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박한수,김승희,김부영,장일무,Park, Han-Soo,Kim, Seung-Hee,Kim, Pu-Young,Chang, Il-Moo The Korean Society of Toxicology Korea Environment 1990 Toxicological Research Vol.6 No.1
Aconiti Tuber is the root of Aconitum sp (Ranunclaceae) which has been considered as one of the most important medicinal plant having cordiotonic, diuretic and analgesic effect. On the other hand, it has been known that Aconiti Tuber contained toxic agent, aconitine alkaloids so that only processed Aconiti Tubers have been used as herbal drug traditionally. For the safety evaluation of processed Aconiti Tuber, quantitative determination of aconitine and acute, subacute toxicity test were performed on 5 commercial processed Aconiti Tubers. Arapid and precise method using HPLC has been developed for the separation and determination of aconitine. Samples were extracted with hydrochloric acid (pH3) and hot water decoction. In case of d-HCL extracts, the contents of aconitine were from 0.08 mg/g to trace. But in case of hot water decoction extracts, the contents of aconitine were not detected. For the investigation of Aconiti Tuber toxicity in rats, hot water decoction samples and methanol extracts were tested. 1) Acute toxicity test Hot water decoction sample and methanol extracts from Aconiti Tuber did not show any toxic effects in rats by an oral administration. $LD_50values of 2 extracts were above 10.0 g/kg. 2) Subacute toxicity study In the repeated administration study, hot water decoction samples were given orally to Sprague-Dawlay rats for 2 week at daily doses of 5.0 g/kg. The results are as follows; No toxic manifestation, body weight changes and lethality were observed during wxperimental period. There were no significant changes in serum enzyme activities such as GOT, GPT, LDH, ALP between treated and control groups. However CPK values were decreased in the Subuja-treated group. (P<0.01). In addition, no gross and microscopic changes were noted in Aconiti Tuber-treated groups.
메탐페타민 유사 분별능 시험을 통한 l-디프레닐의 약물남용가능성 평가
이선희(Sun Hee Lee),김부영(Pu Young Kim) 대한약학회 1998 약학회지 Vol.42 No.1
The antiparkinsonian agent l-deprenyl, a selective monoamine oxidase (MAO)-B inhibitor, is metabolized in part to l-methamphetamine and l-amphetamine. l-Deprenyl was evaluated for amphetamine and methamphetamine-like discriminative stimulus effects in rats and its mechanism of action was investigated. Rats were trained under a 5-response, fixed ratio schedule of stimulus-shock termination or a 10-response. Fixed-ratio schedule of food-presentation which discriminate between d-amphetamine (1mg/kg, i.p.) and saline or d-methamphetamine (1mg/kg, i.p.) and saline in a two-lever, operant conditioning procedure. Full generalization was obtained to d-amphetamine (1~3mg/kg). d-methamphetamine (1~3mg/kg) and l-deprenyl (17~30mg/kg) under both the food presentation and stimulus shock termination schedule. l-Deprenyl has dose-dependent amphetamine-and methamphetamine-like discriminative stimulus properties in rats only at doses of 17 and 30mg/kg. Reversible MAO-B inhibitor, RO 16-6491 didn`t show any amphetamine-like discriminative properties. Aromatic amino acid decarboxylase inhibitor, NSD 1015 decreased % responding of l-deprenyl in the methamphetamine-trained rats under the stimulus-shock termination schedule. SKF-525A produced partial inhibition of methamphetamine-like discriminative effects of l-deprenyl under the food presentation schedule. These results suggest that l-deprenyl has no abuse liability at the therapeutic range but there needs some caution at high doses and furthermore, drug discrimination studies under the food presentation and shock termination schedule are useful for the assessment of abuse liability of psychostimulants.
소염진통제 약물에 대한 In vitro 피부자극 시험연구
이종권,김대병,이은희,이선희,류승렬,최기환,김윤정,김부영,Lee, Jong-Kwon,Kim, Dai-Byung,Lee, Eun-Hee,Lee, Sun-Hee,Ryu, Seung-Rel,Choi, Ki-Hwan,Kim, Yoon-Jeong,Kim, Pu-Young 한국독성학회 1998 Toxicological Research Vol.14 No.3
In vitro skin iritation of anti-inflammatory drugs was investigated in terms of the cytotoxicity method to human skin fibroblast cells. Five anti-inflammatory drugs (Diclofenac, Naproxen, Meclofenamic acid, Ibuprofen and Fnoprofen) which are commercially available as oral preparations or injections were tested. The cytotoxicity of 5 chemicals was evaluated by using MTT[tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. NRU (neutral red uptake) assay and Alamar Blue assay after fibroblast cells had been exposed to the chemicals for 24 hours or 489 hours. The $IC_{50}$ values of the chemicals showed the comparative strength of cytotoxicity as following order of Meclofenamic acid>Diclofenac>Fenoprofen>Ibuprofen>Naproxen. The values of $IC_{50}$ determined by Alamar Blue assay were lower than those of MTT and NRU assay. These data suggest Alamar Blue assay can be useful method for assessing in vitro skin irritation potential of anti-inflammatory drugs.
류승렬(Seung Rel Ryu),김혜진(Hye Jin Kim),홍진태(Jin Tae Hong),이종권(Jong Kwon Lee),이선희(Sun Hee Lee),이병무(Byung Mu Lee),김부영(Pu Young Kim) 대한약학회 1999 약학회지 Vol.43 No.5
Abuse liability of ephedrine was investigated by measurement of locomotor activity and self-administration in Sprague-Dawley rats. Locomotor activity was determined in rats treated with 3, 10 and 30mg/kg ephedrine for 14 days. Self-administration by ephedrine (0.23, 1 and 2.3mg/kg) was examined in food-trained rats. We also examined effect of dopamine receptor antagonist (spiperone, 30mcg/kg) on the ephedrine-induced response of self-administration. Body weight was not statistically difference between control and ephedrine treatment group, but locomotor activity was dose-dependently increased. Self-administration for ephedrine was decreased in the early response (day 1 and 2) but the response was increased by higher dose of ephedrine. Self-administration was decreased by dopamine receptor antagonist (spiperone). These data showed that ephedrine increased locomotor activity and induced response of self-administration, and the effects of ephedrine were partially related to the dopaminergic system, which suggest that ephedrine may have abuse liability.
톨루엔 흡인이 뇌내 아미노산 신경전달물질 함량에 미치는 영향
이선희(Sun Hee Lee),신대섭(Dae Sup Shin),김부영(Pu Young Kim) 한국응용약물학회 1995 Biomolecules & Therapeutics(구 응용약물학회지) Vol.3 No.1
The effects of toluene inhalation on the contents of amino acid neurotransmitters in rat brain were investigated and blood toluene concentrations inducing changes of behavior and amino acid neurotransmitter contents in rat brain were observed. Male wistar rats were exposed to toluene vapor (single dose : 1700, 5000 and 10000 ppm for 2 hrs, repeated dose : 1700 and 5000 ppm for 2 hrs/dayx6 days). Toluene concentrations in blood and the inhalation chamber were assayed by GC with headspace sampler. HPLC method foliowing PITC derivatization was used to measure the amino acid contents in brain tissues such as frontal cortex, caudate, hippocampus, cerebellum and brain stem. Glutamic acid and aspartic acid levels were increased by single inhalation of toluene (5000 ppm) in all the brain areas assayed in this experiment. In caudate and cerebellum, taurine levels were decreased by single inhalation of low dose toluene (1700 ppm), but increased by repeated administration. At high blood toluene concentration, GABA levels were increased in all the brain areas assayed in this experiment and the increasing extents of inhibitory amino acid contents measured in caudate and hippocampus were greater than those of excitatory amino acids. These results suggest that the changes of amino acid neurotransmitter contents in brain by exposure to toluene may modulate toluene-induced behaviors.
이종권(Jong Kwon Lee),남기택(Ki Taek Nam),김부영(Pu Young Kim) 한국예방수의학회 1999 예방수의학회지 Vol.23 No.3
인체 피부세포의 배양을 이용한 시험은 피부독성을 평가하는 시험에 유용하게 사용하고 있다. 본 연구는 사람 각질 세포로 알려진 HaCaT 세포를 이용하여 수종의 보습제에 대한 세포독성을 평가하고자 시행하였다. 보습제의 자극 정도에 대한 세포의 독성평가는 Neutral Red Uptake (NRU) assay 방법과 Alamar Blue(AB) assay 방법을 이용하여 평가하였으며, in vivo 시험은 인체 첩포시험을 이용하여 평가하였다. 세포독성을 두 assay로 검증해 본 결과 용량 의존성을 보였다. 인체 첩포시험과 in vitro 시험반응과는 좋은 상관관계를 보였다. In vivo 시험인 인체 첩포시험과 in vitro 시험인 NRU assay의 IC₅₀값과의 상관지수는 0.714를 보였고 또 다른 in vitro 시험인 AB assay의 IC₅₀값과의 상관지수는 0.657을 나타내었다. 본 연구결과 배양된 HaCaT cell을 이용한 AB assay와 NRU assay는 수종의 보습제에 대한 인체 피부의 자극을 예측하는 방법으로 유용하게 사용될 수 있을 것으로 사료된다. Cultured human skin cells have been widely used for assessing the skin irritancy of various humectants. In this study we used HaCaT cell (immortalized human keratinocyte). The irritation potential of humectants was assessed by human skin patch test, the neutral red uptake (NRU) and Alamar Blue (AB) assays. As a result of cytotoxicity assessed by NRU and AB assays, six humectants were seen in a dose dependent manner. There was a relatively good correlation between the in vitro and human patch test scores for the humectants tested. The correlation of NRU assay on the basis of IC₅₀ values with human patch test data yielded a correlation coefficient of r=0.714. The correlation of AB assay data on the basis of IC₅₀ values with human patch test yielded a correlation coefficient of r=0.657. The result of our study suggest that AB and NRU assay using cultured HaCaT cell can be used as an alternative method for screening the dermal irritancy of various humectants. And we found NRU assay would be possible alternative method to evaluate skin irritation potential and was better than the AB assay.
MK-801 투여에 의한 몰핀의존성랫드 뇌선조체중 도파민신경전달물질의 변화
이선희(Sun Hee Lee),신대섭(Dae Sup Shin),이덕주(Duck Joo Rhie),유영아(Young A Yoo),류승렬(Seung Rel Ryu),김대병(Dai Byung Kim),이종권(Jong Kwon Lee),김부영(Pu Young Kim) 한국응용약물학회 1998 Biomolecules & Therapeutics(구 응용약물학회지) Vol.6 No.1
The roles of dopamine(DA) and N-methyl-D-aspartate(NMDA) system in the development and expression of morphine dependence were investigated by monitoring the concentrations of extracellular DA and its metabolites by in vivo microdialysis and simultaneous observation of behavioral changes in morphinedependent rats. Extracellular DA level in caudate putamen of morphine-dependent rat was decreased and the concentrations of its metabolites, dihydroxy phenylacetic acid(DOPAC) and homovanillic acid(HVA), were increased during naloxone-precipitated withdrawal. DA contents were recovered to normal levels by pretreatment of MK-801, a noncompetitive NMDA receptor antagonist, which may explain the mechanism of diminishing effect of MK-801 on withdrawal symptoms in morphine-dependent rats. MK-801(0.3 mg/kg, i.p.) induced the untoward harmful neurological signs such as ataxia and severe rotations, which may be produced by hyperactivation of dopaminergic system. These results suggest that MK-801 may inhibit the expression of morphine dependence by altering the dopamine release.