• Korean Journal of Clinical Pharmacy
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• v.18 no.2
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• pp.84-96
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• 2008

In the recent, pharmacokinetic (PK)/pharmacodynamic (PD) modeling has appeared as a critical path tools in new drug development to optimize drug efficacy and safety. PK/PD modeling is the mathematical approaches of the relationships between PK and PD. This approach in new drug development can be estimated inaccessible PK and PD parameters, evaluated competing hypothesis, and predicted the response under new conditions. Additionally, PK/PD modeling provides the information about systemic conditions for understanding the pharmacology and biology. These advantages of PK/PD model development are to provide the early decision-making information in new drug development process, and to improve the prediction power for the success of clinical trials. The purpose of this review article is to summarize the PK/PD modeling process, and to provide the theoretical and practical information about widely used PK/PD models. This review also provides model schemes and the differential equations for the development of PK/PD model.

• The Korean Journal of Pain
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• v.26 no.4
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• pp.336-346
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• 2013

Intrathecal drug delivery is an effective and safe option for the treatment of chronic pathology refractory to conventional pain therapies. Typical intrathecal administered drugs are opioids, baclofen, local anesthetics and adjuvant medications. Although knowledge about mechanisms of action of intrathecal drugs are every day more clear many doubt remain respect the correct location of intrathecal catheter in order to achieve the best therapeutic result. We analyze the factors that can affect drug distribution within the cerebrospinal fluid. Three categories of variables were identified: drug features, cerebrospinal fluid (CSF) dynamics and patients features. First category includes physicochemical properties and pharmacological features of intrathecal administered drugs with special attention to drug lipophilicity. In the second category, the variables in CSF flow, are considered that can modify the drug distribution within the CSF with special attention to the new theories of liquoral circulation. Last category try to explain inter-individual difference in baclofen response with difference that are specific for each patients such as the anatomical area to treat, patient posture or reaction to inflammatory stimulus. We conclude that a comprehensive evaluation of the patients, including imaging techniques to study the anatomy and physiology of intrathecal environment and CSF dynamics, could become essential in the future to the purpose of optimize the clinical outcome of intrathecal therapy.

• BMB Reports
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• v.57 no.2
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• pp.71-78
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• 2024

Melanoma is one of the most aggressive skin tumors, and conventional treatment modalities are not effective in treating advanced melanoma. Although immunotherapy is an effective treatment for melanoma, it has disadvantages, such as a poor response rate and serious systemic immune-related toxic side effects. The main solution to this problem is the use of biological materials such as hydrogels to reduce these side effects and amplify the immune killing effect against tumor cells. Hydrogels have great advantages as local slow-release drug carriers, including the ability to deliver antitumor drugs directly to the tumor site, enhance the local drug concentration in tumor tissue, reduce systemic drug distribution and exhibit good degradability. Despite these advantages, there has been limited research on the application of hydrogels in melanoma treatment. Therefore, this article provides a comprehensive review of the potential application of hydrogels in melanoma immunotherapy. Hydrogels can serve as carriers for sustained drug delivery, enabling the targeted and localized delivery of drugs with minimal systemic side effects. This approach has the potential to improve the efficacy of immunotherapy for melanoma. Thus, the use of hydrogels as drug delivery vehicles for melanoma immunotherapy has great potential and warrants further exploration.

• Journal of Pharmaceutical Investigation
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• v.23 no.3
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• pp.165-177
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• 1993

The relationship between the plasma haloperidol (HP) concentration and clinical response, and the effects of its active metabolite, reduced haloperidol (RH) on clinical response of HP were investigated in schizophrenic patients. In clinical study I, with 17 schizophrenic patients (male 8, fermale 9) who were administered with three different fixed doses of HP (15, 30 and 50 mg/day) for 3 weeks, the concentrations of HP and RH in plasma and blood and clinical response had been checked before and every week during the study. The clinical response was evaluated by the method of brief psychiatric rating scale (BPRS), and relative improvement of clinical response based on baseline BPRS (before drug treatment) was calculated. The concentrations of HP and RH in plasma and blood were assayed by HPLC. In clinical study II, the plasma RH/HP concentration ratios were checked in 11 patients who were administered with high doses of HP, over 60 mg a day, because of the poor clinical response at usual doses of HP. Plasma HP concentration and relative improvement of BPRS at 3 week in schizophrenic patients showed a 'curvilinear' relationship, and the clinical response was improved relatively over 50% based on the baseline BPRS in the range of $5{\sim}57\;ng/ml $ of HP in plasma. Also, the plasma RH concentrations were increased nonlinearly as the plasma HP concentration increased, and in high plasma HP concentration, over 30 ng/mI, clinical response gradually decreased, while the plasma RH/HP concentration ratio increased nonlinearly. Blood partition coefficients of HP and RH were not changed according to daily HP dose and duration of drug therapy. From these results, it is noted that the higher plasma RH/HP concentration ratio, resulted from the accumulation of RH as HP concentration increased, might explain the 'curvilinear' decrease of HP clinical response.

• Molecular & Cellular Toxicology
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• v.2 no.4
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• pp.236-243
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• 2006

Microarray analysis of gene expression has become a powerful approach for exploring the biological effects of drugs, particularly at the stage of toxicology and safety assessment. Acetaminophen (APAP) has been known to induce necrosis in liver, but the molecular mechanism involved has not been fully understood. In this study, we investigated gene expression changes of APAP using microarray technology. APAP was orally administered with a single dose of 50 mg/kg or 500 mg/kg into ICR mice and the animals were sacrificed at 6, 24 and 72 h of APAP administration. Serum biochemical markers for liver toxicity were measured to estimate the maximal toxic time and hepatic gene expression was assessed using high-density oligonucleotide microarrays capable of determining the expression profile of >30,000 well-substantiated mouse genes. Significant alterations in gene expression were noted in the liver of APAP-administered mice. The most notable changes in APAP-administered mice were the expression of genes involved in apoptosis, cell cycle, and calcium signaling pathway, cystein metabolism, glutatione metabolism, and MAPK pathway. The majority of the genes upregulated included insulin-like growth factor binding protein 1, heme oxygenase 1, metallothionein 1, S100 calcium binding protein, caspase 4, and P21. The upregulation of apoptosis and cell cycle-related genes were paralleled to response to APAP. Most of the affected gene expressions were returned to control levels after 72 hr. In conclusion, we identified potential hepatotoxicity makers, and these expressions profiling lead to a better understanding of the molecular basis of APAP-induced hapatotoxicity.

• Molecular & Cellular Toxicology
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• v.3 no.2
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• pp.98-106
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• 2007

Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. In this study, we investigated to examine gene expression profiles and genotoxic response in TK6 cells treated with DNA damaging agents MNNG (N-methyl-N'-nitrosoguanidine) and hydrogen peroxide $(H_2O_2)$. We extracted total RNA in three independent experiments and hybridized cRNA probes with oligo DNA chip (Applied Biosystems Human Genome Survey Microarray). We analyzed raw signal data with R program and AVADIS software and identified a number of deregulated genes with more than 1.5 log-scale fold change and statistical significancy. We indentified 14 genes including G protein alpha 12 showing deregulation by MNNG. The deregulated genes by MNNG represent the biological pathway regarding MAP kinase signaling pathway. Hydrogen peroxide altered 188 genes including sulfiredoxins. These results show that MNNG and $H_2O_2$ have both uniquely regulated genes that provide the potential to serve as biomarkers of exposure to DNA damaging agents.

• Biomolecules & Therapeutics
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• v.25 no.5
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• pp.482-489
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• 2017

Individual differences in drug responses are associated with genetic and epigenetic variability of pharmacogene expression. We aimed to identify the relevant miRNAs which regulate pharmacogenes associated with drug responses. The miRNA and mRNA expression profiles derived from data for normal and solid tumor tissues in The Cancer Genome Atlas (TCGA) Research Network. Predicted miRNAs targeted to pharmacogenes were identified using publicly available databases. A total of 95 pharmacogenes were selected from cholangiocarcinoma and colon adenocarcinoma, as well as kidney renal clear cell, liver hepatocellular, and lung squamous cell carcinomas. Through the integration analyses of miRNA and mRNA, 35 miRNAs were found to negatively correlate with mRNA expression levels of 16 pharmacogenes in normal bile duct, liver, colon, and lung tissues (p<0.05). Additionally, 36 miRNAs were related to differential expression of 32 pharmacogene mRNAs in those normal and tumorigenic tissues (p<0.05). These results indicate that changes in expression levels of miRNAs targeted to pharmacogenes in normal and tumor tissues may play a role in determining individual variations in drug response.

• Molecules and Cells
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• v.24 no.2
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• pp.247-254
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• 2007

Improvement in the pharmacokinetic properties of short interfering RNAs (siRNAs) is a prerequisite for the therapeutic application of RNA interference technology. When injected into mice as unmodified siRNAs complexed to DOTAP/Chol-based cationic liposomes, all 12 tested siRNA duplexes caused a strong induction of cytokines including interferon ${\alpha}$, indicating that the immune activation by siRNA duplexes is independent of sequence context. When modified by various combinations of 2'-OMe, 2'-F, and phosphorothioate substitutions, introduction of as little as three 2'-OMe substitutions into the sense strand was sufficient to suppress immune activation by siRNA duplexes, whereas the same modifications were much less efficient at inhibiting the immune response of single stranded siRNAs. It is unlikely that Toll-like receptor 3 (TLR3) signaling is involved in immune stimulation by siRNA/liposome complexes since potent immune activation by ds siRNAs was induced in TLR3 knockout mice. Together, our results indicate that chemical modification of siRNA provides an effective means to avoid unwanted immune activation by therapeutic siRNAs. This improvement in the in vivo properties of siRNAs should greatly facilitate successful development of siRNA therapeutics.

• Journal of Microbiology and Biotechnology
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• v.17 no.10
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• pp.1738-1741
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• 2007

The first vaccine against human papillomaviruses (HPV) formulated with HPV16 L1 virus-like particles (VLPs) produced in yeast was approved by the FDA in June 2006. Nevertheless, there have been few studies of the immunogenicity in mice of VLPs. In this study, we evaluated the cell-mediated immune response to VLPs produced in Saccharomyces cerevisiae. After immunization of mice with HPV16 L1 VLPs, we measured splenocytes proliferation and the levels of IFN$_{\gamma}$, IL2, IL4, and IL5. Splenocytes proliferation was significantly increased and a mixed Th1/Th2 response was indicated. IgG subtype immunoresponses were strongly induced and IgG1 titers were higher than those of IgG2a.

• Genomics & Informatics
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• v.16 no.3
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• pp.52-58
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• 2018

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.