• Archives of Pharmacal Research
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• 제25권5호
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• pp.718-723
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• 2002

CKD-602 (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin) is a recently-developed synthetic camptothecin analogue and currently under clinical development by Chong Kun Dang Pharm (Seoul, Korea). CKD-602 showed potent topoisomerase inhibitory activity in vitro and broad antitumor activity against various human tumor cells in vitro and in vivo in animal models. This study describes the pharmacodynamics of the immediate and delayed cytotoxicity induced by CKD-602 in a human colorectal adenocarcinoma cell line, HT-29, and its intracellular drug accumulation by HPLC. The present study was designed to address whether the higher activity of CKD-602 with prolonged exposure is due to delayed exhibition of cytotoxicity and/or an accumulation of anti proliferative effect on continuous drug exposure. The drug uptake study was performed to determine whether the delayed cytotoxicity is due to a slow drug accumulation in cells. CKD-602 produced a cytotoxicity that was exhibited immediately after treatment (immediate effect) and after treatment had been terminated (delayed effect). Both the immediate and delayed effects of CKD-602 showed a time dependent decrease in 4IC_{50}$ values. Drug uptake was biphasic and the second equilibrium level was obtained as early as at 24hr, indicating that the cumulative and delayed antitumor effects of CKD-602 were not due to slow drug uptake. On the other hand, CKD-602 treatment was sufficient to induce delayed cytotoxicity after 4hr, however, longer treatment (＞24hr) enhanced its cytotoxicity due to the intracellular accumulation of the drug, which requires 24hr to reach maximum equilibrium concentration. In addition, $C^n$$\times$T=h analysis (n=0.481) indicated that increased exposure times may contribute more to the overall antitumor activity of CKD-602 than drug concentration. Additional studies to determine the details of the intracellular uptake kinetics (e.g., concentration dependency and retention studies) are needed in order to identify the optimal treatment schedules for the successful clinical development of CKD-602.

• Journal of Preventive Medicine and Public Health
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• 제22권2호
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• pp.223-235
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• 1989

To grasp the idea about how drugs are used under Medical Insurance Scheme, the amount and share of drug cost in the total medical fee have been reviewed and analyzed for different types of patients (in-patient out-patient), medical institutions and frequently seen diseases and following findings were revealed. In 1986, drug cost took 32.78% of total medical fee for in-patients and 32.98% for out-patients averaged over 30% share as a whole. When drug cost per case in 1980 be indexed to 100, it has shown steady growth to become 200 for in-patients and about 150 for out-patients in 1986. The contribution of drug cost to the total medical fee is, regardless of patient type-in-patients and out-patients, the highest in University hospitals and followed by General hospitals, Hospitals and Clinics in decending order That for the most frequent 10 diseases came out the highest,79 a with the essential benign hypertension of out-patients in the General hospitals, 61% for the gastric ulcer of out-patients in Hospitals and 33% for the female genital diseases of out-patients in Clinics. The drug cost of oral formula was contributed the most, 7.93% by cardiovascular agents followed by hepatic detoxicants(5.47%) and out-patients(4.93%), and that of injectable formula was contributed the most by antibiotics(24.17%), followed by protein amino-acid preparations(6.19%). The order of drug usage by specialty for the in-patients was the highest with internal medicine followed by general surgery and E.N.T, and that for the out-parients was in the order of Internal medicine, neuropsychology and Ob/Gy. This study revealed that the drug dependency was characteristically different to specialty. In view of the fact that drug cost on average exceeds over 30% of total medical fee, proper drug administration appears to be vitally important for the stabilization of the financial standing of the Medical Insurance Scheme. As a consequence, drug usage guidelines including antibiotics usage shall be established first of all and the voluntary participation for the regulation of drug usage and propagation of the guidelines to medical institutions are strongly coerced.

• 대한간호학회지
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• 제36권7호
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• pp.1215-1223
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• 2006

Purpose: This study was done to understand elderly women within a community who have used lots of drugs. Method: Data was collected through in-depth interviews with four elderly women from April 2001 to February 2002. Data was analyzed by Giorgi's phenomenological method(2000). Results: The components in common with drug usage of elderly women were as follows: 'Awareness of the limitation of physical strength and uncertainty of life', 'Dread of a crisis situation occurring', 'Attachment and dependency on drugs', 'Expectation of a comfortable life and death', 'Prevention of family burden', and 'Pursuit of psychological comfort'. The general structure of experiences was as follows: causal factors were 'Awareness of uncertainty and limitation', 'dread of a crisis situation occurring' the results factor was 'Attachment and dependency on drugs' and the facilitating factors were 'Expectation of a comfortable life and death', 'Prevention of family burden', and 'Pursuit of psychological comfort'. The causal relation was cyclic. This structure showed a realistic adaptation pattern. Conclusion: This study contributed to provide fundamental data for nursing interventions for health promotion and promoting quality of life in elderly women by increasing understanding of the experiences of drugs use.

• 한국생물정보학회:학술대회논문집
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• 한국생물정보시스템생물학회 2001년도 제2회 생물정보 워크샵 (DNA Chip Bioinformatics)
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• pp.165-196
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• 2001

DNA chip 또는 microarray는 다수의 유전자 또는 유전자 조각을 (보통 수천내지 수만 개)칩상에 고정시켜 놓고 DNA hybridization 반응을 이용하여 유전자들의 발현 양상을 분석할 수 있는 기술이다. 이러한 high-throughput기술은 예전에는 생각하지 못했던 여러가지 분자생물학의 문제에 대한 해답을 제시해 줄 수 있을 뿐 만 아니라, 분자수준에서의 질병 진단, 신약 개발, 환경 오염 문제의 해결 등 그 응용 가능성이 무한하다. 이 기술의 실용적인 적용을 위해서는 DNA chip을 제작하기 위한 하드웨어/웻웨어 기술 외에도 이러한 데이터로부터 최대한 유용하고 새로운 지식을 창출하기 위한 bioinformatics 기술이 핵심이라고 할 수 있다. 유전자 발현 패턴을 데이터마이닝하는 문제는 크게 clustering, classification, dependency analysis로 구분할 수 있으며 이러한 기술은 통계학과인공지능 기계학습에 기반을 두고 있다. 주로 사용된 기법으로는 principal component analysis, hierarchical clustering, k-means, self-organizing maps, decision trees, multilayer perceptron neural networks, association rules 등이다. 본 세미나에서는 이러한 기본적인 기계학습 기술 외에 최근에 연구되고 있는 새로운 학습 기술로서 probabilistic graphical model (PGM)을 소개하고 이를 DNA chip 데이터 분석에 응용하는 연구를 살펴본다. PGM은 인공신경망, 그래프 이론, 확률 이론이 결합되어 형성된 기계학습 모델로서 인간 두뇌의 기억과 학습 기작에 기반을 두고 있으며 다른 기계학습 모델과의 큰 차이점 중의 하나는 generative model이라는 것이다. 즉 일단 모델이 만들어지면 이것으로부터 새로운 데이터를 생성할 수 있는 능력이 있어서, 만들어진 모델을 검증하고 이로부터 새로운 사실을 추론해 낼 수 있어 biological data mining 문제에서와 같이 새로운 지식을 발견하는 exploratory analysis에 적합하다. 또한probabilistic graphical model은 기존의 신경망 모델과는 달리 deterministic한의사결정이 아니라 확률에 기반한 soft inference를 하고 학습된 모델로부터 관련된 요인들간의 인과관계(causal relationship) 또는 상호의존관계(dependency)를 분석하기에 적합한 장점이 있다. 군체적인 PGM 모델의 예로서, Bayesian network, nonnegative matrix factorization (NMF), generative topographic mapping (GTM)의 구조와 학습 및 추론알고리즘을소개하고 이를 DNA칩 데이터 분석 평가 대회인 CAMDA-2000과 CAMDA-2001에서 사용된cancer diagnosis 문제와 gene-drug dependency analysis 문제에 적용한 결과를 살펴본다.

• The Korean Journal of Physiology and Pharmacology
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• 제21권2호
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• pp.169-177
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• 2017

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine $(5-HT)_3$ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine ($1{\sim}300{\mu}M$) resulted in a concentration-dependent reduction in peak amplitude of currents induced by $3{\mu}m$ of 5-HT for an $IC_{50}$ value of $28.2{\pm}3.6{\mu}M$ with a Hill coefficient of $1.2{\pm}0.1$. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, $5-HT_3$-mediated currents evoked by 1 mM dopamine, a partial $5-HT_3$ receptor agonist, were inhibited by lamotrigine co-application. The $EC_{50}$ of 5-HT for $5-HT_3$ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate $5-HT_3$ receptor desensitization, inhibited $5-HT_3$ receptor currents in a concentration-dependent manner. The deactivation of $5-HT_3$ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of $5-HT_3$ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the $5-HT_3$ receptor currents. These results indicate that lamotrigine inhibits $5-HT_3$-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

• 한국환경성돌연변이발암원학회지
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• 제26권4호
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• pp.125-132
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• 2006

Previous studies showed that epigallocatechin gallate(EGCG) have substantial effects of suppressing the N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)-initiated cell transformation process on the bases of foci formation frequency and loss of anchorage dependency. In this study we tried to clarify the molecular mechanism of suppressing the cell transformation process. Mouse cell line balb/c 3T3 A31-1-1 was exposed 2 days to MNNG followed by 15 days 12-O-tetradecanoylphorbol-13-acetate(TPA) treatment for our transformation process. EGCG was added after the time point of 24 hours exposure to TPA and incubated for 19 days. 2029 genes were selected in our transformation process that showed fold change value of 1.5 or more in the microarray gene expression analysis covering the mouse full genome. These genes were found to be involved mainly in the cell cycle pathway, focal adhesion, adherens junction, TGE-$\beta$ signaling, apoptosis, lysine degradation, insulin signaling, ECM-receptor interaction. Among the genes, we focused on the 631 genes(FC>0.5) reciprocally affected by EGCG treatment. Our study suggest that EGCG down-regulate the gene expressions of up stream signaling factors such as nemo like kinase with MAPK activity and PI3-Kinase, Ras GTPase and down stream factors such as cyclin D1, D2, H, T2, cdk6.

• Archives of Pharmacal Research
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• 제20권4호
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• pp.379-383
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• 1997

Cyclosporin A, an potent immunosuppressant, has been known to be one of the modulators of drug resistance as well as a cytostatic drug. Despite many attempts to basic or clinical application of cyclosporin A, there are few reports on the inhibition of brain tumor cells. In the present experiment, the possibility of cyclosporin A as synergic adjuvant was investigated by MTT assay, $[^{3}H]$ thymidine uptake and through flowcytometric anaysis. Sole treatment of cyclosporin A on the CRT and CH235-MG glioma cell line revealed dose dependent cytotoxicity within a range of tested dose. Combined treatment of cyclosporin A with ACNU, BCNU and hydroxyurea on various glioma cancer cell line led to a significant synergistic cytotoxicity as well as inhibition of DNA synthesis with dose-dependency. In addition, cyclosporin A alone or combined treatment caused discernible changes of cell cycle in the tested cells. These data provide that cyclosporin A could potentiate the effect of nitrosourea compounds in vitro on human glioma cells.

• Genomics & Informatics
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• 제1권2호
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• pp.65-74
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• 2003

Data mining differs primarily from traditional data analysis on an important dimension, namely the scale of the data. That is the reason why not only statistical but also computer science principles are needed to extract information from large data sets. In this paper we briefly review data mining, its characteristics, typical data mining algorithms, and potential and ongoing applications of data mining at biopharmaceutical industries. The distinguishing characteristics of data mining lie in its understandability, scalability, its problem driven nature, and its analysis of retrospective or observational data in contrast to experimentally designed data. At a high level one can identify three types of problems for which data mining is useful: description, prediction and search. Brief review of data mining algorithms include decision trees and rules, nonlinear classification methods, memory-based methods, model-based clustering, and graphical dependency models. Application areas covered are discovery compound libraries, clinical trial and disease management data, genomics and proteomics, structural databases for candidate drug compounds, and other applications of pharmaceutical relevance.

• The Korean Journal of Physiology and Pharmacology
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• 제3권3호
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• pp.245-250
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• 1999

The effects of an antipsychotic, chlorpromazine, on the electroencephalogram (EEG) were observed while rats were awake but immobile. The time course and the dose-dependency of the EEG changes were examined. The method of the power spectrum analysis was used to examine the EEG changes by the drug. The bands were divided into delta $(1{\sim}3.5\;Hz),$ theta $(3.5{\sim}8\;Hz),$ alpha $(8{\sim}13\;Hz),$ beta1 $(13{\sim}21\;Hz),$ beta2 $(21{\sim}30\;Hz)$ and gamma $(30{\sim}50\;Hz).$ In rats, the low dose of chlropromazine (1 mg/kg, i.p.) produced a significant increase in the power of the beta1 band. The higher doses (5, 10 mg/kg, i.p.) produced a significant increase in the power of the delta, theta, alpha and beta1 bands, and the decrease in the power of the gamma band. The powers of the bands changed dose-dependently. Then, the authors discussed whether the EEG effects produced by a drug are associated with the accompanying behavioral changes specifically.

• 통합자연과학논문집
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• 제6권1호
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• pp.8-11
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• 2013

In this manuscript, we report a protocol to determine most of the lowest energy conformations from the ensemble of conformations. 12-crown-4 was taken as study compound to get the most of energy minima conformations. Molecular dynamic (MD) simulation for 1 nanosecond (ns) was performed at 300, 500, 700, 900 and 1100 K temperature. At particular interval conformations were sampled. Then Gaussian program was used to minimize compounds using PM6 energy levels. Duplicates were removed by checking energy as well as mirror image conformations, and only unique conformations were retained for the next $6-31+G^*$ level minimization. It was observed that upto certain increment in temperature the number of unique conformations were increased, but afterword it decreased.