• Korean Journal of Clinical Pharmacy
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• v.16 no.2
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• pp.155-164
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• 2006

Great inter-variability in drug response and adverse drug reactions is related to inter-variability of drug bioavailability, drug interaction and patient's disease and physyological state that cause change in absorption, distribution, metabolism and excretion of drugs. However, these alone do not sufficiently predict and explain inter-variability in drug response. In recent studies, it is reported that inter-variability in drug response and adverse drug reactions may largely resulted from genetically determined differences in drug absoption, distribution, metabolism and drug target proteins. Especially, the major human drug-metabolizing enzymes such as CYP450, N-acetyl tranferase, thiopurine S-methyl transferase, glutathione S-transferase are identified as the major gene variants that cause inter-individual variability in drug's response and adverse drug reactions. These variations may have most significant implications for those drugs that have narrow therapeutic index and serious adverse drug reactions. Therefore, the genetic variation such as polymorphisms in drug metabolizing enzymes can affect the response of individuals to drugs that are used in the treatment of depression, psychosis, cancer, cardiovascular disorders, ulcer and gastrointestinal disorders, pain and epilepsy, among others. This review describes the pharmacogenomics of the drug metabolizing enzymes associated with the drug response and its clinical applications.

• Interdisciplinary Bio Central
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• v.5 no.2
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• pp.3.1-3.7
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• 2013

Recently, the productivity of drug discovery has gradually decreased as the limitations of single-target-based drugs for various and complex diseases become exposed. To overcome these limitations, drug combinations have been proposed, and great efforts have been made to predict efficacious drug combinations by statistical methods using drug databases. However, previous methods which did not take into account biological networks are insufficient for elaborate predictions. Also, increased evidences to support the fact that drug effects are closely related to metabolic enzymes suggested the possibility for a new approach to the study drug combinations. Therefore, in this paper we suggest a novel approach for analyzing drug combinations using a metabolic network in a systematic manner. The influence of a drug on the metabolic network is described using the distance between the drug target and an enzyme. Target-enzyme distances are converted into influence scores, and from these scores we calculated the correlations between drugs. The result shows that the influence score derived from the targetenzyme distance reflects the mechanism of drug action onto the metabolic network properly. In an analysis of the correlation score distribution, efficacious drug combinations tended to have low correlation scores, and this tendency corresponded to the known properties of the drug combinations. These facts suggest that our approach is useful for prediction drug combinations with an advanced understanding of drug mechanisms.

• Biomolecules & Therapeutics
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• v.14 no.1
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• pp.1-10
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• 2006

Drug dependence deals a heavy socioeconomic burden to the society. For adolescents, the damage from drug dependence is greater than adults considering their higher susceptibility to drug effect and increasing chance for violence leading to criminal punishment process. Habitual drug use depends on genetic and environmental factors and the complex interactions between the two. Mammalian model systems have been useful in understanding the neurochemical and cellular impacts of abused drugs on specific regions of the brain, and in identifying the molecular targets of drugs. More elucidation is required whether biological effects of drugs actually cause the habitual dependence at the cellular level. Although there is much insight available on the nature of drug abuse problems, none of the systems designed to help drug dependent individuals is efficient in screening functional ingredients of the drug, and thus resulting in the failure of helping drug dependent individuals recover from drug dependence. Alternative model systems draw the attention of researchers, such as the invertebrate model systems of nematodes (Caenorhabditis elegans) and fruit flies (Drosophila melanogaster). These models should provide new insight into the mechanisms leading to the behavior of drug users (even functional studies analyzing molecular mechanism), and screening useful components to help remove drug dependence among drug users. The relatively simple anatomy and gene expression of the invertebrate model systems should enable researchers to coordinate current knowledge on drug abuse. Furthermore, the invertebrate model systems should facilitate advance in experiments on the susceptibility of specific genetic backgrounds and the interaction between genetic factors to drug dependence.

• Korean Journal of Clinical Pharmacy
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• v.21 no.2
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• pp.90-99
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• 2011

Health Insurance Review & Assessment Service (HIRA) claims database has a high potential to detect signals of new drug interactions. The aim of this study was to evaluate the usefulness of information component (IC) and relative risk (RR) as a tool for signal detection, and to analyze the possible drug interactions caused by clopidogrel using HIRA claims database. This study was performed in elderly patients over 65 years of age who administered clopidogrel from January 2005 to June 2006 in South Korea. Serious Adverse Events (SAEs) as drug interactions of clopidogrel were defined as any ambulatory hospitalization for ischemic diseases within comcomitant medication period of clopidogrel. Information Component (IC) and Relative Risk (RR) were calculated to compare the proportion of drug-SAE pairs in order to select drug specific SAEs. IC and RR signals of clopidogrel drug interaction were screened when IC's 95% confidence interval was greater than 0 and RR's 95% confidence interval was greater than 1 respectively. All detected signals were compared to references such as $Micromedex^{(R)}$ and 2010 Drug Interaction $Facts^{TM}$. Sensitivity, specificity, positive predicted value and negative predicted value were used to evaluate usefulness of this method. Among 13,252,930 cases of elderly patients who co-administered clopidogrel and other drugs, 47,485 cases were detected as SAE. Of these, one-hundred nine cases were detected by the IC-based data-mining approach and ninety one cases were detected by the RR-based data-mining approach. Total One-hundred sixty three unrecognized signals were detected by IC or RR. Twelve signals from IC-based data-mining (57.1%) were corresponded with drug interactions from references and eight signals from RR-based data-mining (38.1%) were corresponded with drug interactions from references. These signals include proton pump inhibitors, calcium channel blockers and HMG CoA reductase Inhibitors, which were known to affect CYP450 metabolism. Further studies using HIRA claims database are necessary to develop appropriate data-mining measure.

• BMB Reports
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• v.49 no.11
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• pp.585-586
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• 2016

Extracellular vesicles (EVs) are natural carriers of biomolecules that play central roles in cell-to-cell communications. Based on this, there have been various attempts to use EVs as therapeutic drug carriers. From chemical reagents to nucleic acids, various macromolecules were successfully loaded into EVs; however, loading of proteins with high molecular weight has been huddled with several problems. Purification of recombinant proteins is expensive and time consuming, and easily results in modification of proteins due to physical or chemical forces. Also, the loading efficiency of conventional methods is too low for most proteins. We have recently proposed a new method, the so-called exosomes for protein loading via optically reversible protein-protein interaction (EXPLORs), to overcome the limitations. Since EXPLORs are produced by actively loading of intracellular proteins into EVs using blue light without protein purification steps, we demonstrated that the EXPLOR technique significantly improves the loading and delivery efficiency of therapeutic proteins. In further in vitro and in vivo experiments, we demonstrate the potential of EXPLOR technology as a novel platform for biopharmaceuticals, by successful delivery of several functional proteins such as Cre recombinase, into the target cells.

• YAKHAK HOEJI
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• v.59 no.1
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• pp.29-39
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• 2015

In recent years, physiologically based pharmacokinetic (PBPK) modeling has been widely used in pharmaceutical industries as well as regulatory health authorities for drug discovery and development. Several application areas of PBPK have been introduced so far including drug-drug interaction prediction, transporter-mediated interaction prediction, and pediatric PK prediction. The purpose of this review is to introduce PBPK and illustrates one of its application areas, particularly pediatric PK prediction by utilizing existing adult PK data and in vitro data. The evaluation of the initial PBPK for adult was done by comparing with experimental PK profiles and the scaling from adult to pediatric was conducted using age-related changes in size such as tissue compartments, and protein binding etc. Sotalol and lorazepam were selected in this review as model drugs for this purpose and were re-evaluated using the PBPK models by GastroPlus$^{(R)}$. The challenges and strategies of PBPK models using adult PK data as well as appropriate in vitro assay data for extrapolating pediatric PK at various ages were also discussed in this paper.

• Journal of Pharmaceutical Investigation
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• v.36 no.4
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• pp.263-269
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• 2006

Deficiencies in the early ADMET(absorption, distribution, metabolism, elimination and toxicity) information on drug candidate extract a significant economic penalty on pharmaceutical firms. Microscale cell culture analogue-microscale gastrointestinal(${\mu}CCA-{\mu}GI$) device using Caco 2, L2 and HEp G2/C3A cells, which mimic metabolic process after absorption occurring in humans was used to investigate the toxicity of the model chemical, acetaminophen(AAP). The toxicity of acetaminophen determined after induction of CYP 1A1/2 in Caco 2 cells was not significant. In a coculture system, although no significant reduction in viability of HEp G2/C3A and L2 cells was found, approximately 5 fold increase in the CYP 1A1/2 activity was observed. These results appear to be related to organ-organ interaction. The oral administration of a drug requires addition of the absorption process through small intestine to the current ${\mu}CCA$ device. Therefore, a perfusion coculture system was employed for the evaluation of the absolution across the small intestine and resulting toxicity in the liver and lung. This system give comprehensive and physiologic information on oral uptake and resulting toxicity as in the body. The current ${\mu}CCA$ device can be used to demonstrate the toxic effect due to organ to organ interaction after oral administration,

• Natural Product Sciences
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• v.29 no.2
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• pp.104-112
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• 2023

COVID-19 caused a catastrophe in human health. People infected with COVID-19 also suffer from various clinical illnesses during and after the infection. The Boerhavia diffusa plant is well known for its antihypertensive activity. ACE-II inhibitors and calcium channel blockers are reported as mechanisms for the antihypertensive activity of B. diffusa phytoconstituents. Various studies have said ACE-II is the virus's binding site to attack host cells. COVID-19 treatment commonly employs a variety of synthetic antiviral and steroidal drugs. As a result, other clinical illnesses, such as hypertension and hyperglycemia, emerge as serious complications. Safe and effective drug delivery is a prime objective of the drug development process. COVID-19 is treated with various herbal treatments; however, they are not widely used due to their low potency. Many herbal plants and formulations are used to treat COVID-19 infection, in which B. diffusa is the most widely used plant. The current study relies on discovering active phytoconstituents with ACE-II inhibitory activity in the B. diffusa plant. As a result, it can be used as a treatment option for patients with COVID-19 and related diseases. Different phytoconstituents of the B. diffusa plant were selected from the reported literature. The activity of phytoconstituents against ACE-II proteins has been studied. Molecular docking and ligand-protein interaction computation tools are used in the in-silico experiment. Physicochemical, drug-likeness, water solubility, lipophilicity, and pharmacokinetic parameters are used to evaluate phytoconstituents. Liriodenine has the best drug-likeness, bioactivity, and binding score characteristics among the selected ligands. The in-silico study aims to find the therapeutic potential of B. diffusa phytoconstituents against ACE-II. Targeting ACE-II also shows an effect against SARS-CoV-2. It can serve as a rationale for designing a drug for patient infected with COVID-19 and associated diseases.

• Journal of Pharmaceutical Investigation
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• v.27 no.1
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• pp.71-77
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• 1997

With the aim of improving periodontal regeneration efficacy, as a biodegradable local drug delivery device, drug releasing chitosan beads were prepared. Chitosan beads were prepared through the formation of intermolecular or intramolecular ionic interaction bewteen chitosan and sodium tripolyphosphate and were loaded with flurbiprofen. The mean diameter of the beads was $250\;{\mu}m$. Drug loading efficiency was improved by regulating the pH of tripolyphosphate solution. The drug release kinetics mainly depended upon the hydrophobic properties of the flurbiprofen, that is, the release of flurbiprofen showed initial burst with rapid release for the first day followed by a levelling off of the release rate. However, the release rate could be controlled by the formulation factor including the pH, concentration of the tripolyphosphate solution, gelation time, drug contents. From these results, flurbiprofen loaded chitosan beads were anticipated as biodegradable local drug delivery devices for periodontal regeneneration.

• Journal of Pharmaceutical Investigation
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• v.40 no.1
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• pp.33-38
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• 2010

Sibutramine is a serotonin-norepinephrine reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The oral administration of sibutramine is followed by its dose-related side effects. In this study, sibutramine was formulated into drug in adhesive (DIA) patches in an attempt to overcome these problems. The effects of different formulation variables including pressure-sensitive adhesive (PSA), loading amount of drug, thickness of matrix and enhancer on the skin permeation of the drug were evaluated using excised hairless mouse skin. In the acrylic adhesive with carboxyl functional group, low release of sibutramine was observed due to the strong interaction between carboxyl group of adhesive and amine group of sibutramine. The acrylic adhesive without functional group provided good adhesion force and allowed high drug loading. Changing drug load as well as thickness of the matrix was found to alter permeation rate. $Crovol^{(R)}$ PK40 and $Crovol^{(R)}$ A40, were found to be effective enhancers for sibutramine. The optimized patch contained 20% sibutramine, and 5% $Crovol^{(R)}$ A40 as permeation enhancer, in $80\;{\mu}m$ thick Duro-$Tak^{(R)}$ 87-9301 matrix.