Aspartate 및 Asparagine 투여가 알코올 대사 및 중추신경계 효과에 미치는 영향

임동석(Dong-Seok Yim),이경훈(Kyung-Hun Lee),장인진(In-Jin Jang),신상구(Sang Goo Shin),이윤성(Yoon-Sung Lee),박상철(Sang-Chul Park) 대한약리학회 1995 대한약리학잡지 Vol.31 No.2

Background; To explore the efficacy of aspartate as NAD regenerating agent for ethanol and acetaldehyde oxidation, we performed crossover challenge in two groups of volunteers by coadministration of various doses of aspartate, asparagine and ethanol. Methods; 18 healthy male volunteers were randomly divided into two groups. 6 volunteers of the first group were administered 5 gm monosodium aspartate(MSA), 5 gm asparagine or placebo with 100 ml of 40˚ whiskey by the 3 way-crossover design, while 12 volunteers of the other group were administered placebo, 1, 2 or 5 bottles of Aspar^?? containing 1 gm of MSA per bottle with 100 ml of 40˚ whiskey by the 4 way-crossover design. Ethanol(and acetaldehyde) concentrations in venous blood drawn at 0, 0.25, 0.5, 1, 2, 4, 8th hour after ethanol ingestion were analysed by gas chromatogaphy. Subjective symptoms, liver function tests and psychomotor function tests were also performed during the study periods. Result; Plasma concentration and AUC of acetaldehyde in asparagine and MSA trials on ethanol ingestion were significantly lower than those of placebo trial in the 1st group. Plasma ethanol concentration of 5 bottle Aspar^?? trial was significantly lower than that of placebo trial in the 2nd group. Improvement of subjective symptoms or psychomotor performance by the treatment was not statistically significant. Conclusion; Aspartate and asparagine may be prospective candidates for acceleration of ethanol metabolism and prevention of ethanol toxicity.

실험견에서 Metoprolol 약리효과의 약동/력학적 검토

오동진(Dong-Jin Oh),장인진(In-Jin Jang),이경훈(Kyung-Hun Lee),임동석(Dong-Seok Yim),김형기(Hyung-Kee Kim),신상구(Sang-Goo Shin),박찬웅(Chan-Woong Park),신재국(Jae-Gook Shin) 대한약리학회 1995 대한약리학잡지 Vol.31 No.2

Pharmacokinetics and pharmacodynamics of metoprolol, a selective beta-l blocker, were examined for 360 minutes after intravenous bolus administration of metoprolol to 6 dogs. Plasma concentration and excreted amount in the urine metoprolol were measured by liquid chromatography with fluorescence detection. PR interval and heart rate were measured by ECG monitoring. Blood pressure was monitored through intraarterial catheter in femoral artery and cardiac output by thermodilution method using Swan-Ganz catheter. To analyze the effect site concentration-response relationship, plasma concentration and pharmacological effects were simultaneously fitted to a two pharmacokinetic compartment linked to pharmacodynamic model with NONLIN program. Results are as follows. 1) The plasma concentration of metoprolol after intrvenous injection decreased biexponentially. The terminal half-life estimated was 1.33 ± 0.40 hours and the volume of distribution at steady state (Vdss) and the total body clearance were 1.04 ± 0.4 L/kg, 6.55 ± 2.21 L/hr, respectively. The central compartment volume of distribution and peripheral compartment volume of distribution were 0.35 ± 0.14L/kg and 0.69 ± 0.34L/kg. The renal clearance and intercompartment clearance were 0.53 ± 0.25 L/min and 0.35 ± 0.19 L/min. 2) Simulated biophase concentration-response curve shows hyperbolic relationship and the estimated concentration-effect relationship was best explained by Emax model when the prolongation of PR interval and the reduction of the heart rate were used as pharmacodynamic parameters. Emax and EC50 were estimated to be 26.3 ± 4.7 msec and 88.8 ± 82.3 g/ml for PR interval, and 48.7 ± 18.8 beats/min and 113.5 ± 78.7 ng/ml for heart rate, respectively. 3) The changes of cardiac output-effect site concentration relationship was best fitted by a linear model and the slope of the relationship was 0.005 ± 0.003. Diastolic blood pressure-effect site concentration relationship was also explained by the linear model and the slope of the relationship was 0.038 ± 0.034.

임상시험에서 사용되는 기본통계개념에 관한 고찰

최경미,이종태,전상일,홍태곤,백정기,한승훈,임동석,Choi, Kyungmee,Lee, Jongtae,Jeon, Sangil,Hong, Taegon,Paek, Jeongki,Han, Seunghoon,Yim, Dong-Seok 대한임상약리학회 2012 臨床藥理學會誌 Vol.20 No.2

Statistical analysts engaged in typical clinical trials often have to confront a tight schedule to finish massive statistical analyses specified in a Standard Operation Procedure (SOP). Thus, statisticians or not, most analysts would want to reuse or slightly modify existing programs. Since even a slight misapplication of statistical methods or techniques can easily drive a whole conclusion to a wrong direction, analysts should arm themselves with well organized statistical concepts in advance. This paper will review basic statistical concepts related to typical clinical trials. The number of variables and their measurement scales determine an appropriate method. Since most of the explanatory variables in clinical trials are designed beforehand, the main statistics we review for clinical trials include univariate data analysis, design of experiments, and categorical data analysis. Especially, if the response variable is binary or observations collected from a subject are correlated, the analysts should pay special attention to selecting an appropriate method. McNemar's test and multiple McNemar's test are respectively recommended for comparisons of proportions between correlated two samples or proportions among correlated multi-samples.

만성 간질환 환자에서 Metoprolol의 약동학에 관한 연구

채희복,이경훈,차영남,이영상,서동진,윤영란,신재국,임동석,신상구,장인진,Chae, Hee-Bok,Lee, Kyung-Hoon,Cha, Young-Nam,Lee, Young-Sang,Suh, Dong-Jin,Yoon, Young-Ran,Shin, Jae-Gook,Yim, Dong-Seok,Shin, Sang-Goo,Jang, In-Jin 대한임상약리학회 1999 臨床藥理學會誌 Vol.7 No.1

연구배경 : 간기능은 심하게 진행되기 전까지는 단백합성기능, 배설기능, 약물대사기능 등이 잘 보존되며, 고추출율 약물은 저추출율 약물에 비해 약물 대사능과 간기능의 장애 정도간에 더 밀접한 상관관계가 있음이 알려져 있다. 선택적 ${\beta}_1$-adrenoceptor 길항제인 metoprolol은 주로 간에서 대사되며 경구투여시 1차통과효과(first pass effect)가 큰 고추출율 약물로, metoprolol의 ${\alpha}$-수산화 대사는 간장의 CYP2D6 활성도를 측정하는데 이용되고 있다. 따라서 본 연구에서는 비교적 진행된 간기능 장애를 지닌 modified Child-Pugh class B군과 C군에 해당하는 만성 간질환 환자에서 metoprolol 및 ${\alpha}-OH$ Metoprolol의 약동학적 성상을 대조군과 비교함으로써, 간기능 장애정도에 따른 약물대사능의 변화(특히 CYP2D6 활성도의 변화)를 규명하고자 하였다. 대상 및 방법 : 정상대조군 피험자 8명과 modified Child-Pugh class B군 9명 및 C군 7명을 대상으로, metoprolol 50 mg을 경구로 일회투여후 경시적으로 혈장과 요중 metoprolol 및 그 대사체인 ${\alpha}$-OH metoprolol의 농도를 관찰하였다. Metoprolol 및 ${\alpha}$-OH metoprolol의 혈장과 요중 농도는 형광검출기를 이용하여 HPLC로 측정하였으며, 약동학적 파라미터는 noncompartmental 분석법으로 산출하였다. 결과 : Metoprolol의 약동학적 변수중 $C_{max},\;T{max},\;t_{1/2{\beta}}$, $ACU_{0-12hr}$가 환자군과 대조군간에 통계적으로 유의한 차이를 나타내었으며 , ${\alpha}$-OH metoprolol에 대해서는 $C_{max}$와 $T_{max}$가 두 군간에 통계적으로 유의한 차이를 나타내었다. 환자들을 modified Child-Pugh class B군과 C군으로 나누어 비교시에는 약동학적 파라미터들에 차이가 없었다. 결 론 : 본 연구결과 정상대조군의 metoprolol 혈장농도곡 선하면적은 만성 간질환 환자군의 약 35%였으므로, 만성 간질환 환자에서 metoprolol의 초기용량은 정상인의 약 3분의 1 용량으로 시작하고 유지용량은 각 환자의 임상반응에 따라 조정하는 것이 바람직할 것으로 사료된다. Background : Metoprolol, the selective ${\beta}_1$-adrenoceptor antagonist, is eliminated primarily by hepatic metabolism. Usually less than 5% of an oral dose is excreted unchanged in the urine. Metoprolol is a highly extracted drug and its ${\alpha}$-hydroxylation pathway is mediated by CYP2D6. Therefore, it is often used as a probe drug to measure the metabolic capacity of liver. Method : The effects of impaired liver function on the pharmacokinetics of metoprolol were studied in 16 patients with hepatic cirrhosis (modified Child-Pugh class B and C group : 9 and 7 persons, respectively) together with 8 healthy volunteers. Pharmacokinetic parameters in these patients were compared to those in normal subjects. All subjects were given single oral doses of 50mg in the morning fasting state. Blood and urine samples were collected serially. The concentrations of metoprolol and ${\alpha}$-OH metoprolol in the biological fluids were measured by high-performance liquid chromatography using fluorescence detector. Results : There were statistically significant differences in $C_{max},\;T_{max},\;t_{1/2{\beta}}$, and $AUC_{0-12hr}$ of metoprolol between the patients and the normal subjects (p<0.05), ${\alpha}$-OH metoprolol produced by CYP2D6 was also measured and significant differences in both $C_{max}$ and $T_{max}$ were observed. There was no statistically significant difference in pharmacokinetic parameters between modified Child-pugh class B and C groups. Conclusion : For the sake of safety, the reasonable initial dose of metoprolol for the patients with portocaval shunts or advanced liver disease would be about one third of the usual dose, although the potential for adverse reactions is tempered by the flat dose response curve and the wide therapeutic index of this drug.

시스템 약리학 기술을 이용한 통합 생체 심혈관 안전성 예측 모델 구축 연구

오건희 ( Kunhee Oh ),김기석 ( Ki-suk Kim ),이향애 ( Hyang-ae Lee ),한승훈 ( Seunghoon Han ),임동석 ( Dong-seok Yim ) 한국동물실험대체법학회 2018 동물실험대체법학회지 Vol.12 No.1

ICH S7B and E14 guidelines, which were first released in 2005, are focused on hERG blockade and QT prolongation by drugs. However, cumulated evidences on some pitfalls of the guidelines resulted in the initiation of the comprehensive in vitro proarrhythmia assay (CiPA) project. Results of the CiPA are expected to change global regulatory environment on the cardiac safety of drugs. In this study, we reproduced two components of the CiPA to assess the performance of their in silico biomarker using in vitro ion channel assay data. The process to obtain qNET, a biomarker proposed by CiPA, was fully reproduced through in vitro and in silico studies in selected three drugs (verapamil, ranolazine, moxifloxacin). Throughout the reproducing research, we obtained many practical experiences not included in publications by the CiPA. For further understanding of this new regulatory paradigm, clinical ECG in human and another in silico method are to be performed.

Ketoprofen 첩포제(Ketotop : )의 경피적용에 따른 혈장농도 및 피부자극의6 검토

임동석,장인진,신상구,유재학,은희철 大韓臨床藥理學會 1994 臨床藥理學會誌 Vol.2 No.1

정상인 및 신기능장애환자에서 Carumonam(AMA-1080)의 약동학

임동석,이경훈,엄재호,한진석,김성권,장인진,신상구 大韓臨床藥理學會 1994 臨床藥理學會誌 Vol.2 No.1

국내 Cefaclor 캅셀 제제의 약동학적 특성

장인진,임동석,신상구 大韓臨床藥理學會 1994 臨床藥理學會誌 Vol.2 No.2

호중구 감소성 발열환자에게 경험적으로 투여한 Teicoplanin의 효과

이동건,임동석,최수미,박선희,유진홍,최정현,민우성,신완식,김춘추 대한감염학회 2004 감염과 화학요법 Vol.36 No.2

목적 : 호중구감소성 발열 환자에게 경험적으로 teicoplanin을 투여할 때의 효과를 알아보고자 전향적 연구를 시행하였다. 방법 : 2003년 7월부터 12월까지 가톨릭조혈모세포이식센터에 입원하여 항암치료 혹은 조혈모세포이식을 시행하고 호중구감소성 발열이 있는 환자 중 초기 항균요법에 반응이 없어 경험적 teicoplanin 투여가 필요한 49명을 대상으로 A, B 제조회사에서 제공한 teicoplanin을 무작위로 어느 한 쪽 치료군에 배정하여 투여하였다. 용량은 첫날 400㎎ 부하용량을 정맥내 bolus로 투여하고 매 24시간마다 200㎎ 유지용량을 투여하였다. 결과 : A군 27명, B군 22명이 연구에 참여하였고 대부분의 환자가 신독성이 있는 약제를 병용하고 있었다. A군 8명, B군 7명에서 그람양성균이 동정되었고, teicoplanin에 대한 내성률은 A군 22.2%, B군 28.6%로 유의한 차이는 없었다(P=1.00; 0.61<95%CI<1.95). 미생물학적 확인 감염이 있었던 환자 중 평균 53.3%에서 완치 혹은 개선의 반응이 있었고 양 군간 유의한 차이는 없었다(A군 4명 [50.0%], B군 4명 [57.1%], P=1.00; 0.29<95%CI<2.60). 미생물학적 제거율은 평균 62.5% (A군 55.6%, B군 71.4%)이었고 그 외 미생물학적 효과는 A군에서 제거 후 재발 2명(22.2%), 내성 2명(22.2%)이었고 B군에서 각각 0명(0.0%), 2명(28.6%)이었으며 양 군간 유의한 차이는 없었다(P=0.28). 발열기간(P=0.89), teicoplanin 사용기간(P=0.47) 및 전체적인 사망률(P=1.00; 0.78<95%CI<1.24)도 양 군간 유의한 차이는 없었다. 이상반응 중 신독성은 16.3% (A군 18.5%, B군 13.6%)에서 나타났고 양 군에 차이는 없었으며(P=0.72; 0.39<95%CI<3.51), 신기능 이상과 관련있는 약제를 적어도 2개 이상 병용하고 있었다. 피부발진은 A군에서 1명, B군에서 3명 발생하였다(P=0.31; 0.93<95%CI<1.34). 결론 : 호중구감소성 발열환자에게 teicoplanin을 투여하였을 때 임상적 반응률은 평균 53.3%(A군 50.5%, B군 57.1%), 미생물학적 제거율은 평균 62.5%(A군 55.6%, B군 71.4%)이었고 두 제조회사간 차이가 없었고 이상반응도 양 군간 차이가 없었다. 앞으로 국내 호중구감소증 환자에서의 teicoplanin의 적정 용량, 용법 등을 알기 위한 집단 약동학 등의 연구를 시행할 예정이다. Background : This study was done to elucidate the efficacy of teicoplanin as the empirical treatment for febrile neutropenia. Methods : Patients were randomized to two groups according to pharmaceutical company (company A or B). Total of 49 patients (A, 27; B, 22) with neutropenic fever were studied prospectively for 6 months (Jul. 2003-Dec. 2003). Patients received 400 mg i.v. once, then 200 mg i.v. once daily. Results : Groups were matched for all demographic variables. Most of the patients were concurrently receiving nephrotoxic drugs. Gram positive microorganisms were isolated in 8 patients for A and 7 patients for B. Resistance rate against teicoplanin was 22.2% in A and 28.6% in B (P=1.0; 0.61 < 95% confidence interval [Cl] < 1.95). Among the patients with microbiologically documented infection, clinical cure or improvement was seen in 4 (50%) of 8 patients for A and 4 (57.1%) of 7 patients for B (P=1.00; 0.29 <95%CI <2.60). Bacteriologic efficacy was assessed as follows; elimination in 5 (55.6%), elimination with relapse in 2 (22.2%), resistance in 2 (22.2%) out of 9 gram-positive bacteria for A and 5 (51.4%), 0 (0.0%), 2 (28.6%) out of 7 bacteria for B, respectively (P=Q.28). There were no significant differences in duration of fever, duration of use of teicoplanin, and overall mortality. The incidence of nephrotoxicity and ototoxicity was not significant. Conclusion : For using teicoplanin as the empirical therapy for febrile neutropenia, the rate of clinical, microbiological response, and nephrotoxicity was 53.3%, 62.5%, and 16.3% respectively with no significant differences between the 2 preparations of teicoplanin. Supplementary evaluation on the adequate dose and duration of teicoplanin may be required.

경피흡수제제의 약동학적 분석 : Ketoprofen 첩포제의 예

장인진,임동석,이우영,신상구 大韓臨床藥理學會 1994 臨床藥理學會誌 Vol.2 No.2