• YAKHAK HOEJI
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• v.41 no.3
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• pp.305-311
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• 1997

Sustained release-microspheres and immediate release-pellets were prepared to develop a controlled release multiparticulate system containing both water soluble and insoluble dr ug. Pseudoephedrin.HCl (EPD) and terfenadine (TRF) were used as model drugs, respectively. Sustained release-EPD microspheres were prepared by solvent evaporation method using Eudragit RL or RS as a matrix combined with pH-insensitive film coating. Smaller EPD microspheres were obtained when smaller amount of Eudragit as a matrix material or larger amount of magnesium stearate as a dispersing agent was used. However the obtained microspheres did not show syfficient sustained release characteristics. About 97% of EPD was released after 1 hr irrespective of matrix material used. Subsequent coating of the microspheres with pH-insensitive polymer such as Eudragit RS or ethylcelulose (EC) resulted good sustained in 37.5, 73.3 and 92.0% release of encapsulated EPD in distilled water after 1, 3 abd 7 hr, respectively. It corresponds to mean dissolution time (MDT) of 2.3 hr, which is much larger than that of un-coated EPD microspheres (0.0048 hr). Immediate release TRF pellets were prepared by spherically agglomerated crystallization using Eudragit E as an inert matrix and methylene chloride as a liquid binder. Using Eudragit E alone as a matrix resulted in satisfactory physical properties of the pellets such as sphericity, surface texture and flowability, but led to slower release of TRF from pellets than un-modified TRF powder (MDT of 1.70 vs 1.43 hr in pH 1.2 dissolution medium). Introducing propylene glycol or sodium lauryl sulfate as an emulsifier brought about faster release of TRF from pellets (MDT of 1.14 and 0.95 hr, respectively). In conclusion, microencapsulation by solvent evaporation combined with film coating and spherically agglomerated crystallization were successfully utilized to prepare controlled release multiparticulate system composed of sustained release EPD-microspheres and immediate release TRF pellets.

• YAKHAK HOEJI
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• v.50 no.2
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• pp.129-135
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• 2006

Two Antihistamines, terfenadine and astemizole have been withdrawn from major markets for the reason that these durgs have been reported to induce QT interval prolongation associated with the onset of Torsades do Pointes (TdP), resulting in a life-threatening ventricular arrhythmia. In this study, we investigated effects of diphenhydramine on electrocardiograms and hemodynamic parameters in conscious telemetered dogs. We validated and defined the sensitivity of the test system by monitoring basal parameters and using positive control substance, terfenadine. Single administration effects were tested during 24 hours for each test drug at dose 1 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg. We monitored QT, QTc, heart rate, blood pressure and body temperature after administering test drugs. In conscious telemetered dogs, diphenhydramine significantly prolonged $QT\;(6.8\%\;of\;basal)\;and\;QTc\;(7.8\%\;of\;basal)$ at 100 mg/kg. Other parameters were not affected significantly. These findings suggest that antihistamines could induce important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias. Future studies that include other antihistamines and other classes will be necessary to predict the torsadogenic risk of drugs in humans.

• Journal of Life Science
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• v.23 no.9
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• pp.1126-1132
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• 2013

Cytochrome P450 2J2 (CYP2J2) is an enzyme mainly found in human extrahepatic tissues, with predominant expression in the cardiovascular system. CYP2J2 plays important roles in the metabolism of endogenous metabolites and therapeutic drugs, such as arachidonic acid, astemizole, ebastine, and terfenadine. CYP2J2 is also overexpressed in human cancer tissues and cancer cell lines and may represent a potential target for therapy of human cancers. In this study, 10 natural products obtained from plants and microorganisms were screened as potential CYP2J2 inhibitors. Among them, thelephoric acid showed strong inhibition of astemizole O-demethylation activity ($IC_{50}=3.23{\mu}M$) in a dose-dependent manner. Evaluation of the substrate dependency of the inhibitory activity of thelephoric acid showed that it strongly inhibited CYP2J2-mediated ebastine hydroxylation ($IC_{50}=5.32{\mu}M$) and terfenadine hydroxylation ($IC_{50}=3.27{\mu}M$) in a substrate nondependent manner. The present data suggest that this compound might be a potential candidate for further evaluation for anticancer activity.

• Korean Circulation Journal
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• v.53 no.1
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• pp.34-46
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• 2023

Background and Objectives: Diabetes mellitus (DM)-associated heart failure (HF) causes high morbidity and mortality. In this study, we established a zebrafish larvae model for in vivo research on diabetic HF. Methods: DM-like phenotypes were induced by treating zebrafish larvae with a combination of D-glucose (GLU) and streptozotocin (STZ). HF was induced by treatment with terfenadine (TER), a potassium channel blocker. Additionally, myocardial contractility, motility, and viability were evaluated. Results: The zebrafish larvae treated with a combination of GLU and STZ showed significantly higher whole-body glucose concentrations, lower insulin levels, and higher phosphoenolpyruvate carboxykinase levels, which are markers of abnormal glucose homeostasis, than the group treated with only GLU, with no effect on viability. When treated with TER, DM zebrafish showed significantly less myocardial fractional shortening and more irregular contractions than the non-DM zebrafish. Furthermore, in DM-HF with reduced ejection fraction (rEF) zebrafish, a significant increase in the levels of natriuretic peptide B, a HF biomarker, markedly reduced motility, and reduced survival rates were observed. Conclusions: We established a DM-HFrEF zebrafish model by sequentially treating zebrafish larvae with GLU, STZ, and TER. Our findings indicate the potential utility of the developed zebrafish larvae model not only in screening studies of new drug candidates for DM-HFrEF but also in mechanistic studies to understand the pathophysiology of DM-HFrEF.

• YAKHAK HOEJI
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• v.43 no.5
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• pp.642-651
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• 1999

Nonsedating antihistamines do net cause sedation in therapeutic doses because these drugs hardly cross the blood-brain barrier. Since most of the peripheral side dffects of conventional antihistamines are related to their muscarinic receptor blocking action, the present study was performed to investigate whether nonsedating antihistamines interact with the muscarinic receptors and discriminate the muscarinic receptor subtypes in the rat cerebral microsomal fraction which containes both $M_1,{\;}M_2,{\;}M_3{\;}and{\;}M_4$ receptors. Five nonsedating antihistamines at high concentrations inhibited [$^3H$]QNB binding to the muscarinic receptor in a dose-dependent manner. The inhibition curves of these drugs except loratadine which showed positive cooperativity (nH=1.55) were steep (nH=1), indicating interaction with a single homogenous population of the binding sites. Astemizole, clemizole and mequitazine increased the $K_D$ value for [$^3H$]QNB without affecting the binding site concentrations, and this increase in the $K_D$ value resulted from the ability of these drugs to slow [$^3H$]QNB-receptor association. The Ki values of astemizole, clemizole and mequitazine for the inhibition for the inhibition of [$^3H$]QNB binding to muscarinic receptor were 0.58, 5.99 and $0.007{\;}{\mu}M$, respectively. However, loratadine and terfenadine inhibited noncompetitively [$^3H$]QNB binding with the normalized $IC_50$ value of about $2{\;}{\mu}M$. These results demonstrate that; 1) astemizole, clemizole and mequitazine interact directly with the muscarinic receptor at high concentrations; 2) muscarinic receptor blocking potency of these drugs varies widely among drugs; 3) these drugs do not discriminate between muscarinic receptor subtypes.

• The Korea Journal of Herbology
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• v.29 no.3
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• pp.79-85
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• 2014

Objectives : In this study, we attempted to evaluate the effects of Careswell on human mast cell-mediated allergy inflammation in vitro and pruritogen-induced scratching behavior in vivo. Method : The Careswell was extract by distilled water. The anti-itching effects of Careswell were investigated on the compound 48/80 ($50{\mu}g/kg$) or histamine ($100{\mu}g/kg$) induced scratching behavior male ICR mice for 30 min by an observer blind. Terfenadine (10 mg/kg) was used as a positive control drug. The cell toxicity of Careswell was determined by 3-(4,5-dimethylthiazole-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. The regulatory effect of Careswell on interleukin (IL)-6 and tumor necrosis factor (TNF)-${\alpha}$ levels was determined by enzyme-linked immunosorbent assay (ELISA) in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI) stimulated human mast cells (HMC-1). Also, we evaluated the effect of Careswell on PMACI induced the activation of Nuclear factor-kappa B (NF-${\kappa}B$) into nucleus by Western blot analysis. Result : The results revealed that the oral administration of Careswell (200 mg/kg, p.o.) attenuated the compound 48/80 or histamine-induced scratching behavior in mice. We showed that Careswell significantly reduced the PMACI-induced the production of IL-6 (0.5-1 mg/ml) and TNF-${\alpha}$ (0.1-1 mg/ml). Additionally, Careswell significantly inhibited the activation of NF-${\kappa}B$ in PMACI-stimulated HMC-1. Conclusion : Collectively, the findings of this study provide us with a novel insight into the pharmacological actions of Careswell as a potential molecule for use in the treatment of allergic inflammation diseases.

• Journal of Life Science
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• v.24 no.4
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• pp.447-453
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• 2014

In this study, a test for the immunity control effect by ethanolic extract of Eurya emarginata (EE-70E) on NC/Nga mice as the models for atopic dermatitis was conducted with the following results. Atopic dermatitis in NC/Nga mice was induced by repeated application of 1-chloro-2,4-dinitrobenzene (DNCB) for 5 weeks. Mice were orally administered EE-70E or terfenadine, positive control for 3 weeks. Scratching behavior, clinical skin severity, and the levels of IL-4, L-13, IL-17, total serum IgG1, and total serum IgE were measured. The oral administration with EE-70E doses of 200 or 400 mg/kg significantly decreased scratching behavior scores and clinical skin severity score in a dose-dependent manner (p<0.05). The administration of EE-70E at 400 mg/kg significantly decreased cytokines within the blood serum, that is, IL-4, L-13, and IL-17 compared to the control group (p<0.05). The level of blood histamine was statistically significantly decreased. Administration of EE-70E at 400 mg/kg significantly decreased the levels of total serum IgE (p<0.05). The above results indicated that EE-70E was effective in improving the symptoms of atopic dermatitis through various immunity control mechanisms.