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Milk Transfer and Toxicokinetics of Valproic Acid in Lactating Cynomolgus Monkeys

  • Lee, Jong-Hwa;Yu, Wook-Joon;Jeong, Eun Ju;Chung, Moon-Koo
    • Toxicological Research
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    • v.29 no.1
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    • pp.53-60
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    • 2013
  • Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup's plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations (< 0.5 ${\mu}g/ml$) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.

Safening Mode of Action of 1, 8-Naphthalic Anhydride on Corn and Soybean Against Herbicide Bensulfuron and Imazaquin (제초제(除草劑) bensulfuron과 imazaquin에 대한 1, 8-naphthalic anhydride(NA)의 옥수수와 콩에 대한 약해경감작용기구(藥害輕減作用機構))

  • Hwang, I.T.;Choi, J.S.;Kim, J.S.;Cho, K.Y.;Chun, J.C.
    • Korean Journal of Weed Science
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    • v.14 no.1
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    • pp.8-15
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    • 1994
  • The mode of safening action and potency of the 1, 8-naphthalic anhydride(NA) were investigated in corn(Zea mays) and soybean(Glycine max) treated with herbicide bensulfuron[2-{{{{{(4,6-dimethoxy-2-pyrimidinyl)amino}carbonyl}amino}sulfonyl}methyl}benzoic acid] and imazaquin[2-{4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl} 3-quinolinonecarboxylic acid]. Seed dressing with 0.2%(w/w) NA showed successful protection in corn against injury from herbicide bensulfuron and imazaquin but not in soybean. Safening factors of NA against bensulfuron and imazaquin were 10.2 and 5.0, respectively, in corn, while they were both 1.3 in soybean. In vivo, Glutathione-S-transferase(GST) activity of NA-treated corn and soybean increased 1.8-and 1.3-fold, respectively, but the activity was not affected by the herbicides in vitro. Acetolactate synthase(ALS) levels of NA-treated corn was increased 1.3-fold, but not changed in soybean. Tolerance of ALS activity to the herbicides was slightly greater in ALS obtained from NA-treated corn than that from the untreated, whereas the difference was not found in soybean. A significant increase of ACCase due to NA occurred in corn, but not in soybean. The herbicides did not affect in vitro ACCase activity.

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Antioxidative Responses of Transgenic Tobacco Plants Expressing both Superoxide Dismutase and Ascorbate Peroxidase in Chloroplasts to Several Herbicides (Superoxide Dismutase와 Ascorbate Peroxidase가 엽록체내로 동시에 과대발현된 형질전환 담배의 제초제들에 대한 항산화 반응)

  • Kim Jin-Seog;Lee Byung-Hoi;Kwon Suk-Yoon;Kim Yun-Hee;Kim So-Hee;Cho Kwang-Yun
    • Journal of Plant Biotechnology
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    • v.32 no.2
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    • pp.97-103
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    • 2005
  • Antioxidative responses of transgenic tobacco plants expressing both superoxide dismutase (SOD) and ascorbate peroxidase (APX) in chloroplasts was investigated with several herbicides. In greenhouse test, tolerance of SOD/APX-overexpressed tobacco (CA) to photosystem (PS) I inhibitor paraquat was increased by about 40%. However, any response differences between CA and wild type (WT) tobacco was not observed in a treatment with PS II inhibitors (bromoxynil, diuron and bromacil), chlorophyll biosynthesis inhibitor(oxyfluorfen), carotenoid biosynthesis inhibitor (fluridone) and 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase inhibitor (glyphosate). This tendency was also similar in the growth chamber test of low light intensity, using paraquat and diuron. That is, increased antioxidant activity of CA was shown only in paraquat treatment. When paraquat was foliar-treated to 6 to 9-leaf stage plant, the third to fourth placed leaf from shoot tip showed relatively higher antioxidant activity. Ascorbate supplemented to paraquat solution alleviated the phytotoxicity with a similar range in both CA and WT. In conclusion, CA specifically responded to oxidative stress induced by paraquat among tested herbicides in a whole plant assay.

Thermal and Mechanical Properties of Epoxy Composites Using Silica Powder (실리카 파우더를 이용한 에폭시 복합소재의 열적/기계적 특성)

  • Lee, Hye Ryeon;Song, JeeHye;Kim, Daeyeon;Lim, Choong-Sun;Seo, BongKuk
    • Journal of Adhesion and Interface
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    • v.17 no.1
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    • pp.7-14
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    • 2016
  • Epoxy composites with concentrations of 5-70 wt% of silica particles were prepared in order to improve mechanical property and poor thermal stability. The mechanical and thermal properties were investigated and compared to the corresponding properties of neat epoxy composite. Furthermore, the effects of silane compound treatment on silica particles were observed by the experimental results of the tensile strength, glass transition temperature, and thermal stability of epoxy composite. Tensile strength of epoxy composites was measured by universal testing machine (UTM) and after that, the structure and morphology analysis of epoxy nanocomposites were analyzed by field emission scanning electron microscope (FE-SEM) and energy dispersive spectroscopy (EDS). The increased solid content of CA0030 particle improved the tensile strength of epoxy/ modified composites to give 30-50 MPa. The thermal expansion coefficients (CTE) of neat epoxy resin and epoxy/silica composites measured with a thermomechanical analyzer (TMA) showed that the incorporation of silica particles was helpful to reduce the CTE of neat epoxy resin.

Study on Preparation of Methyl N-Phenyl Carbamate by Oxidative Carbonylation of Aniline and Methanol (아닐린과 메탄올의 산화 카르보닐화에 의한 Methyl N-phenyl carbamate 제조 연구)

  • Roh, Jong-Seon;Lee, Kwan-Young;Kim, Tae-Soon;Chang, Tae-Seon;Yoon, Byung-Tae;Kim, Seong-Bo
    • Korean Chemical Engineering Research
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    • v.56 no.1
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    • pp.119-124
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    • 2018
  • The production of methyl N-phenyl carbamate by an oxidative carbonylation method of aniline and methanol is of great interest as an environmentally friendly process that can replace the monomer production process of a polymer produce using conventional phosgene. In this study, heterogeneous catalysts were prepared by using Y-zeolite, $SiO_2$, $Al_2O_3$ as support, and oxidative carbonylation continuous operation from aniline and methanol was attempted using the prepared heterogeneous catalyst. Batch reactor was used to determine the support, and various reaction conditions such as reaction temperature, reaction pressure, and effect of promoter were established using palladium catalyst. A reaction kinetics study was conducted under optimum reaction conditions. The basic data for carbamate process development were obtained by performing continuous operation for a long time under established reaction condition.

A Study on The Preparation of Poly(alkyl methacrylate-co-maleic anhydride) as Cold Flow Improvers for Biodiesel Fuels (바이오디젤용 저온 유동성 향상제로서의 폴리 (알킬메타크릴레이트-공-무수말레인산) 제조 연구)

  • Hong, Jin-Sook;Chung, Keun-Wo;Kim, Young-Wun;Kim, Nam-Kyun;Im, Dae-Jae
    • Applied Chemistry for Engineering
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    • v.23 no.2
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    • pp.232-240
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    • 2012
  • Bio-diesel (BD) is the mono alkyl esters of long chain fatty acids derived from renewable feed stocks like vegetable oils or animal fats. Bio-diesel shows poorer fuel properties than that of diesel fuel in a cold condition. For the diesel fuel, many cold flow improvers have been developed; however, since primary ingredients of bio-diesel are different from those of the diesel fuel, there is a limit to the cold flow improvement when the same cold flow improvers are added to bio diesel. In this study, to improve low temperature properties of bio-diesel, we developed a cold flow improver using an alkyl methacrylate monomer, prepared via ester reaction, and maleic anhydride and also conducted a ring opening reaction using amine. We characterized the products using $^1H-NMR$, FT-IR and GPC methods. In addition, the cold flow improvements of the products in Soybean BD and Palm BD in the concentration rage of 1000~10000 ppm were investigated. It was found that the addition of LMA2SMA6MA2-C8A in Soybean BD improved the pour point by $12.5\;^{\circ}C$.