• Biomolecules & Therapeutics
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• 제19권2호
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• pp.255-260
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• 2011

The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 $mg{\cdot}kg^{-1}$) with ticlopidine (3 or 9 $mg{\cdot}kg^{-1}$). The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activities were also evaluated. Ticlopidine inhibited CYP3A4 enzyme activity in a concentrationdependent manner with a 50% inhibition concentration ($IC_{50}$) of 35 ${\mu}M$. In addition, ticlopidine did not significantly enhance the cellular accumulation of rhodamine-123 in NCI/ADR-RES cells overexpressing P-gp. Compared with the control (given diltiazem alone), ticlopidine significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration ($C_{max}$) and the area under the plasma concentration-time curve (AUC) of diltiazem were significantly (9 $mg{\cdot}kg^{-1}$, p<0.05) increased in the presence of ticlopidine. The AUC of diltiazem was increased by 1.44-fold in rats in the presence of ticlopidine (9 $mg{\cdot}kg^{-1}$). Consequently, the absolute bioavailability (A.B.) of diltiazem in the presence of ticlopidine (9.3-11.5%) was signifi cantly higher (9 $mg{\cdot}kg^{-1}$, p<0.05) than that in the control group (8.0%). Although ticlopidine significantly (p<0.05) increased the AUC of desacetyldiltiazem, the metabolite-parent AUC ratio (M.R.) in the presence of ticlopidine (9 $mg{\cdot}kg^{-1}$) was significantly decreased compared to that in the control group, implying that ticlopidine could effectively inhibit the metabolism of diltiazem. In conclusion, the concomitant use of ticlopidine significantly enhanced the oral bioavailability of diltiazem in rats by inhibiting CYP3A4-mediated metabolism in the intestine and/or liver rather than by inhibiting intestinal P-gp activity or renal elimination of diltiazem.

• 한국가금학회지
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• 제31권3호
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• pp.151-155
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• 2004

본 실험은 육계사료 내에 맥반석 분말을 첨가 급여했을 때 육계의 성장에 미치는 효과와 생산된 계육의 관능적 품질에 미치는 영향을 조사하기 위하여 실시하였다. 5일령 Avian 육계 수평아리를 반복별로 체중이 동일하도록 임의 배치하였다. 맥반석 분말을 첨가하지 않은 대조구에 맥반석 분말을 1% 및 2% 수준으로 첨가한 처리구를 두었으며, 각각의 처리구 내에는 항생제 음수 투여구와 무투여구를 두어 5처리에 3반복, 반복당 30수씩 총450수를 공시하여 30일간 실험사료를 급여하였다. 실험기간 중의 사료섭취 량 및 증체량을 조사하여 사료요구율을 구하였고, 5주령에 각 반복구 내에서 체중의 평균치에 해당하는 개체를 2수씩 선발하여 희생시킨 후 필요 조직을 채취하였고, 근육 내의 화학적 조성과 육질 평가를 실시하였다. 종료 시 체중 및 증체량은 대조구에 비해 맥반석 분말을 첨가 급여한 처리구에서 다소 증가하는 경향을 나타내었다. 맥반석 분말 1% 첨가구에서 사료 요구율이 개선되었으나, 유의한 차이는 아니었다. 단위 체중당 간 중량 및 복강지방 중량은 맥반석 분말의 첨가 급여에 의해 다소 감소하는 경향을 보여 주었다. 맥반석 분말 2% 첨가구에서 가슴근육의 중량이 가장 높았으며, 다리근육중량은 반대로 낮아지는 경향이 관찰되었으나 통계적인 유의차는 인정되지 않았다. 관능검사 결과에서는 대조구에 비해 맥반석 분말 1% 첨가구에서는 첨가 효과가 나타나지 않았으나, 맥반석 분말 2% 첨가구에서는 맛, 연도 및 다즙성의 전 항목에 걸쳐 유의하게 높아지거나 높아지는 경향을 보여 주었다.

• Molecules and Cells
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• 제38권2호
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• pp.122-129
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• 2015

DBM-2198, a six-membered azasugar nucleotide (6-AZN)-containing phosphorothioate (P = S) oligonucleotide (AZPSON), was described in our previous publication [Lee et al. (2005)] with regard to its antiviral activity against a broad spectrum of HIV-1 variants. This report describes the mechanisms underlying the anti-HIV-1 properties of DBM-2198. The LTR-mediated reporter assay indicated that the anti-HIV-1 activity of DBM-2198 is attributed to an extracellular mode of action rather than intracellular sequence-specific antisense activity. Nevertheless, the antiviral properties of DBM-2198 and other AZPSONs were highly restricted to HIV-1. Unlike other P = S oligonucleotides, DBM-2198 caused no host cell activation upon administration to cultures. HIV-1 that was pre-incubated with DBM-2198 did not show any infectivity towards host cells whereas host cells pre-incubated with DBM-2198 remained susceptible to HIV-1 infection, suggesting that DBM-2198 acts on the virus particle rather than cell surface molecules in the inhibition of HIV-1 infection. Competition assays for binding to HIV-1 envelope protein with anti-gp120 and anti-V3 antibodies revealed that DBM-2198 acts on the viral attachment site of HIV-1 gp120, but not on the V3 region. This report provides a better understanding of the antiviral mechanism of DBM-2198 and may contribute to the development of a potential therapeutic drug against a broad spectrum of HIV-1 variants.

• Journal of Pharmaceutical Investigation
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• 제37권2호
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• pp.107-111
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• 2007

Epigallocatechin gallate (EGCC), a flavonoid, is the main component of green tea extracts. EGCG has been reported to be an inhibitor of P-glycoprotein (P-gp) and cytochrom P450 3A(CYP3A4). This study investigated the effect of long-term administration of EGCG on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats pretreated with EGCG (7.5 mg/hg) for 3 and 9 days. Compared to oral control group, the presence of EGCG significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 102% (coad), 83.2% (3 days) and 52.3% (9 days), and the peak concentration $(C_{max})$ by 134% (coad), 120% (3 days) and 66.1% (9 days). The absolute bioavailability (A.B.%) of verapamil was significantly (p<0.01) higher by 8.4% (coad), 7.7% (3 days), 6.4% (9 days) compared to control (4.2%), and presence of EGCG was no significant change in the terminal half-life $(t_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of verapamil. Our results indicate that EGCG significantly enhanced oral bioavailability of verapamil in rats, implying that presence of EGCG could be effective to inhibit the CYP3A4-mediated metabolism and P-gp efflux of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with EGCG or EGCG-containing dietary.

• Biomolecules & Therapeutics
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• 제18권2호
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• pp.226-232
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• 2010

The aim of this study was to investigate the effect of atrovasatatin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine to rats. Nicardipine was administered orally (12 mg/kg) or intravenously (i.v., 4 mg/kg) without or with oral administration of atrovasatatin (0.3 or 1.0 mg/kg) to rats. The effect of atorvastatin on the P-glycoprotein (P-gp) as well as CYP3A4 activity was also evaluated. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 48 ${\mu}M$. Compared to the controls (nicardipine alone), the area under the plasma concentration-time curve (AUC) of nicardipine was significantly (1.0 mg/kg, p<0.05) greater by 16.8-45.4%, and the peak plasma concentration ($C_{max}$) was significantly (1.0 mg/kg, p<0.05) higher by 28.0% after oral administration of nicardipine with atorvastatin, respectively. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.17- to 1.45-fold and the absolute bioavailability (A.B.) of nicardipine with atrovasatatin was significantly greater by 16.7-20.9% compared to that of the controls (14.3%). Compared to the i.v. control, atrovasatatin did not significantly change pharmacokinetic parameters of i.v. administration nicardipine. The enhanced oral bioavailability of nicardipine by atorvastatin suggests that CYP3A subfamily-mediated metabolism were inhibited in the intestine and/or in the liver rather than P-gp-mediated efflux of nicardipine. Based on these results, modification of nicardipine of dosage regimen is required in the patients. Human studies are required to prove the above hypothesis.

• Asian Pacific Journal of Cancer Prevention
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• 제13권2호
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• pp.625-631
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• 2012

In order to investigate whether SKI-II could reverse drug resistance and its possible mechanisms, we treated SGC7901/DDP cells with SKI-II or SKI-II in combination with DDP. Then cell growth, apoptosis, micromorphological changes, and expression of SphK1, P-gp, NF-${\kappa}B$, Bcl-2 and Bax were assessed by MTT assay, flow cytometry, electron microscopy, immunocytochemistry and Western blot assay respectively. SGC7901/DDP cells were insensitive to cisplatin 2.5mg/L, but when pretreated with SKI-II, their proliferation was inhibited by cisplatin 2.5mg/L significantly, the inhibition rate increasing with time and dose. The apoptosis rate was also significantly elevated. Expression of SphK1 and P-gp was decreased significantly, Pearson correlation analysis showing significant correlation between the two (r=0.595, P<0.01). Expression of NF-${\kappa}B$ and Bcl-2 was decreased significantly,while that of Bax was increased, compared to the control group. There were significant correlations between SphK1 and NF-${\kappa}B$(r=0.723, P<0.01), NF-${\kappa}B$ and Bcl-2(r=0.768, P<0.01). All these data indicated that SKI-II could reverse drug resistance of SGC7901/DDP to cisplatin by down-regulating expression of P-gp and up-regulating apoptosis through down-regulation of SphK1. The increased apoptotic sensitivity of SGC7901/DDP to cisplatin was due to the decreasing proportion of Bcl-2/Bax via down-regulating NF-${\kappa}B$.

• 한국임상약학회지
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• 제21권3호
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• pp.215-223
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• 2011

암로디핀과 레파그리니드의 병용은 당뇨병의 합병증으로인한 고혈압 유발 시 병용 처방될 수 있다. 암로디핀과 레파그리니드의 약동학적 상호작용 연구를 위하여 암로디핀 (0.1 및 0.4 mg/kg) 과 레파그리니드를 흰 쥐에 경구(0.5 mg/kg) 및 정맥 (0.2 mg/kg) 투여하여 연구를 실시하였다. 암로디핀이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 암로디핀의 CYP3A4의 50% 효소활성억제는 $9.1{\mu}M$ 이었다. 암로디핀은 P-gp의 활성에는 영향을 미치지 않았다. 암로디핀 (0.4 mg/kg)은 레파그리니드의 혈장곡선하면적(AUC)과 최고혈장농도 ($C_{max}$)를 40.2% 와 22.2% 각각 유의성 (p < 0.05)있게 증가시켰다. 따라서, 레파그리니드의 상대적생체이용률 (RB)은 암로디핀과 병용투여 시 1.18-1.40 배 증가되었으며, 또한 레파그리니드의 절대적생체이용률(AB)은 대조군과 비교하여 41.0% 유의성 있게 증가되었다. 경구 투여 시와는 대조적으로, 암로디핀은 정맥 내로 투여된 레파그리니드에서는 약동학적 파라미터에 어떤 영향도 미치지 않았다. 따라서 암로디핀이 레파그리니드의 생체이용률을 증가시킨 것은 신장배설 감소 또는 P-gp 활성억제 보다는 암로디핀이 소장 또는 간장에서 CYP3A4을 억제시켰기 때문으로 사료된다. 암로디핀과 레파그리니드의 병용투여 시 레파그리니드의 용량을 조절하는 것이 안전하다고 사료된다.

• Natural Product Sciences
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• 제10권6호
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• pp.268-271
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• 2004

In order to examine their effects on the P-glycoprotein (P-gp) activity in human breast cancer cells, MCF-7/ADR, one hundred Indonesian plant extracts were screened. Among them, the five chloroform extracts of Calotropis gigantea, Curcuma aeruginosa, Merremia mammosa, Sindora sumatrana, and Zingiber cassumunar, showed the most potent P-gp inhibitory activity. When each of these extracts was treated together with the anticancer agent, daunomycin, they increased the cytotoxic activity of daunomycin up to $IC_{50}$ values of less than $6.62\;{\mu}M$, which is a value with a positive control, verapamil. Also, other 15 plant extracts exhibited significant P-gp inhibitory activity with $IC_{50}$ values between 6.62 and $13.20\;{\mu}M$. These prospective samples will be subjected to further laboratory phytochemical investigation to find active principles.

• Asian Pacific Journal of Cancer Prevention
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• 제17권1호
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• pp.51-55
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• 2016

Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.

• 한국식품저장유통학회지
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• 제14권4호
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• pp.369-377
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• 2007

백삼분말, 홍삼분말 및 홍삼추출농축액 등의 인삼제품을 첨가하여 기능성 식빵 제조에 이용하고자 인삼제품의 첨가량을 달리하여 반죽에 대한 물성을 측정하고 식빵을 제조하여 품질특성을 조사하였다. Farinograph, extensograph 및 amylograph에 의한 분석결과, 인삼제품의 첨가량이 증가할수록 높은 수분흡수력이 나타났고 반죽의 안정도가 무첨가구에 비하여 불안정하여 반죽시간이 단축되었으며 R/E값 및 점도가 감소하였다. 또한 발효시간의 경과에 따라 pH는 하강하였으며 발효팽창력은 무첨가구보다 우수하였으나 일정량이상의 첨가는 가스보유력을 약화시켰다. 인삼분말제품 첨가에 따른 비용적은 백삼분말 2% 첨가 시 5.41 mL/g으로 가장 높았고 홍삼추출농축액첨가제품은 첨가량이 증가할수록 높아져서 4% 첨가 시 5.82 mL/g을 나타냈다. 인삼제품을 첨가한 식빵의 저장 중 경도를 측정한 결과 백삼 및 홍삼분말첨가 시는 무첨가구에 비하여 초기경도가 높았으며 저장일수가 증가할수록 증가하였고 홍삼추출농축액을 첨가한 제품은 초기경도가 무첨가구보다 낮았으며 저장일수가 증가함에 따라 경도의 증가폭이 작았다. 색도 측정결과 인삼제품첨가량이 증가할수록 적색도와 황색도가 증가하였으며 관능검사결과 전체적인 기호도면에서 홍삼추출농축액 2% 첨가한 제품에서 가장 좋은 기호도를 나타내었다.