Risk assessment includes identification, estimation and evaluation of risk as the first step of risk management on drug development and use. Pharmacovigilance and pharmacoepidemiology are linked in respect to their principles and application methods. The coding systems for adverse drug reactions have been developed as COSTART, WHOART, and MedDRA by the United States, WHO, and ICH, respectively. MedDRA becomes globally accepted coding system due to its comprehensiveness and characteristics of continuous evolution. International organizations including WHO and ICH have developed guidance for accomplishing global standardization on risk assessment. Current pharmacovigilance system needs to be developed further for satisfying the increased concern on drug safety. In Korea, effective risk assessment system has not been established yet because of the lack of trained staffs at KFDA and less active collaboration among academia, regulatory and industry. Korean FDA has to establish more effective system for facilitating spontaneous ADR reporting by the patients as well as from physicians and pharmacists. Highly-qualified experts are also needed to conduct adequate risk assessment activities for detecting signals from the database constructed from the spontaneous ADR reports as well as large automated databases at Health Insurance Review Agency. We reviewed the current status and policy on risk management system focusing on the risk assessment including ADR coding system globally as well as domestically.

Costart, Whoart, and MedDRA have been widely used for classification of drug safety data for the purpose of analysis and retrieval. MedDRA is, however, different from the other dictionaries in many aspects, mainly in size, granularity, and its structure. The MedDRA is characterized by its hierarchical and, multiaxial features and its regular update, which can have an impact on the safety data analysis as well as a presentation of the data. The MedDRA is globally preferred as it is continuously updated by reflecting users requests, and many pharmaceutical companies and regulatory authorities required MedDRA as a compulsory for electronic transmissions. Therefore, understanding the coding system of MedDRA is very important for clinical investigators before they use it to record and report their drug safety data. An appropriate use of coding system should enhance the applicability of drug safety database.

The thalidomide disaster during the early 1960s produced more than 10,000 deformed babies in the countries in which the drug was widely used. Recently phenyl propoanolamine induced hemorrhagic cerebrovascular disease and rofecoxib induced cardiovascular events were reported. At the time when a new drug is marketed the clinical safety database is very limited and comprises a rather small number of patients. So pharmacologically effective drugs are not entirely without hazard and not all hazards can be known before a drug is marketed. Thus, post-marketing surveillance (PMS) of drugs is imperative to quantify common adverse drug reactions (ADRs) and to identify rare adverse reactions. In the UK there are two unique drug adverse reaction monitoring systems, the Medicine Monitoring Service (MEMO) and Prescription-Event Monitoring (PEM). The MEMO is a university based organization that was set up to carry out studies to detect and quantify serious drug toxicity in the Tayside region of Scotland, using record linkage techniques. The PEM is the form of PMS which prompts all doctors using new drugs intended for widespread use in primary care to report the events which follow their use. It is of importance that the MEMO and PEM data represent the real world use of the newly marketed medicines in the age and sex distribution and with the concurrent medication that typifies everyday practical clinical use of the drug. They generate signals which, through pharmacoepidemiology, can be investigated in order to determine relevant concerns over drug safety. We reviewed MEMO and PEM to inquire into efficient PMS in general population.

강력한 항우울작용을 나타내는 세로토닌 재흡수 억제제의 하나인 paroxetine에 의해 유발된 유루증은 매우 드문 경우로 알려져 있는데 본 2개의 증례는 정신과적 치료를 위해 paroxetine을 지속적으로 복용한 상태에서 그 부작용으로 유루증을 보인 국내 최초의 보고이다. 첫 번째 예는 우울증 치료를 위해 paroxetine을 4개월 동안 꾸준히 복용한 결과 유루증이 발생된 경우이다. 지속적인 우울증 증세로 paroxetine은 지속하면서 bromocriptine을 사용한 후 1개월에 걸쳐 유루증은 사라졌고 더 이상 유루증을 보이지 않았다. 두 번째 예는 교통사고 후 생긴 외상후 스트레스 장애의 치료를 위해 proxetme으로 3개월간 치료하던 중 유루증이 발생하였고 이후 이 약제 복용을 중단한 지 3주쯤에 유루증은 소실되었다. 두 증례 모두에서 과거에 한번도 유루증을 경험 하지 못한 여성들이었고 뇌하수체 뇌자기공명영상은 정상이었으며 유루증을 일으킬만한 다른 원인들을 찾을 수 없어 약제(paroxetine)에 의한 유루증으로 진단하였다, 보통 유루증은 혈중 프로락틴의 증가에 의해 발현되는 것으로 생각되지만, 특이하게도 유루증을 보인 이번 두 증례 모두에서는 혈중 프로락틴 수치가 정상이었다. 이로써 정상적인 혈중 프로락틴 농도에서도 paroxetine을 지속적으로 사용시 그 부작용으로 유루증을 보일 수 있다는 것을 본 증례는 보여주고 있으며 가장 효과적인 치료는 다른 증례들에서와 마찬가지로 사용하고 있는 항우울제인 paroxetine을 중단하는 것이 지만 우울증세 지속시 도파민 항진제의 사용도 고려해 볼 수 있음을 시사해 주고 있다. 하지만 아직까지 혈중 프로락틴 농도가 정상인 유루증에 대한 원인은 분명치 않은 것으로 알려져 있다.

Background : Licorice, a core traditional herbal medicine, is frequently coadministered with the conventional medications in Korea. Several reports suggested that the licorice treatment induced the cytochrome P450(CYP) in rats, especially for CYP3A isoform However, no report has been addressed to the effect of licorice on midazolam, CYP3A substrate, in human. This study was performed to evaluate the effect of licorice on the disposition and pharmacodynamic effects of midazolam in human. Methods : One gram of freeze dried water extract of licorice (extraction ratio ; 25%) or placebo were orally administered divided in two times to 10 healthy male subjects for 7 days as one blind randomized crossover manner with 2 weeks washout. On the day after completion of 7 days pretreatment, multiple blood samples were drawn and urine was collected for 24 hours after oral dose of 7.5 mg midazolam. Psychomotor performance tests including digit span test and digit symbol substitution test were conducted for 4 hours after midazolam administration on each phase of midazolam treatment and before pretreatment of placebo or licorice extract. The plasma concentration of midazolam and 1-hydroxymidazolam were determined with using HPLC and pharmacokinetic parameters were estimated by noncompartmental method. Results : After 1 week treatment of licorice extract, the plasma clearance of midazolam was significantly increased (1.15+0.50 vs 1.59+0.81 L/min, p<0.05) and the half-life was shortened ( 2.07+0.74 vs 1.34+0.60 hr, p<0.05) compared to those obtained after placebo treatment. Mean AUC of midazolam was decreased from 102.13+ 28.84 ng/ml hr to 85.06+48.51 ng/ml hr after licorice treatment, but not significantly different (p=0.11). There was no significant changes in AUC and urinary amount of 1-hydroxymidazolam by licorice pretreatment. The changes in the score of psychomotor performance tests (DST and DSST) measured after midazolam dosing were not significantly different between placebo and licorice pretreatment. Conclusions : Licorice water extract seems to affect the disposition of midazolam in human, but it is suggested that the CYP3A4 induction is not the major mechanism of the interaction. Further studies are remained to evaluate the mechanism of the pharmacokineitc interaction between midazolam and licorice water extract.

Background : Mesoglycan, a preparation of natural glycosaminoglycans, has pleiotropic protective effects on cerebral vasculature, including anti-thrombotic, fibrinolytic and anti-atherogenic activity. It also has shown a feasible potential in the secondary prevention for cerebral ischemia, In this study. we investigated the effect of mesoglycan and aspirin combination on fibrinogen levels in patients with previous ischemic stroke. Methods : Patients with previous ischemic stroke were randomly assigned as either mesoglycan group (mesoglycan 50mg twice daily + aspirin 300mg once daily) or control group (placebo twice daily + aspirin 300mg once daily), and treated in double-blinded manner. Efficacy variable included the fibrinogen level, which was checked on every visit for 8 weeks (at the second, forth and eighth week). Results : Forty-five outpatients (22 control group and 23 mesoglycan group) were included and analyzed. There was no significant difference in the baseline characteristics, including age, sex, baseline fibrinogen and cholesterol profiles, between the mesoglycan group and the control group, No clinical or laboratory adverse effects were reported in the mesoglycan group, while two non-treatment emerging adverse effects were reported in the control group. Mesoglycan group exerted no significant change of the fibrinogen level compared with the control group. Conclusions: In this study, mesoglycan and aspirin combination in patients with previous cerebral ischemia showed a favorable tolerability without any adverse effects. However, to verify the efficacy of mesoglycan and aspirin combination on the fibrinolytic system or the secondary prevention, further study is warranted based on a larger scaled subjects and long-term period.

Background & Objectives : Calcium channel blockers(CCB) have been used primary antihyperetensives. among them, second generation CCB, amlodipine besylate(Norvasc), has been used worldwide recent 10years because of it's high bioavailibility and long half life. but, non-besylate amlodipine such as amlodipine maleate has not been used even though it's many biochemical, pharmacological and toxicological information. so, we compared amlodipine besylate with amlodipne maleate in anti-hyperetensive activity and safety. Methods : We used 8weeks, multi-center, randomized, double blinded, double dummy, parallel-group comparative phase 3 clinical trial to assess the efficacy and safety of amlodipine maleate compared to amlodipine besylate in patients with mild-to-moderate hypertension. Results : In anti-hyperertensive efficacy, the mean declines in sDBP was $12.8{\pm}6.5mmHg$ vs $1l.5{\pm}7.3mmHg$ in each cases. difference is 1.2mmHg, and this is meaningless statistically. In safety, there were several side effects such as rash, urticaria, headache, insomnia and so on. But, no severe side effects and statistically meaningful differences were noted in each cases. According to our study, there are little differences between amlodipine besylate and amlodipine maleate in efficacy and safety. Conclusions : Besylate and maleate, are just carriers of amlodipine in the body. amlodipine itself acts on the net anti-hypertensive effect. so, we found that amlodipine besylate and amlodipine maleate show nearly same anti-hypertensive effect and safety regardless of their salt compounds.

Background : Loperamide, a peripherally acting opioid receptor agonist with a methadone-like structure and antidiarrheal action, is mainly metabolized to desmethylloperamide through. N-demethylation pathway. It has been reported that CYP2C8 and CYP3A4 might playa crucial role in loperamide Ndemethylation in therapeutic concentrations and loperamide might be an inhibitor of CYP3A4. However, there has been no available data to reveal it. The inhibitory effect of loperamide on CYP3A4 using midazolam 1'-hydroxylation was evaluated in vitro by human liver microsomes. Methods : Various concentrations of loperamide or ketoconazole (a selective and potent inhibitor of CYP3A4) were co-incubated with midazolam in human liver microsomes. CYP3A4-catalyzed midazolam metabolite, l'-hydroxymidazolam was analyzed by high-performance liquid chromatography (HPLC) to determine the inhibitory potency of loperamide on midazolam 1'-hydroxylation using $IC_{50}$ (the concentration of inhibitor representing 50% inhibitory potency) and Ki (apparent inhibitory constant) values. Results : Loperamide inhibited concentration-dependently CYP3A4-catalyzed midazolam 1'-hydroxylation with apparent $IC_{50}$ values of 0.78 ${\mu}M$ in human liver microsomes. Graphical analysis showed that loperamide had a potent inhibitory effect on midazolam l'-hydroxylation with a Ki value of 0.54 ${\mu}M$ in a competitive manner. Conclusions : Loperamide had a potent inhibitory effect on CYP3A4-catalyzed midazolam 1'-hydroxylation in human liver microsomes. However the predicted inhibition of loperamide within therapeutic ranges on the metabolism l'-hydroxylation showed the low possibility of in vivo drug interaction of 10peramide with the drug metabolized by CYP3A4.

Ethylene glycol is used primarily as automobile antifreeze, and other industrial solutions as well. Ingestion can cause intoxication, showing metabolic acidosis, central nervous system depression, cardiovascular collapse, and renal failure, which is attributable to the biotransformation and accumulation of the toxic metabolites. A 41-year-old man was brought to the emergency room two hours after ingesting about 400 ml of antifreeze in a suicide attempt. His initial state was unremarkable except stuporous mental state, but he soon developed metabolic acidosis(pH 7.17), increased osmolar and anion gaps, and acute renal failure. Oral ethanol was administered via nasogastric tube and hemodialysis was performed twice together with intensive supportive care. He had an uneventful recovery and was discharged from the hospital 9 days after the ingestion. In order to prevent mortality and morbidity, early recognition and management of ethylene glycol toxicity is important.

Background and Objectives : Nicorandil has the pharmacologic effects similar to currently-taken nitrate and in respect to the K-channel opening action in vascular smooth muscle cells, and the frequency of use is being increased. This study was designed to compare the effect of nicorandil with nitrates as early therapeutic agent for acute non-ST segment elevation myocardial infarction (NSTEMD. Subjects and Methods : A total of 67 patients (34 nicorandil group, 33 nitrates group) who had acute NSTEMI on admission into emergency room were enrolled and randomized in this study. All patients in both group underwent coronary angiography / percutaneous coronary intervention during hospitalization, and follow-up after discharge was performed at OPD on 1st, 3rd, & 6th months. The frequency of major adverse cardiac event (MACE) and significant adverse effect of used agents was investigated. Results : There was no demonstrable difference of clinical profile between both group. The result of comparative analysis revealed slight decrease of reinfarction rate in nicorandil group without statistical significance(2.9% versus 9.1%, p value = 0.076), and no meaningful difference on aspect of target vessel revascularization and cardiac-origin death. No ominous distinction of frequency of the adverse drug effect was noted in both group. Conclusion : In spite of statistical insignificance, the early use of nicorandil for acute NSTEMI may reduce in-hospital reinfarction incidence. The other profile showed no notable advantage compared with nitrates.