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Yongin, South Korea

Jung H.J.,Dankook University | Han S.D.,Dong A ST Research Institute | Kang M.J.,Dankook University
Bulletin of the Korean Chemical Society | Year: 2015

Solid dispersion (SD) systems have been widely used to increase the dissolution rate and oral absorption of poorly water-soluble compounds. In order to enhance the dissolution rate of dronedarone hydrochloride (DRN), a recent antiarrhythmic agent, SDs of DRN were formulated using conventional solvent evaporation method with amorphous polymers including hydroxypropyl methyl cellulose (HPMC), poly(vinyl pyrrolidone) (PVP), and vinylpyrrolidone-vinyl acetate copolymer (VA64). The prepared SDs were characterized in terms of drug crystallinity, morphology, and in vitro dissolution profile in aqueous medium. The physical characterization using differential scanning calorimetry and X-ray powder diffraction revealed that the active compound was molecularly dispersed in all polymeric carriers tested, in a stable amorphous form in drug to polymer ratios ranging from 1:0.5 to 1:2. The dissolution rates of DRN in all SDs were much higher than those from the corresponding physical mixture and drug powder alone. In particular, the greatest dissolution enhancement was obtained from the VA64-based SD in a drug to polymer weight ratio of 1:1, achieving almost complete drug release after 120 min at pH 1.2. Thus, VA64-based SD with higher drug dissolution rate along with a simple preparation process is suggested as an alternative for the oral formulation of the benzofuran derivative. © 2015 Korean Chemical Society & Wiley-VCH Verlag GmbH & Co. KGaA.

Kim M.-K.,Ewha Womans University | Kim M.-K.,Dong A ST Research Institute | Cho J.-H.,Ewha Womans University | Lee J.-J.,Ewha Womans University | And 2 more authors.
PLoS ONE | Year: 2015

Beta cell death caused by endoplasmic reticulum (ER) stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide. © 2015 Kim et al.

Kwon Y.S.,Dong A ST Research Institute | Son M.,Dong A ST Research Institute
Biomolecules and Therapeutics | Year: 2013

Motilitone® (DA-9701) is a new herbal drug that was launched for the treatment of functional dyspepsia in December 2011 in Korea. The heterogeneous symptom pattern and multiple causes of functional dyspepsia have resulted in multiple drug target strategies for its treatment. DA-9701, a compound consisting of a combination of Corydalis Tuber and Pharbitidis Semen, has being developed for treatment of functional dyspepsia. It has multiple mechanisms of action such as fundus relaxation, visceral analgesia, and prokinetic effects. Furthermore, it was found to signifi cantly enhance meal-induced gastric accommodation and increase gastric compliance in dogs. DA-9701 also showed an analgesic effect in rats with colorectal distension induced visceral hypersensitivity and an antinociceptive effect in beagle dogs with gastric distension-induced nociception. The pharmacological effects of DA-9701 also include conventional effects, such as enhanced gastric emptying and gastrointestinal transit. The safety profi le of DA-9701 is also preferable to that of other treatments. © 2013 The Korean Society of Applied Pharmacology.

Yang S.-J.,Catholic University of Korea | Han S.-H.,Catholic University of Korea | Lee A.-R.,Catholic University of Korea | Jun J.-H.,Dong A ST Research Institute | And 4 more authors.
BMB Reports | Year: 2015

Streptococcus mutans is frequently associated with dental caries. Bacterial fermentation of food debris generates an acidic environment on the tooth surface, ultimately resulting in tooth deterioration. Therefore, various mouthwashes have been used to reduce and prevent Streptococcus mutans. The aim of this study was to evaluate the antimicrobial activities of 4 commercial mouthwashes and those of 10% and 20% ethanol solutions (formula A, B, C, D, E and F) against Streptococcus mutans using biofilm and planktonic methods. The range of reduction in the viable cell count of Streptococcus mutans as estimated by the biofilm and planktonic methods was 0.05-5.51 log (P ≤ 0.01) and 1.23-7.51 log (P ≤ 0.001) compared with the negative control, respectively, indicating that the planktonic method had a stronger antibacterial effect against S. mutans. Among the tested formulations, formula A (Garglin regular® mouthwash) was the most effective against Streptococcus mutans (P = 0.001). © 2015 by the The Korean Society for Biochemistry and Molecular Biology.

Lee M.J.,Dong A ST Research Institute | Lee M.J.,Sungkyunkwan University | Cho K.H.,Dong A ST Research Institute | Park H.M.,Dong A ST Research Institute | And 3 more authors.
European Journal of Pharmacology | Year: 2014

DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2 mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2 mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10 mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation. © 2014 Elsevier B.V.

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