• 사상체질의학회지
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• 제24권4호
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• pp.84-91
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• 2012

Objectives : The purpose of this study is to investigate the inhibitory or inductive potentials of Yuldahanso-tang (YDT) and Chungsimyonja-tang (CST), herbal formulas for Taeeumin, on cytochrome P450 (CYP450) drug metabolizing enzyme. The mechanisms for the herbal formula-drug interaction has not been well reported in spite of the chance for co-administration with conventional drugs. Methods : To evaluate the interaction potential of YDT-drug or CST-drug, the fluorescence-based enzyme assays on CYP450 isozymes including CYP3A4, CYP2C19, CYP2D6 and CYP2E1 were established in vitro. The inhibitory effects of herbal formulas were characterized with $IC_{50}$ values. Results : YDT showed inhibitory effects on CYP2D6 and CYP2E1-mediated metabolism, while it exhibited week inhibition on CYP3A4 and CYP2C19 relatively. CST exerted relatively weak inhibitory effects on the four CYP450 isozymes compared to that of YDT. Conclusions : These results suggest that the herbal formula-drug interaction could be occur when YDT are co-administered with drugs mediated by CYP2D6 or CYP2E1.

• Molecules and Cells
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• 제39권3호
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• pp.229-241
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• 2016

We have previously reported the role of miR-326-HDAC3 loop in anti-cancer drug-resistance. CAGE, a cancer/testis antigen, regulates the response to anti-cancer drug-resistance by forming a negative feedback loop with miR-200b. Studies investigating the relationship between CAGE and HDAC3 revealed that HDAC3 negatively regulated the expression of CAGE. ChIP assays demonstrated the binding of HDAC3 to the promoter sequences of CAGE. However, CAGE did not affect the expression of HDAC3. We also found that EGFR signaling regulated the expressions of HDAC3 and CAGE. Anti-cancer drug-resistant cancer cell lines show an increased expression of $pEGFR^{Y845}$. HDAC3 was found to negatively regulate the expression of $pEGFR^{Y845}$. CAGE showed an interaction and co-localization with EGFR. It was seen that miR-326, a negative regulator of HDAC3, regulated the expression of CAGE, $pEGFR^{Y845}$, and the interaction between CAGE and EGFR. miR-326 inhibitor induced the binding of HDAC3 to the promoter sequences in anti-cancer drug-resistant $Malme3M^R$ cells, decreasing the tumorigenic potential of $Malme3M^R$ cells in a manner associated with its effect on the expression of HDAC3, CAGE and $pEGFR^{Y845}$. The down-regulation of HDAC3 enhanced the tumorigenic, angiogenic and invasion potential of the anti-cancer drug-sensitive Malme3M cells in CAGE-dependent manner. Studies revealed that $PKC{\delta}$ was responsible for the increased expression of $pEGFR^{Y845}$ and CAGE in $Malme3M^R$ cells. CAGE showed an interaction with $PKC{\delta}$ in $Malme3M^R$ cells. Our results show that HDAC3-CAGE axis can be employed as a target for overcoming resistance to EGFR inhibitors.

• BMB Reports
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• 제50권11호
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• pp.535-536
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• 2017

A novel approach has been used to identify functional interactions relevant to human disease. Using high-throughput human-yeast genetic interaction screens, a first draft of disease interactome was obtained. This was achieved by first searching for candidate human disease genes that confer toxicity in yeast, and second, identifying modulators of toxicity. This study found potentially disease-relevant interactions by analyzing the network of functional interactions and focusing on genes implicated in amyotrophic lateral sclerosis (ALS), for example. In the subsequent proof-of-concept study focused on ALS, similar functional relationships between a specific kinase and ALS-associated genes were observed in mammalian cells and zebrafish, supporting findings in human-yeast genetic interaction screens. Results of combined analyses highlighted MAP2K5 kinase as a potential therapeutic target in ALS.

• Translational and Clinical Pharmacology
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• 제26권3호
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• pp.115-117
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• 2018

This tutorial explains the basic principles of mechanistic ligand-receptor interaction model, which is an operational model of agonism. A growing number of agonist drugs, especially immune oncology drugs, is currently being developed. In this tutorial, time-dependent ordinary differential equation for simple $E_{max}$ operational model of agonism was derived step by step. The differential equation could be applied in a pharmacodynamic modeling software, such as NONMEM, for use in non-steady state experiments, in which experimental data are generated while the interaction between ligand and receptor changes over time. Making the most of the non-steady state experimental data would simplify the experimental processes, and furthermore allow us to identify more detailed kinetics of a potential drug. The operational model of agonism could be useful to predict the optimal dose for agonistic drugs from in vitro and in vivo animal pharmacology experiments at the very early phase of drug development.

• 약학회지
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• 제47권6호
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• pp.382-389
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• 2003

This study has collected prescriptions of individual chronic outpatients in an army hospital, analysed them, and investigated the possible drug interactions. It also reviewed the mechanism of drug interactions. Out of total of 42 outpatients with chronic diseases, the percentages of populations having hypertension, hypertension with diabetes, uncomplicated diabetes, hyperlipidemia, hypertension with cardiac insufficiency, and ventricular septal defect were 62%, 19%, 10%, 5%, 2%, and 2%, in the corresponding order. The average number medications prescribed for the outpatients were 2.5 with the highest frequency of five medications in two patients. The number of drug-drug interactions detected was 456 prescriptions out of total of 1104 prescriptions during the study period, accounting for 41.3%. The most frequent drug-drug interaction was between beta-blockers and calcium channel blockers with 132 prescriptions followed by one between beta-blockers and cimetidine with 89 prescriptions. Based on the high incidence of possibly dangerous drug interactions, much attention needs to be aid to the drug-drug interactions in the pharmacotherapy for the treatment of outpatients with chronic diseases in army hospital setting.

• 한국임상약학회지
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• 제19권1호
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• pp.1-17
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• 2009

Adverse drug reactions (ADR) caused by inappropriate prescription are responsible for major socioeconomic loss. Drug-drug interactions (DDI) has been recognized as a major part of ADRs and, therefore, healthcare professionals should prevent possible DDIs to minimize preventable ADRs. This study aimed to examine DDI information in drug information references and Korea Food & Drug Administration (KFDA) drug labeling information. Drug ingredients from the formulary of Health Insurance Review and Assessment Service in Korea (HIRA) were included for the study. DDI information source used for the study were Micromedex Drugdex and Drug Information Facts (DIF) with the DDI severity level of "moderate" or more. The DDI information in KFDA drug labeling were collected and compared. Drug ingredients were classified with KFDA Drug Classification and ATC Classification of WHO for the analysis. Among the total 1,355 drug ingredients satisfying inclusion criteria, 738 ingredients involved at least one DDI, which was described in Micromedex and/or DIF. Drug Ingredients of 176 involved DDI only described in KFDA drug labeling, but not Micromedex nor DIF. Drug ingredients of 35 which DDIs were described in Micromedex or DIF did not have DDI based on KFDA drug labeling. Micromedex and DIF retrieved 7,582 and 3,071 DDIs, respectively 57.6% and 58.5% of DDIs were also described in KFDA drug labeling. Central nervous system (CNS) drugs, cardiovascular system (CVS) drugs and the antiinfectives appeared to have higher frequency of DDIs among all drug classes. The highest number of DDIs with high severity level ("contraindicated" or "major") were the DDIs of CNS drugs. The antiinfectives are the second drug group having serious DDIs. The DDI pairs of the CNS drug and the antiinfective had the highest contraindication risk (13.6%). DDI information from Micromedex and DIF were not consistent with the result that only 465 ingredients' DDIs are common in both literature (total DDI numbers were 715 vs 488, respectively). And 1,652 DDI information are common in both references among 7,582 vs 3,071 DDIs, respectively. Only 55.2% of DDI information in the database contained in the KFDA drug labeling. Prescribers and pharmacists should pay attention to the drugs for CV system, CNS and infections because of higher risk of possible DDIs compared to other drug classes. KFDA drug labeling is not likely to be recommended as a good information source for DDI due to significant inconsistency of information. Drug information providers should be aware that DDI information from different sources are not consistent and therefore multiple references should be used.

• Biomolecules & Therapeutics
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• 제26권5호
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• pp.458-463
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• 2018

The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.

• 대한본초학회지
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• 제33권6호
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• pp.9-18
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• 2018

Objective : Many patients take antihypertensive drugs as well as herbal medicines at the same time in order to treat other symptoms or to keep their well-being. In this study, interactions between herbal medicines and synthetic antihypertensive drugs were analyzed. Methods : To investigate the interaction between herbal medicines and synthetic antihypertensive drugs, three electronic databases, including OASIS, Mediline and Sciencedirect were searched. Experimental and clinical studies on the interaction between herbal medicines and antihypertensive drugs were independently reviewed and included. Results : Analyzing selected studies, twenty herbs were found to interact with antihypertensive drugs. Herbs found to increase the antihypertensive effect were Panax ginseng, Carthamus tinctorius, Magnolia officinalis, Silybum marianum, Scutellaria baicalensis, Schisandra chinensis, Sophora flavescens, Piper nigrum, Curcuma longa, Ginkgo biloba, Juncus effuses and Hydrastis canadensis. In contrast, Commiphora myrrha, Rhodiola rosea, Hypericum perforatum, Eurycoma longifolia, and Daturae metel were found to inhibit the antihypertensive effect. Stephania tetrandra could increase or decrease the effect depending on the type of antihypertensive drug. Epedria sínica was suspected of pharmacodynamic interaction with antihypertensive drug. Glycyrrhiza uralensis has been reported to have serious side effects in combination with antihypertensive drugs. Conclusion : These results imply that when used in combination with herbal medicines and synthetic antihypertensive drugs, proper doses and herbs which are to avoid need to be informed to the patients. Despite concerns about interactions between herbal medicines and synthetic drugs, related research is very limited. More systematic researches are needed to give information on patient safety as well as to guide clinical practice.

• Archives of Pharmacal Research
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• 제25권4호
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• pp.397-415
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• 2002

This paper deals with a crucial mechanism for interaction of basic drugs and cardiac glycosides at the hepatic uptake level. Available literature data is provided and new material is presented to picture the differential transport inhibition of bulky (type2) cationic drugs by a number of cardiac glycosides in rat liver. It is shown that the so called organic anion transporting peptide 2 (oatp2) is the likely interaction site: differential inhibition patterns as observed in oocytes expressing oatp2, could be clearly identified also in isolated rat hepatocytes, isolated perfused rat liver and the rat in vivo. The anticipation of transport interactions at the hepatic clearance level should be based on data on the relative affinities of interacting substrates for the transport systems involved along with knowledge on the pharmacokinetics of these agents as well as the chosen dose regimen in the studied species. This review highlights the importance of multispecific tranporter systems such as OATP, accommodating a broad spectrum of organic compounds of various charge, implying potential transport interactions that can affect body distribution and organ clearance.

• Biotechnology and Bioprocess Engineering:BBE
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• 제6권5호
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• pp.326-331
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• 2001

With the aim of developing of pH-sensitive controlled drug release system, a poly(Llysine) (PLL) based cationic semi-interpenetrating polymer network (semi-IPN) has been synthesized. This cationic hydrogel was designed to swell at lower pH and de-swell at higher pH and therefore be applicable for achieving regulated drug release at a specific pH range. In addition to the pH sensitivity, this hydrogel was anticipated to interact with an ionic drug, providing another means to regulate the release rate of ionic drugs. This semi-IPN hydrogel was prepared using a free-radical polymerization method and by crosslinking of the polyethylene glycol (PEG)-methacrylate polymer through the PLL network. The two polymers were penetrated with each other via interpolymer complexation to yield the semi-IPN structures. The PLL hydrogel thus prepared showed dynamic swelling/de-swelling behavior in response to pH change, and such a behavior was influenced by both the concentrations of PLL and PEG-methacrylate. Drug release from this semi-IPN hydrogel was also investigated using a model protein drug, streptokinase. Streptokinase release was found to be dependent on its ionic interaction with the PLL backbones as well as on the swelling of the semi-IPN hydrogel. These results suggest that a PLL semi-IPN hydrogel could potentially be used as a drug delivery platform to modulate drug release by pH-sensitivity and ionic interaction.