Clinical trial is the most important step in new drug development, for only through which the efficacy and safety of a new drug can be explored and proved. Phases of clinical trials at present have been established through a series of changes with improvements of relevant regulations and laws following drug tragedies such as thalidomide baby in Europe around 1960. But it was not until the Kefauver-Harris Amendments was announced in 1962 and Investigational New Drug(IND) and New Drug Application(NDA) enforced in 1963 that regulations for safety and efficacy of a new drug and concrete guidelines for clinical trial enacted. FDA had propelled the development of clinical trial in respect of science and ethics since Helsinki proclamation in 1964 and obligated Good Clinical Practice(GCPs). But since International Conference on Harmonization(ICH), a movement for international standardization of new drug development process in 1992, conceptual change in preclinical, clinical data and clinical stage of new drug development goes on. Thus, we tried to help understand the new drug development process and clinical trial by reviewing them and to investigate the condition in Korea.

Background: Sildenafil citrate$(Viagra^{\circledR})$ improves sexual functions in men with erectile dysfunction and is widely prescribed. But little is known about the effects of sildenafil citrate on autonomic nervous system. Methods : Seventeen health male subjects$(age\;26{\sim}36\;years)$ were investigated. Blood pressure (BP), heart rate(HR), and autonomic nervous function tests, such as BP rise in the sustained hand-grip, sympathetic skin reflex(SSR), HR variation with deep breathing(HR variation), and Valsalva ratio, were measured before and 60 minutes after administration of a single 50mg oral dose of sildenafil citrate. Results : Systolic BP were slightly decreased after sildenafil citrate administration $(118.8{\pm}11.77mmHg{\rightarrow}112.7{\pm}13.8mmHg,\;p=0.048)$. HR and diastolic BP were not changed significantly after sildenafil citrate administration. And autonomic nervous function tests were not changed significantly after sildenafil citrate. Conclusions : Sildenafil citrate does not cause significant changes in autonomic nervous system except systolic BP.

Introduction : Our study was designed to prove the anti-anginal effect and adverse effects of molsidomine instead of nitrates on the patients with ischemic heart disease. Subjects and Methods : From January to June in 1999, total 58 patients who were diagnosed as ischemic heart disease (exclude AMI, variant angina) was included. We checked vital signs, liver function test, creatine phosphokinase, creatinine, calcium, ECG, echocardiography, urinalysis, treadmill test of all patients before starting molsidomine. Then 51 patients prescribed molsidomine 2mg tid, 5 patients 2mg bid, and 2 patients 4mg tid. After 8 weeks above laboratories were rechecked. The efficacy was determined as excellent, good, fair, poor response. Excellent response was decided when symptoms improved over 2 stage of Canadian Class, good when symptoms improved 1stage. fair when symptoms not changed, and poor response was decided when symptoms aggravated or adverse effects occurred. Results : Patient received molsidomine for mean 10.4 weeks. 7 patients received less than 8 weeks due to adverse effects and aggravated symptoms. The efficacy was excellent in 7 patients, good 34 patients, fair 10 patients, and poor in 7 patients. ECG was changed from nonspecific ST change to normal in 7 patients who showed good efficacy. In 7 patients who showed poor response, 6 patients stopped medication due to adverse effects, as hypotension in one, headache and dizziness in one, hepatotoxicity in two(one was liver cirrhosis), insomnia in one, rash in one, and G.I trouble in one. After stopped medication, all adverse effects except hypotension were recovered. Conclusions : Despite some adverse effects occurred, Molsidomine could be used as anti anginal drug safely, and had relatively good effects. So we concluded that molsidomine can be used in patients of ischemic heart disease except hypotensive patients.

Background/Aims : Godex is a mixture of PMC(diphenyl-dimethyl-dicarboxylate) and Hepadif, each of which has been used for managing chronic liver disease in Korea and other countries. The purpose of this study was to evaluate the efficacy and safety of Godex in Korean patients with chronic liver disease. Methods : In this study, 154 patients with chronic hepatitis, who showed increased level of serum alanine aminotransferase(ALT), were randomly allocated into three groups. Fifty-two patients were administered 100mg/day of PMC, 48 patients were administered low dose of Godex(PMC 100mg+hepadif 600mg/day) and 53 patients were administered high dose of Godex(PMC 150mg+hepadif 900mg/day) orally for 8 weeks. To evaluate the efficacy and safety of Godex capsule, we considered primary variable as the proportion of patients who showed normal ALT blood level after treatment for 8 weeks and second variable as a proportion of patient who showed normal ALT at 4 weeks, the degree of difference of serum ALT level between 0 and 8 weeks, and incidence of adverse events during treatment period. Results : The percentage of subjects whose serum ALT levels decreased below upper normal level in control, low-dose and high-dose group were 64.54%, 67.35%, 81.13% after 8 weeks-treatment(p=0.0407) and 59.62%, 63.27%, 81.13% after 4 weeks-treatment of Godex(p=0.0790) using ITT analysis. There were no significant difference in incidence of adverse events among three groups. Conclusions : Response rate of high-dose group was significantly higher than those of low-dose group and control group. It is suggested that Godex 6 capsules per day(PMC 150mg+hepadif 900mg/day) is optimal dose for Korean patients with chronic liver disease who show elevated serum alanine aminotransferase(ALT) level.

Background : We evaluated the physician's response on clinical pharmacokinetic consultation including dose readjustment predicted from therapeutic drug monitoring(TDM). This study was also designed to examine factors influencing on the acceptance of clinical pharmacokinetic consultation. Methods : Medical records of two hundred in-patients(119 male and 81 female) were carefully reviewed for the acceptance of dose readjustment consultation of TDM unit in Pusan Paik Hospital. The acceptance was defined as a compliance on the dose readjustment recommended by TDM unit. Data were analysed for the relative factors with acceptance rate on clinical pharmacokinetic consultation using Chi-square test. Results : Among the 474 consultations for 200 patients, the overall acceptance rate was estimated to 74.5%. Factors influencing the acceptance were as follows : changes of dose regimen, the observed drug level in relation to therapeutic range, the age of charge doctor. Follow up TDM was requested in 58.8% of consultations and that rate was significantly higher in the cases of toxic and subtherapeutic level than normal level. In the follow up TDM, only 39.2% of drug level were found to be within normal range when the recommended dose regimen was not accepted by prescribers. However, 79.9% were within normal range in following TDM when prescriber accepted dose regimen recommended by TDM unit. Conclusions : The acceptance of clinical pharmacokinetic consultation seems to be effective to find optimum dose regimen of reaching to target concentration. The education of TDM for physician in charge and the relationship between clinical pharmacokinetists and prescribing doctors contribute to improve the response rate for TDM consultation.

Background : naive pooled data(NPD) or two-stage method, the two traditional population approaches in pharmacokinetic/pharmacodynamic(PK/PD) analysis, have much limitation in their application. Nonlinear mixed-effect modeling approach has many advantages over the traditional approaches. It provides a solution for analysis of nonexperimetntal or observational data, such as those from clinical situations, which have characteristics of sparseness, unbalancedness, and fragmentariness and so on. In addition, it can be also adopted as a method for estimation of PK/PD parameters in clinical trial of less stringent and restrictive design condition and by doing so we can design clinical trial more flexibly, which will be helpful especially if PK/PD are to be investigated in patients. We analyzed a dose-titration trial for barnidipine, an antihypertensive agent, with nonlinear mixed effect modeling and naive pooled data method and based on the actual trial we simulated dose-titration trials of various conditions with Monte-Carlo method and analyzed with both nonlinear mixed effect modeling and naive pooled data method and compared the results. Methods : A dose-titration trial 'Blood-pressure lowering effect of barnidipine HCI in renal parenchymal hypertension' which was performed in three general hospitals of Seoul, was analyzed with nonlinear mixed effect modeling and naive pooled data method And based on the actual trial, we simulated dose-titration trials of various conditions for barnidipine with Trial Simulator $2.1l^{\circledR}(Pharsight)$ which uses Monte-Carlo method in simulation. We designed and simulated a total of 6 trials adopting linear model and Emax model with conditions of drop-outs of study subjects or high BSV/BOV. The simulated outcomes were analyzed with nonlinear mixed effect modeling and naive pooled data method respectively using $NONMEM^{\circledR}$. We used $NONMEM^{\circledR}$, a computer software for the analyses. Results : When we analyzed the actual dose-titration trial, linear model was superior with regard to model building criteria and serum creatinine level was found to be the sole covariate. When we analyzed the simulated data, 18 out of 21(85.7%) population parameters (6 out of 9 in linear model, 12 out of 12 in Emax model) estimated with nonlinear mixed effect modeling or naive pooled data method were statistically different from each other. And 16 of them (88.9%) showed values closer to the true values(those introduced for simulation), which suggested the superiority of nonlinear mixed effect modeling to naive pooled data method in the analysis of parameters. But, when we tested with ANOVA$({\alpha}=0.05)$, parameter sets from base designs, those with drop-outs and those with high variability grouped by nonlinear mixed effect modeling and naive pooled data method combinated with linear and Emax model, only 3 out of 7(43 %) population parameters(1 out of 3 in linear model and 2 out of 4 in Emax model) showed no difference in parameters. Conclusion : In the simulation of dose-response of barnidipine with the parameter estimates from actual clinical data, the results showed a propensity of the lower responses at higher dosages with parameter estimates from naive pooled data method than with those from nonlinear mixed effect modeling in both linear and Emax model. And these are due to the dose-titration design in itself, in which at higher dosage, only poor responders will remain to be administered the higher dosage. Thus, naive pooled data method is not appropriate for the analysis, but nonlinear mixed effect modeling, which reflects the individual differences in analysis, is required for accurate parameter estimation in this kind of trials. When estimated parameters from simulated data, we can confirm that parameters can be estimated more accurately with nonlinear mixed effect modeling than with naive pooled data method in various conditions.

Background : Low solubility and poor oral absorption have been major problems of DDB(Dimethyl Dime-thoxy Biphenylate), the liver protection agent. The purpose of the study was to evaluate safety, tolerablilty, and pharmacokinetics of DDB-S(Dimethoxybiphenylmonocarboxylate hydro-chloride) which was the newly developed soluble injectable form of DDB. Method : Single dose trial was conducted in 24 healthy Korean subjects with single blind, randomized, placebo controlled parallel-group design( 4 groups : 7.5, 15, 30, 60mg). DDB-S was administrated by intravenous infusion during 60 minutes. Serial blood and urine sample were collected till 24 hours after the drug administration. Plasma concentrations were assayed by HPLC. Pharmacokinetic parameters were analyzed by noncompartmental methods. Results : Total 13 cases of adverse events from 7 subjects were reported. All the events were mild, temporary, and spontaneously resolved. There were no differences in dose normalized AUC, dose normalized Cmax, CL, Vd, Tmax, Fe, $CL_R$ and elimination rate constant between groups. Linear regression analysis confirmed PK linearity within this dose range. Half of the dose$(49.86{\pm}10.97%)$ was excreted as an unchanged form through kidney. Conclusion : DDB-S was safe in Korean healthy subjects. It showed linear pharmacokinetic characteristics. Phase II clinical study for patients will be conducted.

Background and Purpose : $Clopidogrel(Plavix^{\circledR})$, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate(ADP). There has been no comparative study between clopidogrel and aspirin on its antiplatelet aggregatory effect and side effects in Korea. The aim of our study was to evaluate the efficacy and the side effect of clopidogrel in patients with acute ischemic stroke. Methods : Clopidogrel(75mg once daily) and aspirin(300mg once daily) were administered for 4 weeks in 4.0 patients, who suffered from acute ischemic stroke. Their efficacy was evaluated by platelet aggregation test and the recurrence of ischemic event at before and after the medication schedule. The efficacy and the incidence of clinical and laboratory side effects were compared in 4 weeks after the administration of the drugs. Results : Platelet aggregation induced by ADP, collagen and epinephrine was significantly inhibited in both clopidogrel and aspirin groups. There was no significant difference of platelet aggregation effect between two groups and there was no recurrence of ischemic event. The side effects induced by clopidogrel were dyspepsia(4.5%), gastric discomfort(4.5%) and abnormal LFT(9.0%), and the incidence of side effects was lower in clopidogrel group(18%) than aspirin group(26%). Conclusion : The anti-platelet effect of clopidogrel was comparable to that of aspirin, and the adverse effect of clopidogrel was lower than that of aspirin. Thus clopidogrel is as effective as aspirin and safe drug for acute ischemic stroke. Considering long term medication is essential for the treatment of arteriothrombotic diseases, we would say that clopidogrel is effective as well as safe.

Background : The bioavailability of a generic preparation of aceclofenac(Acer from Kyungdong Pharmaceutical Company) was evaluated in comparison with a proprietary product(Airtal from Daewoong Pharmaceutical Company). Methods : Sixteen healthy male volunteers participated in the study conducted according to a two-way crossover, open-labeled Latin square design. The bioavailability was compared using the parameters total area under the plasma concentration-time curve$(AUC_{0-{\infty}})$, peak plasma concentration$(C_{max})$ and time to reach peak plasma concentration$(T_{max})$. Results : No statiscally significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic-transformed $AUC_{0-{\infty}}\;and\;C_{max}$ values of Acer over those of Airtal was found to lie between 0.94-1.03 and 0.94-1.06, respectively, being within the acceptable bioequivalence limit of 0.80-1.25. Conclusion : These findings indicate that the two preparations are comparable in the extent and rate of absorption.

Background : Carbamazepine is a commonly used anticonvulsant agent, particularly in the management of partial seizures. Because of the low incidence of adverse effects associated with this drug, these are often ignored or forgotten. We present a patient in whom transient neutropenia and Stevens-Johnson syndrome has developed after short-term therapy with carbamazepine.