• Archives of Pharmacal Research
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• 제28권8호
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• pp.970-976
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• 2005

The purpose of this study was to investigate the effect of morin, a flavonoid, on the pharmacokinetics of diltiazem and one of its metabolites, desacetyldiltiazem in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) in rats pretreated with morin (1.5, 7.5, and 15 mg/kg). Compared with the control group (given diltiazem alone), pretreatment of morin significantly increased the absorption rate constant $(K_a)$ and peak concentration $(C_{max})$ of diltiazem (p<0.05, p<0.01). Area under the plasma concentration-time curve (AUC) of diltiazem in rats pretreated with morin were significantly higher than that in the control group (p<0.05, p<0.01), hence the absolute bioavailability $(AB\%)$ of diltiazem was significantly higher than that of the control group (p<0.05, p<0.01). Relative bioavailability $(RB\%)$ of diltiazem in rats pretreated with morin was increased by 1.36- to 2.03-fold. The terminal half-life $(t_{1/2})$ and time to reach the peak concentration $(T_{max})$ of diltiazem were not altered significantly with morin pretreatment. AUC of desacetyldiltiazem was increased significantly (p<0.05) in rats pretreated with morin at doses of 7.5 and 15 mg/kg, but metabolite-parent ratio (MR) of desacetyldiltiazem was decreased significantly (p<0.05), implying that pretreatment of morin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. There were no apparent changes of $T_{max}$ and $t_{1/2}$ of desacetyldiltiazem with morin pretreatment. Collectively, the pretreatment of morin significantly altered pharmacokinetics of diltiazem, which can be attributed to increased intestinal absorption as well as reduced first-pass metabolism. Based on these results, dose modification should be taken into consideration when diltiazem is used concomitantly with morin or morin-containing dietary supplements in clinical setting.

• Bulletin of the Korean Chemical Society
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• 제35권8호
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• pp.2385-2390
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• 2014

Novel 2,6-difuctionalized 2H-benzopyrans were synthesized and evaluated for a sphingosylphosphorylcholine(SPC) inhibitor. The synthetic 2H-benzopyrans 1c and 3a showed high potency in SPC-induced cell proliferation assay ($IC_{50}$ < 20 nM). Neither hERG $K^+$ channel binding (> $10{\mu}M$) nor CYP inhibitions (> $10{\mu}M$) were observed. Also, the simple structure-activity relationship (SAR) results were obtained from analysis of 2H-benzopyran derivatives 1-3 and the anti-SPC effect of 2H-benzopyran 1c was confirmed by a HUVEC tube formation assay.

• 대한의생명과학회지
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• 제15권1호
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• pp.97-99
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• 2009

Geldanamycin is a benzoquinone ansamycin antibiotic that binds to cytosol HSP90 (Heat Shock Protein 90) and changes its biological function. HSP90 is involved in the intracellular important roles for the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. To identify genes expressed during geldanamycin treatment against neurons of rats (PC12 cells), DNA microarray method was used. We have isolated 2 gene groups (up-or down-regulated genes) which are geldanamycin differentially expressed in neurons. Granzyme B is the gene most significantly increased among 204 up-regulated genes (more than 2 fold over-expression) and Chemokine (C-C motif) ligand 20 is the gene most dramatically decreased among 491 down-regulated genes (more than 2 fold down-expression). The gene increased expression of Cxc110, Cyp11a1, Gadd45a, Gja1, Gpx2, Ifua4, Inpp5e, Sox4, and Stip1 are involved stress-response gene, and Cryab, Dnaja1, Hspa1a, Hspa8, Hspca, Hspcb, Hspd1, Hspd1, and Hsph1 are strongly associated with protein folding. Cell cycle associated genes (Bc13, Brca2, Ccnf, Cdk2, Ddit3, Dusp6, E2f1, Illa, and Junb) and inflammatory response associated genes (Cc12, Cc120, Cxc12, Il23a, Nos2, Nppb, Tgfb1, Tlr2, and Tnt) are down-regulated more than 2 times by geldanamycin treatment. We found that geldanamycin is related to expression of many genes associated with stress response, protein folding, cell cycle, and inflammation by DNA microarray analysis. Further experimental molecular studies will be needed to figure out the exact biological function of various genes described above and the physiological change of neuronal cells by geldanamycin. The resulting data will give the one of the good clues for understanding of geldanamycin under molecular level in the neurons.

• 대한기관식도과학회지
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• 제10권2호
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• pp.35-42
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• 2004

Background and objective : Rabeprazole is a new generation proton pump inhibitor, which has a rapid onset after first dose, predictable efficacy in all patients regardless of CYP2C19 genotype status, and less nocturnal acid breakthrough. The aim of the study is to investigate clinical efficacy and safety of rabeprazole sodium (Pariet 10mg qd)when administered once daily to patients with laryngopharyngeal reflux(LPR) disease. Methods : Among the patients who had visited the Department of Otolaryngology, those with LPR symptoms, had undergone laryngoscopy. Symptoms and endoscopic laryngeal sings were recorded initially, at 1 month, 2 months, 3 months, and more than 3 months, All patients were evaluated for clinical efficacy on the basis of symptom scores, reflux finding score(RFS), and side effects. Results : In general, most symptom scores and RFS improved over the time. Efficacy of the Pariet on LPR-related symptoms were $63.2\%,\;77.5\%,\;78.7\%,\;and\;90.9\%$ before 4 weeks, 4 to 8 weeks, 8 to 12 weeks, and after 12 weeks respectively. Efficacy on the RFS were $61.8\%,\;78.4\%,\;82.9\%,\;and\;85.5\%$ before 4 weeks, 4 to 8 weeks, 8 to 12 weeks, and after 12 weeks respectively. Pariet was well tolerated and was associated with few drug-related side effects. Conclusion Because of its efficacy and safety, Pariet may prove to be an alternative to currently available proton pump inhibitors.

• 한국환경성돌연변이발암원학회지
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• 제26권3호
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• pp.77-85
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• 2006

2,3,7,8-Tetrachlorodibenzo-$\rho$-dioxin(TCDD) displays high toxicity in animals and has been implicated in human carcinogenesis. Although TCDD is recognized as potent carcinogens, relatively little is known about their role in the tumor promotion and carcinogenesis. It is known that TCDD can increase of cancer risk from various types of tissue by a mechanism possibly involving the aryl hydrocarbon receptor (AhR) activation. In this study, effects of TCDD on cellular proliferation of normal human skin and lung fibroblasts, Detroit551 and WI38 cells were investigated. In addition, to enhance our understanding of TCDD-mediated carcinogenesis, we have investigated process in which expression of Erk1/2, cyclinD1, oncogene such as Ha-ras and c-myc, and their cognate signaling pathway. TCDD that are potent activators of AhR-mediated activity was found to induce significant increase of cytochrome P4501A1 mRNA expression, suggesting a presence of functional AhR. These results support that CYP1A1 enzyme may be involved in the generation of TCDD-induced toxicity. Moreover mitogen-activated protein kinases (MARKs) phosphorylation and cyclin D1 overexpression are induced by TCDD, which corresponded with the progression of cellular proliferation. However, TCDD did not affected Ha-ras and c-myc mRNA expression. Taken together, it seems that TCDD are could be a part of cellular proliferation in non-tumorigenic normal human cells such as Detroit551 and WI38 cells through the upregulation of MAPKs signaling pathway regulating growth of cell population. Therefore, AhR-activating TCDD could potentially contribute to tumor promotion and Detroit551 and WI38 cells have been used as a detection system of tumorigenic effects of TCDD.

• BMB Reports
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• 제45권6호
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• pp.331-336
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• 2012

The retinoid-related orphan nuclear receptor gamma ($ROR{\gamma}$) plays critical roles in regulation of development, immunity and metabolism. As transcription factor usually forms a protein complex to function, thus capturing and dissecting of the $ROR{\gamma}$ protein complex will be helpful for exploring the mechanisms underlying those functions. After construction of the recombinant tandem affinity purification (TAP) plasmid, pMSCVpuro $ROR{\gamma}$-CTAP(SG), the nuclear localization of $ROR{\gamma}$-CTAP(SG) fusion protein was verified. Following isolation of $ROR{\gamma}$ protein complex by TAP strategy, seven candidate interacting proteins were identified. Finally, the heat shock protein 90 (HSP90) and receptor-interacting protein 140 (RIP140) were confirmed to interplay with $ROR{\gamma}$ by co-immunoprecipitation. Interference of HSP90 or/and RIP140 genes resulted in dramatically decreased expression of CYP2C8 gene, the $ROR{\gamma}$ target gene. Data from this study demonstrate that HSP90 and RIP140 proteins interact with $ROR{\gamma}$ protein in a complex format and function as co-activators in the $ROR{\gamma}$-mediated regulatory processes of HepG2 cells.

• 대한기관식도과학회지
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• 제9권1호
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• pp.60-66
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• 2003

Although there is a wide range of diseases caused by gastric acid reflux and the number of cases is on the rise, it is difficult for the laryngologist to make the correct diagnosis. The treatment for laryngopharyngeal reflux can be grouped into 3 categories - changes in lifestyle, medication, and surgery. The medication used to treat laryngopharyngeal reflux are prokinetic agents and acid supressive agents such as antacids, H2 blockers, and PPIs(Proton pump inhibitor). Rabeprazole sodium($Pariet^{\circledR}$) is a newly developed agent belonging to the PPI group, but in contrast with the existing drugs such as omeprazole, lansoprazole, pantoprazole, has a low dependency on CYP2C19 during the metabolic cycle. Thus, it is known to have a quick but fixed antiacid effect and less individual differences. We analyzed 2166 patients from 32 hospitals who were prescribed $Pariet^{\circledR}$ from May, 2001 to April, 2002. The patients were divided into 4 groups according to the duration of treatment - Group 1: 1-14 days, Group 2: 15-28 days, group 3: 29-56 days, Group 4: more than 56 days. The cases were then analyzed for improvement of 8 symptoms(heart bum, regurgitation, chronic cough, hoarseness, globus sensation, chronic throat clearing, sore throat, and dysphagia), improvement on laryngoscope, usefulness to the doctor, and complication development. Of the total of 2116 patients, 1627(75.1%) cases showed at least 50% improvement of symptoms and the amount of improvement increased according to the duration of medical treatment. Most of the patients showed objective improvement on the laryngoscope, with 32.9% showing significant improvement and 38.7% showing moderate improvement. 37.6% of the doctors questioned replied that $Pariet^{\circledR}$ was very useful and 50.3% said it was useful, showing that most were satisfied with the treatment results. The complications known to develop after taking PPI are headache, nausea, diarrhea, abdominal pain, constipation, dizziness, fatigue, and of these, only a small percentage of the patients complained of mild headache. $Pariet^{\circledR}$ has shown to be a relatively safe and effective drug for the treatment of laryngopharyngeal reflux.

• 대한기관식도과학회:학술대회논문집
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• 대한기관식도과학회 2002년도 제2차 추계학술대회
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• pp.9-9
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• 2002

이비인후과 영역에 있어서 위산 역류에 의한 질환의 진단은 쉽지 않고 분명하지 않은 점이 많지만, 병변의 영향은 광범위하며, 실제로 역류에 의한 증상을 가지고 내원하는 환자도 증가하는 추세이다. 인후두역류질환의 치료는 크게 생활습관의 변경, 약물복용, 항역류수술로 나눌 수 있으며, 사용약제는 크게 두 부류로 나누는데, 제산제, H2 수용체 차단제, PPI(Proton Pump Inhibitor) 제제와 같은 산억제 약물군과 Prokinetic 약물군이다. Rabeprazole sodium(Pariet(R))은 PPI 제제에 해당하는 약제로 기존의 omeprazole, lansoprazole, pantoprazole과는 달리 대사 과정 중 CYP2C19에 대한 의존도가 낮아, 개체 간 차이가 적고 빠르고 일정하게 산분비 억제 효과를 나타내는 것으로 알려져 있은 약물이다. 2001년 5월부터 2002년 4월까지 32개 병원에서 Pariet(R) 를 복용한 2166명의 환자를 대상으로 분석하였다. 복용기간에 따라 4군(1군;1-14일, 2군;15-28일, 3군;29-56일, 4군:57일 이상)으로 나누었으며, 8가지 증상(Heart burn, Regurgitation, Chronic cough, Hoarseness, Globus sensation, Chronic throat clearing, Sore throat, Dysphagia)에 대한 호전 여부 및 후두내시경상 개선 정도, 의사에 의한 유용도 평가, 부작용 발생 여부에 대해 연구하였다. 증상개선율 50%이상을 치료 반응군으로 했을때 전체 2166명중 1627명(75.1%)에서 증상의 호전을 보았으며, 이는 복용기간이 길수록 증가하였다. 후두 내시경상 개선 정도는 현저한 개선이 32.9%, 중등도 개선이 38.7%로 대부분 환자에서 객관적인 병변의 호전을 보였으며, 유용도 평가에서는 매우 유용이 37.6%, 유용이 50.3%로 치료효과에 대한 만족도도 높은 것을 알수 있었다. PPI 제제의 부작용으로 보고되고 있는 두통, 오심, 설사, 복통. 변비, 어지럼증. 피곤 중. 소수의 환자가 두통을 호소하였으나, 그다지 심각한 정도는 아니었다. 인후두역류증 치료제로서 Pariet(R) 는 비교적 안전하고 효과가 높은 약물임이 임상 연구 결과 밝혀졌기에 보고하는 바이다.

• Mass Spectrometry Letters
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• 제9권1호
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• pp.24-29
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• 2018

DC23, a triazolothione resorcinol analogue, is known to inhibit heat shock protein 90 and pyruvate dehydrogenase kinase which are up-regulated in cancer and diabetes, respectively. This study was performed to elucidate the metabolism of DC23 in human liver microsomes (HLMs). HLMs incubated with DC23 in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA) and/or ${\beta}$-nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the formation of four metabolites, M1-M4. M1 was identified as DC23-N-Oxide, on the basis of LC-MS/MS analysis. DC23 was further metabolized to its glucuronide conjugates (M2, M3, and M4). In vitro metabolic stability studies conducted with DC23 in HLMs revealed significant glucuronide conjugation with a $t_{1/2}$ value of 1.3 min. The inhibitory potency of DC23 on five human cytochrome P450s was also investigated in HLMs. In these experiments, DC23 inhibited CYP2C9-mediated tolbutamide hydroxylase activity with an $IC_{50}$ value of $8.7{\mu}M$, which could have implications for drug interactions.