• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.77.1-77.1
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• 2003

Prolongation of the QT interval may result in a potentially dangerous arrhythmia. The most commonly proposed mechanism for QT interval prolongation(LQT) by pharmaceuticals is inhibition of the rapid delayed rectifier potassium channel (I$\sub$Kr). The LQT potency of pharmaceuticals can be effectively evaluated by examining the effect on human ether-a go-go-related gene (hERG) channels expressed in CHO cells, known to be equal to I$\sub$kr/. We have transfected JERG into CHO cell lines transiently to express high levels of functional hERG channels. (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.90.3-91
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• 2003

The most commonly proposed mechanism for QT interval prolongation(LQT) by pharmaceuticals is inhibition of the rapid delayed rectifier potassium channel (I$\_$Kr/). The LQT potency of pharmaceuticals can be effectively evaluated by examining the effect on hERG channels expressed in CHO cells, known to be equal to I$\_$Kr/. But, It was known that hERG channels according to increase the bath temperature have several changes, including a marked increase in the amplitude of the outward and tail currents, and acceleration of the rates of activation, recovery from inactivation, and deactivation. (omitted)

• The Korean Journal of Physiology and Pharmacology
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• 제17권1호
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• pp.37-42
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• 2013

Taxifolin glycoside is a new drug candidate for the treatment of atopic dermatitis (AD). Many drugs cause side effects such as long QT syndrome by blocking the human ether-a-go-go related gene (hERG) $K^+$ channels. To determine whether taxifolin glycoside would block hERG $K^+$ channels, we recorded hERG $K^+$ currents using a whole-cell patch clamp technique. We found that taxifolin glycoside directly blocked hERG $K^+$ current in a concentration-dependent manner ($EC_{50}=9.6{\pm}0.7{\mu}M$). The activation curve of hERG $K^+$ channels was negatively shifted by taxifolin glycoside. In addition, taxifolin glycoside accelerated the activation time constant and reduced the onset of the inactivation time constant. These results suggest that taxifolin glycoside blocks hERG $K^+$ channels that function by facilitating activation and inactivation process.

• 대한화학회지
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• 제53권6호
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• pp.653-662
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• 2009

흡수, 분포, 대사, 배설 특성 및 독성을 예측하기 위한 효과적인 툴을 개발하는 것은 신약개발의 초기단계에서 NCE(new chemical entity)에 대한 가장 중요한 업무 중의 하나이다. 최근에 이런 시도중의 하나로서 ADME/T(absorption, distribution, metabolism, excretion, toxicity)관련 성질들의 예측에 support vector machine(SVM)을 이용하고 있다. 그리고 SVM은 ADME/T 성질들을 정확하게 예측하는데 많이 사용 되고 있다. 그러나 SVM 모델링에 두 가지 문제가 있다. 특성 선택(feature selection) 과 매개변수 설정(parameter setting)은 여전히 해결해야 할 과제이다. 이 두 가지 문제들은 SVM 분류의 효율성과 정확도에 결정적인 영향을 끼친다. 특히 특성 선택과 최적화된 SVM 변수의 설정은 서로 영향을 주기 때문에 동시에 다루어져야 한다. 여기서 우리는 genetic algorithm(GA) – 특성 선택에 사용 – 과 grid search(GS) method– 변수최적화에 사용 – 두 가지를 통합하는 효과적인 해결책을 제시하였다. ADME/T관련 성질 중 하나인 심장부정맥을 야기시키는 hERG 이온채널 저해제 분류 모델이 여기서 제안된 GA-GS-SVM을 위해 할당되고 테스트 되었다. 1891개의 화합물을 가지는 트레이닝 셋으로 단일 모델 3개, 앙상블 모델 3개, 총 6개의 모델을 만들었고 175개의 외부 데이터를 테스트 셋으로 사용하여 검증하였다. 데이터의 불균형 문제를 해결하기 위하여 GA-GS-SVM 단일 모델에 의한 예측 정확도와 GA-GS-SVM 앙상블 모델 예측 정확도를 비교하였으며, 앙상블모델을 사용하여 예측의 정확도를 높일 수 있었다.

• Reproductive and Developmental Biology
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• 제34권3호
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• pp.153-159
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• 2010

The 34 potently pig pheromonal odorants (1-32, 5755 & 7113) through structure-based virtual screening and ligand-based virtual screening method were selected and their ADMET and pharmacokinetics characters were evaluated and discussed quantitatively. The pheromonal odorants were projected on the following pre-calculated models, Caco-2 cell permeability, blood-brain barrier permeation, hERG inhibition and volume-distribution. From the results of in silico study, it is found that an optimal compound (31) either penetrating or have a little ($P_{caco2}$=-8.143) for Caco-2 cell permeability, moderate penetrating ability ($P_{BBB}$=0.082) for blood-brain barrier permeation, the low QT prolongation ($P_{hERG}$=1.137) for the hERG $K^+$ channel inhibition, and low distribution into tissues ($P_{VD}$=-5.468) for volume-distribution. Therefore, it is predicted that the compound (31) a topical application may be preferable from these based foundings.

• Toxicological Research
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• 제20권2호
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• pp.159-166
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• 2004

Safety pharmacological properties of CJ-11555, an anti-cirrhotic agent, were investigated in experimental animals and in vitro test system. CJ-11555 had no effects on normal body temperature in rats, motor coordination, chemoshock induced by pentetrazol, electric shock induced by electric shocker and writhing syndromes in mice at dose levels of 100, 300 and 1,000 mg/kg. CJ-11555 inhibited intestinal activity and prolonged hexobarbital-induced sleeping time in mice at the dose level of 1,000 mg/kg. CJ-11555 affected on general activity and behaviour tests in SD rats, such as lacrimation, ptosis, piloerection, decreased body tone, abnormal dispersion within the cage, diarrhoea, red colored faeces, slight hypothermia and decreased grooming, at the dose level of 1,000 mg/kg in rats. CJ-11555 was effected on cardiovascular and respiratory system in anesthetized beagle dogs, such as tachycardia, increase of mean blood pressure and decrease of PR interval, decrease of respiratory rate and minute volume, at dose levels of 10 and 30 mg/kg. However, these effects were also observed in vehicle treated anesthetized beagle dogs. In in vitro experiments, CJ-11555 inhibited agonists (histamine, acetyl-choline or $BaCl_2$) induced contraction of isolated guinea-pig at the concentration of 30$\times$$10^6$ M. CJ-11555 was weekly inhibited hERG channel current at concentrations of 10 and 30$\times$$10^6$ M, and $IC_{50}$ was estimated to be higher than 30${\times}$$10^6$M. Based on these results, it was concluded that CJ-11555 affected on cardiovascular and respiratory system, general activity and behaviour and hexobarbital-induced sleeping time at the dose level of 1,000 mg/kg and contraction of the smooth muscle and hERG channel current at the concentration of 30$\times$$10^6$ M.

• The Korean Journal of Physiology and Pharmacology
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• 제16권5호
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• pp.327-332
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• 2012

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In these experiments, we have used the whole cell patch clamp technique to examine the effects of sertraline on the major cardiac ion channels expressed in HEK293 cells and the native voltage-gated $Ca^{2+}$ channels in rat ventricular myocytes. According to the results, sertraline is a potent blocker of cardiac $K^+$ channels, such as hERG, $I_{Ks}$ and $I_{K1}$. The rank order of inhibitory potency was hERG > $I_{K1}$ > $I_{Ks}$ with $IC_{50}$ values of 0.7, 10.5, and 15.2 ${\mu}M$, respectively. In addition to $K^+$ channels, sertraline also inhibited $I_{Na}$ and $I_{Ca}$, and the $IC_{50}$ values are 6.1 and 2.6 ${\mu}M$, respectively. Modification of these ion channels by sertraline could induce changes of the cardiac action potential duration and QT interval, and might result in cardiac arrhythmia.

• Translational and Clinical Pharmacology
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• 제26권4호
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• pp.145-149
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• 2018

Cases of drug-induced QT prolongation and sudden cardiac deaths resulted in market withdrawal of many drugs and world-wide regulatory changes through accepting the ICH guidelines E14 and S7B. However, because the guidelines were not comprehensive enough to cover the electrophysiological changes by drug-induced cardiac ion channel blocking, CiPA was initiated by experts in governments and academia in the USA, Europe, and Japan in 2013. Five years have passed since the launch of the CiPA initiative that aimed to improve the current ICH guidelines. This report reviews the current achievements of the CiPA initiative and explores unresolved issues.

• Biomolecules & Therapeutics
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• 제23권4호
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• pp.386-389
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• 2015

Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an $IC_{50}$ of $3.92{\mu}M$ in patch clamp assay and increased the heart rate and blood pressure ($76{\Delta}bpm$ in heart rate and $51{\Delta}mmHg$ in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at $10{\mu}M$ and $30{\mu}M$, resulted in 15% and 29% decreases in $APD_{50}$, and 9% and 17% decreases in $APD_{90}$, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.

• Molecules and Cells
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• 제37권9호
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• pp.656-663
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• 2014

Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits $[Ca^{2+}]_i$ transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier $K^+$ ($I_{Ks}$) channel is a cardiac $K^+$ channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating $I_{Ks}$ channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human $I_{Ks}$ channel activity by expressing human $I_{Ks}$ channels in Xenopus oocytes. We found that gintonin enhances $I_{Ks}$ channel currents in concentration- and voltage-dependent manners. The $EC_{50}$ for the $I_{Ks}$ channel was $0.05{\pm}0.01{\mu}g/ml$. Gintonin-mediated activation 1 of the $I_{Ks}$ channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an $IP_3$ receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the $I_{Ks}$ channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 $[Ca^{2+}]_i$/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on $I_{Ks}$ channel. However, gintonin had no effect on hERG $K^+$ channel activity. These results show that gintonin-mediated enhancement of $I_{Ks}$ channel currents is achieved through binding of the $[Ca^{2+}]_i$/CaM complex to the C terminus of KCNQ1 subunit.