Asthma is defined by a chronic airway inflammatory disease, characterized by wide variation over short periods of time in resistance to flow in the airways of the lung. It is well known that IL -13 is a central mediator of allergic asthma and lung specific IL-13 transgenic (TG) (+) mice demonstrated airway inflammation characterized by macrophage and eosinophil infiltrations and airway remodeling, such as subepithelial fibrosis. Lung specific IFN-g TG (+) mice have been well known to have enhanced airway inflammation characterized by macrophage, lymphocyte, and neutrophil infiltrations. Interestingly, these TG mice have markedly enhanced airways hyperresponsiveness (AHR) on methacholine challenge. Moreover, IFN-g mRNA expression was markedly enhanced in induced sputum from severe asthmatics when compared with mild ones, suggesting that IFN-g is an important mediator on the progression to severe asthma. Taken together, these findings suggest that IFN-g which is secreted from Th1 cells as well as IL-13 are important mediators for the immunopathogenesis of asthma. From this hypothesis this review describes the importance of innate immunity for the development of asthma.

Background : CKD-602 (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin), a new derivative of camptothecin, is a topoisomerase I inhibitor that has shown antitumor activity in many tumors. Because the major dose-limiting toxicity of CKD-602 has been known to be the myelosuppression, particularly neutropenia and thrombocytopenia, a PD model describing the entire time course of myelosuppression rather than a single nadir count is valuable. Methods : CKD-602 at doses ranging from $0.5\;to\;0.9\;mg/m^2/d$ were infused for 30 minutes on 5 consecutive days every 3 weeks to patients with advanced solid malignancies. PK analysis was performed using 26 blood samples per patient on days 1 and 5 in 12 patients of a phase I study, and 2 blood samples per patient in 6 patients of a phase IT study. Complete blood counts for myelosuppression model were conducted once a week or more until recovery in 18 patients of phase I/II studies. Model building was done by evaluating the goodness-of-fit criteria considering the change in MOFV (minimum objective function value). A modified posterior predictive check technique was used to validate the final PK/PD model. Results : The PK of CKD-602 was best described using a 3 compartments model. The derived PK parameters were used in the AUC-dependent PD model which had 4 compartments corresponding to two mitotic compartments of bone marrow (BM), one maturation-storage compartment of BM, and one peripheral blood compartment The baseline value of neutrophilis was used as the covariate of the rate constant in the mitotic compartment The AUCs required for a 50% reduction of the neutrophils and platelets were 5.05 ng*hr/mL and $l.64{\times}10^{-1}\;ng*hr/mL$, respectively. Conclusion : This mechanistic model successfully described the systemic exposure of CKD-602 to the entire time course of myelosuppression using both dense sampling data and sparse sampling data. This population pharmacokineticpharmacodynamic modeling of CKD-602 can be useful in predicting a safe dosage regimen or evaluation of new drugs.

Objectives : The aims of this study were to investigate the effect of three herbal medicines {Ephedra sinica(ma-huang), Scutellaria baicalensis(baical skullcap), Aconitum carmichaeli (aconite)} on cytochrome P450(CYP) activities. A cocktail approach was used to determine whether multiple administration of herbal medicines affects CYP1A2, CYP 2C19, CYP2E1 and CYP3A4 activities. Methods : The study was done as an open-label, randomized, positive-controlled, parallel group study. Twenty four healthy male subjects were randomly allocated to receive ma-huang, baical skullcap, aconite or St. John's wort for 12 days, respectively. They were prepared in extract formulations. Probe drugs for CYP1A2, CYP2C19, CYP2E1, and CYP3A4 were caffeine, omeprazole, chlorzoxazone and midazolam. All of them except chlorzoxazone were administrated by the validated forms of cocktail approach. The activities of CYP enzymes were analyzed by measuring probe drug and metabolite concentration in the blood; paraxanthine/caffeine plasma ratio(6 hour after administrated) for CYP1A2, 5-OH-omeprazole/omeprazole plasma ratio(2 hour) for CYP2C19, 6-OH-chlorzoxazone/chlorzoxazone plasma ratio(2 hour) for CYP2E1, and l-OH-midazolam/midazolam plasma ration(1, 2, 6 hour, respectively) for CYP3A4. The analytic procedure was done by HPLC assays. Results : Comparisons of pre- and post-medication phenotyping results showed that aconite significantly inhibited CYP2E1 activity by $48{\pm}4%(P=0.0312)$. Baical skullcap showed the trends of inhibiting CYP1A2 activity(P=0.2188). CYP2Cl9 enzyme activity was induced by $140{\pm}130%$ in St. John's wort medication group(P=0.0769). Also in St. John's wort group, CYP3A4 enzyme activity was induced by $450{\pm}750%$ after 2 hour-administration of midazolam(P=0.00625), however, the last three results were not significant in a statistical analysis. Conclusions : The CYP2E1 inhibition of Amnitum carmidueli could have hepatoprotective functions from xenobiotics.

Background : Recently marketed Cyclooxygenase 2(COX-2) selective inhibitors promoted as safer nonsteroidal anti-inflammatory drugs(NSAIDs) regarding gastric toxicity. Korea National Health Insurance Review Agency(HIRA) revised claims review criteria of COX -2 selective inhibitors in June 2001 and October 2001. This study was performed to assess the prescribing pattern of COX-2 selective inhibitors across the change in claims review criteria. Methods : This study was a retrospective drug utilization review study from August 1, 2000 through March 31, 2002. Data on drug prescriptions were obtained from the Health Insurance Claims Database which included the whole outpatient clinics prescription data in Busan metropolitan city, Korea. Demographic information such as age, sex and prescription information including brand name, prescription date, daily dose, duration and diagnosis were collected. COX -2 selective inhibitor prescriptions were screened and analyzed by the age, sex, and type of hospitals using SAS Windows ver. 8.1. Results : Total COX -2 selective inhibitor prescription frequency was 115,473 during this period. Among total prescriptions 69.2% was prescribed at primary ambulatory units and 79.1% was used for female patients. The prescription frequency of COX-2 selective inhibitor was significantly decreased from June 2001 to October 2001 (p<0.001). Conclusion : COX -2 selective inhibitors prescription frequency shows sharp decline by change of claims review criteria. This result implies administrative policy such as claims review criteria can substantially influence drug prescription patterns, specially which has its alternatives.

Background : Multi-drug resistance 1 (MDR1) gene encoded P-glycoprotein(Pgp) contributes to the disposition of many substrate drugs. Recently, many reports have been described for the single nucleotide polymorphisms (SNPs) of MDR1 gene and their functional significances in vitro and in vivo. This study is to evaluate the effect of MDR1 C3435T/G2677T genetic polymorphism on the pharmacokinetics (PK) and pharmacodynamics (PD) of fexofenadine, a known Pgp substrate, in Korean healthy subjects. Methods : Fifteen male subjects whose MDRl C3435T/G2677T genotype was determined using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) method were enrolled (8 subjects with CC for 3435 and GG for 2677 ; 7 subjects with TT for 3435 and TT for 2677). After single oral dose of 120 mg fexofenadine, blood samples were serially drawn upto 24 hours. Histamine induced wheal and flare reaction test was also conducted for 3 hours after dosing to measure pharmacodynamic effect of fexofenadine. Concentrations of fexofenadine were analyzed with HPLC using fluorescence detector. Kinetic parameters were calculated by fitting the data to noncompartmental PK models using WinNonlin program. Results : The plasma concentrations of fexofenadine were higher, especially in absorptive phase, in subjects with 3435T/2677T haplotype than those in subjects with 3435C/2677G wild haplotype. Although there was no significant difference of pharmacokinetic parameters between genotype groups, area under the plasma concentration from 0 to $6(AUCe_{6hr})$ showed significant differences between genotype groups (p<0.05). The time course of wheal and flare suppression showed no statistical difference between genotype groups, but subjects with 3435T/2677T haplotype showed higher antihistamine effect that those with 3435C/2677G wild haplotype. Conclusions : These results suggest that MDR1 C3435T/G2677T genetic polymorphism seem likely to be associated with fexofenadine disposition, implying that SNPs at 2677 and 3435 may have an effect on Pgp expression or activity in the intestinal epithelium.

목 적 : UDB캅셀은 DDB(Biphenyl dimethyl Dicarboxylate) 12.5mg와 UCDA(Ursodeoxycholic acid) 50.0 mg의 복합제제이다. 2상연구에서 나타난 최적의 용법 및 용량에 따라 UDB와 대조약(DDB)을 만성 간질환 환자에 투여하면서 8주 무작위배정, 활성약물 대조, 이중맹검, 평행군에 의한 제3상 임상시험을 통해 UDB의 유효성 및 안전성을 알아 보고자 하였다. 대상 및 방법 : 간조직 검사 또는 임상적 소견에 의하여 진단이 확정된 만성 간염 환자 중 자의적으로 본 임상연구에 참가함을 서면으로 동의한122명을 피험자로 하였고 무작위로 두군으로 나누어 각각 UDB와 DDB를 8주간 투여하였다. 총 10주간의 엄상시험에서 시험약의 유효성 검정을 위해 일차 평가변수로 UDB 투여 전(baseline)과 투여4주, 투여8주 및 추적 기간(10주)에 UDB군과 DDB군간 ALT수치의 차이를 비교하였다. 이차 평가변수로 UDB 투여 전, 투여4주 투여8주 및 추적기간(10주)에 ALT 수치의 정상화율을 DDB를 투여한 군과 비교하였다. 또한 임상시험 결과가 각 피험자들의 간염 원인 인자(HBV, HCV, 만성간염, 및 HBV+HCV)에 의해 영향을 받는지를 비교하였다. 결과 : 투여 8주째에 UDB군과 DDB군의 ALT level은 각각 $24.5{\pm}18.5$ IL/U와 $32.3{\pm}22.2$ IU/L(p=0.038)였다. 투여기간 동안 나타난 정상 화율은 4주, 8주에서 UDB군과 DDB군에서 각각 86.9% vs 73.8%(p=0.068), 85.2% vs 72.1% (p=0.068)이었고, 투여종료 후 추적 기간인 10주에서는 각각 19.6% vs 16.4% (p=0.319)였다. 만성 간염의 원인인자가ALT수치의 하강에 미치는 영향은 없었다. 임상시험기간중 전례에서 약물의 부작용은 관찰되지 않았다. 결론 : ALT수치가 지속적으로 상승되어 있는 만성 간질환 환자에서 UDB의 투여시 혈청 ALT수치를 감소시키는 효과가 통계적으로 유의하였으며 혈청 ALT 정상화율도 대조군에 비해 우월한 경향을 나타내었고 약물의 투여 중지 후에도 대조군에 비해 낮은 ALT수치를 유지하였다. 또한 임상시험 기간 동안 약물과 관련된 부작용(ADR)이 발생하지 않았다. 따라서 UDB는 본 임상연구 기준에서 포함하는 모든 병력의 만성 간질환에서 ALT 수치가 지속적으로 상승해 있는 경우 효과적이고도 안전하게 투여할 수 있는 제제로 생각된다.