from Korean Journal of Women Health Nursing published from the year 2004 to 2006. Seventy-six papers were evaluated in accordance with formatted criteria in respect to an inclusiveness of research title, accuracy of statistical methods and presentation styles, and errors in reporting statistical outcomes. Results: Research titles were quite comprehensive, however overall accuracy of statistical values and basic formats reached only 60 to 80% by items. Details of the presentation in the reporting of outcomes were not complied with the guidelines, which need careful concerns of the writers. Errors of English in table presentation were found in more than 30% of the papers. Conclusion: The outcome would be reflected in the submission guidelines for future writers. To reach the level comparable with internationally recognized nursing journals, concrete knowledge to apply statistical methods should be ensured in the processes of submission, reviews, and editing

Analysis of Published Papers and their Keywords in the Korean Journal of Women Health Nursing (2003-2006)

Purpose: This research was aimed to explore the major subjects and research theme and to classify characteristics of the key words in recent Korean Journal of Women Health Nursing. Methods: With survey design, whole 103 published papers during 2003-2006 were analyzed with structured analysis form; research subjects, research methodology, data analysis, and key words of the published papers were classified and extracted. Various theme was founded and classified to 9 domains. Results: Most of the research subjects were women. Eighty-eight percent of papers conducted quantitative research; 83% chose convenience sampling and 69% used survey design, while experimental design was 29%. Key words were categorized 9 domains: demographic, health related concept, health behavior(intervention), sex-related, life event, disease, et al. Among 9 domains, health related concept, especially psycho-social topics such as depression, anxiety, stress were mostly studied and then physiologic topics such as labor pain, fatigue, and menstrual symptoms. Conclusion: Most of the subjects were women and the most common domain studied was health related concepts in Korean Journal of Women Health Nursing. And key words and topics were on women's health issues. We can conclude that Korean Journal of Women Health Nursing has published by her own philosophy