高效液相色谱测定尿中叶枯灵及其代谢产物

本文运用反相高效液相色谱法,采用线性梯度洗脱,两波长切换和两内标法建立了同时测定了染毒大鼠尿中叶枯灵及其代谢产物肼叉-1.3-二噻茂烷,乙酰肼叉-1.3-二噻茂烷和丙酮酸缩肼叉-1.3-二噻茂烷的含量方法。线性范围0.2-100μg/ml,回收率大于91.2%,日内及日间变异系数小于2.46%,本法测定叶枯灵染毒后,经尿排泄叶枯灵及其代谢产物累积量——时间过程。方法简便、快速,有良好的重现性     

新农药叶枯灵的毒性研究

农药叶枯灵(原名“渝—7802”)系四川省重庆农药厂新研制的有机硫杀菌剂,其化学名药2-苯酰胼叉-1,3-二噻茂烷(2-benzoyl-yhdrazono-1,3-ditholane),分子式为C_(10)H_(10)NOS_2,系白色粉剂,易溶于二甲亚砜、丙酮等有机溶剂,难溶于水和油。经     

氚标记2-苯酰肼叉-1,3-二噻茂烷在大鼠体内的分布

为探讨新农药2-苯酰肼叉-1,3-二噻茂烷(BHD)在机体内的吸收、分布、排泄、蓄积及对胎盘屏障透过性,以氚标记该农药(~3H-BHD)并对染毒大鼠进行了观察。     

新农药2-苯酰肼叉-1,3-二噻茂烷的毒理研究

2-苯酰肼叉-1,3-二噻茂烷(渝-7802)为国内新试制的一种农业杀菌剂。经口LD_(50)小鼠为82.2mg/kg(雌)和73.7mg/kg(雄),大鼠为108.3mg/kg(雌)和138.8mg/kg(雄)本品属中等毒类农药,可经胃肠道和呼吸道吸收,但不易经皮吸收,对皮肤粘膜无明显刺激作用。在大鼠体内无明显蓄积作用和致畸作用。Ames试验和染色体畸变试验阴性。     

农药叶枯灵对大鼠离体灌流肝的影响研究

进行了叶枯灵的大鼠肝脏离体循环式灌流肝实验研究,结果表明,灌流肝正常功能至少可维持2小时,叶枯灵在500uM 时,对大鼠灌流肝有毒作用,LDH 酶活性及 K~+浓度对评价叶枯灵的有毒作用是敏感的指标。本文建立了大鼠离体灌流肝的模型,适用于化合物的毒性及代谢的研究。     

全二维气相色谱串联质谱法测定全血中萘烷及其代谢产物

目的 建立全血中萘烷及其代谢产物(萘烷醇、萘烷酮)的全二维气相色谱检测方法。方法 全血经环己烷提取、固相萃取柱净化后，采用Rxi-5Sil MS作一维柱、DB-17 MS作二维柱进行分离，质谱仪检测，以外标法定量。结果 萘烷及其代谢产物萘烷醇、萘烷酮在二维谱图上有效分离，检出限为7～9μg/L,定量限为19～27μg/L,在0～5μg/mL范围内线性关系良好(r>0.999)。血液样本平均加标回收率为96.4%～102.8%,相对标准偏差(RSD)为3.1%～5.9%。结论 建立的方法简便灵敏，分离度好，回收率高，适用于血液样本中萘烷及其代谢产物的检测。     

高效液相色谱分析法检测多噻烷及其主要代谢产物

用ＨＰＬＣ分析法检测多噻烷及其主要代谢产物，色谱条件是：Ｃ１８反相柱．甲醇：水＝５：２（ｖ／ｖ），含０．０３ｍｏｌ／Ｌ醋酸铵，流速０．８ｍｌ／ｍｉｎ，检测波长２２７ｎｍ。结果表明本法对多噻烷、杀虫环和沙蚕毒素及某些有关代谢物有较好的分离效果．且有较好的准确度和精密度．具有较强的实用价值。     

二硫化碳作业工人尿中含硫代谢产物的排泄特征研究

二硫化碳(CS_2)是一种亲血管、神经毒物,主要见于化纤工业。经呼吸道吸收的CS_2中约70～90％在体内经生物转化为代谢产物,从尿中排出,其中约70％为有机硫化合物（硫脲、硫代噻唑啉酮和2-硫代噻唑烷-4-羟酸等）。CS_2含硫代谢产物的生物监测是制订CS_2接触工人健康监护规范的重要基础,但CS_2代谢产物经尿排泄的规律迄今尚未完全阐明。为此,本文对化纤厂CS_2作业工人不同工作时段尿进行了碘叠氮试验(IAT)。     

噻苯哒唑及其代谢产物在蛋鸡体内的残留分布及消除研究

目的探讨噻苯哒唑及其代谢物5-羟基噻苯哒唑在蛋鸡体内和鸡蛋中的残留分布及消除规律。方法选用30只健康蛋鸡进行试验,每天每只蛋鸡经口喂饲噻苯哒唑100mg,连续给药5天,分别于停药后第1天、第3天、第5天和第7天采集鸡蛋以及肝脏、肌肉、脂肪和心脏等组织制备组织匀浆。样品经乙腈提取,MCX固相萃取柱富集净化,超高效液相-串联质谱法测定噻苯哒唑及其代谢物的残留量。结果蛋鸡经口喂饲噻苯哒唑后,主要组织匀浆中5-羟基噻苯哒唑的含量显著高于噻苯哒唑,鸡蛋中两种药物的残留浓度最高。停药第一天时,组织中的残留水平(噻苯哒唑及5-羟基噻苯哒唑的浓度之和)顺序为肝脏>心脏>肌肉>脂肪。鸡蛋中噻苯哒唑的休药期约为7天。结论初步获得了噻苯哒唑及其代谢产物在蛋鸡组织中的残留水平及消除规律。     

接触氯乙烯的生物标志物

氯乙烯是一种可损害多器官的毒物 ,也是已知人类致癌物。其活性代谢中间产物具有强烈烷化作用 ,可在体内形成多种加合物。以氯乙烯的代谢和毒性机制为基础 ,研究了一系列其致机体损伤的指标 ,并试图寻找氯乙烯的生物标志物。本文就氯乙烯在体内的代谢转归及其活性中间产物、接触生物标志物、遗传学改变、血清癌蛋白和肝损伤指标等效应标志物以及基于其代谢酶基因多态性的易感生物标志物进行综述     

Studies on metabolism of fungicide benzoic acid, 1,3-dithiolan-2-ylidenehydrazide in vitro]

The metabolism of fungicide benzoic acid, 1,3-dithiolan-2-ylidenehydrazied (Yekuling) was studied quantitatively in rat liver microsomes and liver soluble fractions pretreated with phenobarbital (PB) and 3-methylcholanthrene (3-MC) by high pressure liquid chromatography. The experimental results indicated that the major metabolic pathway of Yekuling in vitro was hydrolysis. PB can enhance amidase activity to increase formation of benzoic acid and 1,3-dithiolan-2-ylidenehydrazine. 3-MC treatment elevated rat liver microsomal cytochrome P-448, enhancing S-oxidation of Yekuling. On the other hand, S-oxidation of Yekuling by rat liver microsomal MFO was NADPH-dependent.     

叶枯灵在大鼠体内的代谢研究

The metabolism of a fungicide Yekuling was studied in rat after oral administration. Four metabolites were isolated and purified by means of reverse-phase HPLC and TLC. They were identified to be acetic acid, 1,3-dithiolan-2-ylidenehydrazide; pyruvic acid, 1,3-dithiolan-2-ylidenehydrazide; benzoic acid and hippuric acid with UV and MS. The latter was further confirmed by chemical synthesis. The experimental results showed that Yekuling was metabolized extensively in rat. Yekuling was hydrolyzed by amidase to produce benzoic acid and 1,3-dithiolan-2-ylidenehydrazide. The latter was further acetylated by N-acetyltransferase to form acetic acid, 1,3-dithiolan-2-ylidenehydrazide, or condensed spontaneously to form pyruvic acid, 1,3-dithiolan-2-ylidenehydrazide. Benzoic acid was further conjugated with glycine to produce hippuric acid.     

气相色谱—质谱联机分离鉴定叶枯灵的代谢物

经口灌胃给大鼠叶枯灵35.8mg/kg,收集24小时尿,采用气相色谱—质谱(GC—MS)联机分离和鉴定了尿中的主要代谢物。据此推断,叶枯灵进入体内迅速水解,继而在氮原子上乙酰化,并用化学合成品对照确证,该法灵敏度高,分离效果好。     

Synthesis and renin inhibitory activity of novel angiotensinogen transition state analogues modified at the P(2)-histidine position

With the aim of finding new renin inhibitors with improved bioavailability properties, two angiotensinogen transition state analogues 1a and 1b, containing a novel unnatural amino acid at the P(2) position, namely the (2R,3S)- and (2S,3S)-2-amino-3-(1,3-dithiolan-2-yl)-3-hydroxypropanoic acid (ADHPA), have been synthesized and tested for human renin inhibitory activity and for chemical and enzymatic stability. Only compound 1a (the S-isomer) possessed a significant activity, which was lower than that of the corresponding histidyl derivative KRI-1314, and combined with a low stability to the gut enzyme chymotrypsin.     

The antioxidant activity of 2-(4(or 2)-hydroxyl-5-chloride-1,3-benzene-di-sulfanimide)-chitosan

Chitosan (CS) with two different molecular weights was modified by reacting with 4-hydroxyl-5-chloride-1,3-benzene-disulfo-chloride or 2-hydroxyl-5-chloride-1,3-benzene-disulfo-chloride to give new 2-(4(or 2)-hydroxyl-5-chloride-1,3-benzene-di-sulfanimide)-chitosan (2-HCBSAHCS, 2-HCBSALCS, 4-HCBSAHCS, 4-HCBSALCS). The structure of the derivatives was characterized by FT-IR and 13C NMR spectroscopy. The antioxidant activities of the derivatives were investigated employing various established systems, such as hydroxyl radical (.OH)/superoxide anion (O2.-) scavenging/reducing power and chelating activity. All the derivatives showed stronger scavenging activity on hydroxyl radical than chitosan and ascorbic acid (Vc), and IC50 of 4-HCBSAHCS, 4-HCBSALCS, 2-HCBSAHCS and 2-HCBSALCS was 0.334, 0.302, 0.442, 0.346 mg/mL, respectively. The inhibitory activities of the derivatives toward superoxide radical by the PMS-NADH system were strong. The results showed that the superoxide radical scavenging effect of 2-(4(or 2)-hydroxyl-5-chloride-1,3-benzene-di-sulfanimide)-chitosan was higher than chitosan. The derivatives had obviously reducing power and slight chelating activity. The data obtained in in vitro models clearly establish the antioxidant potency of 2-(4(or 2)-hydroxyl-5-chloride-1,3-benzene-disulfanimide)-chitosan.     

Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall

Phosphonate inhibitors of antigen 85C were prepared. The inhibitors, comprising a phosphonate moiety, mycolic acid mimetic and a trehalose surrogate, contain substituted benzyl alcohols, N-(omega-hydroxyalky)phthalimide, 2-phenylethanol or 4-(phthalimido)butanol as trehalose mimetics, and an alkyl chain of different lengths mimicking the mycolic acid side chain. The best compounds inhibited the mycolyltransferase activity of antigen 85C with IC(50) in the low micromolar range and inhibited the growth of Mycobacterium avium in culture. The best compounds in the 3-phenoxybenzyl- and omega-(phthalimido)alkoxy series, ethyl 3-phenoxybenzyl butylphosphonate (4a) and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl ethyl heptylphosphonate (5c) displayed IC(50) values of 2.0 and 1.3 microM, respectively, in a mycolyltransferase inhibition assay. In a M. avium growth inhibition assay MIC of 4a and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl ethyl nonylphosphonate (5d) were 248.8 and 84.5 microg/mL, respectively.     

The rapid hydrolysis and efficient absorption of triglycerides with octanoic acid in the 1 and 3 positions and long-chain fatty acid in the 2 position

We describe rapid hydrolysis of triglycerides with medium-chain fatty acids in the 1 and 3 positions and a long-chain fatty acid in the 2 position. The triglycerides, 2-linoleoyl-1,3-dioctanoyl glycerol (8L8) and 2-oleoyl-1,3-dioctanoyl glycerol, hydrolyzed more rapidly than triglycerides comprising all long-chain fatty acids. The in vitro hydrolysis rate of 8L8 was similar to that of a medium-chain triglyceride of octanoic and decanoic acids in random positions. From intestinal recovery of 14C 45 min after injection into the isolated, irrigated loop of the small intestine of an anesthetized rat, the amount of 2-[1-14C]linoleoyl-1,3-dioctanoyl glycerol absorbed was greater than 2 1/2 times that of its long-chain analog, 2-[1-14C]linoleoyl-1,3-dioleoyl glycerol. These data support the ease of hydrolysis and absorption of 1,3-dioctanoyl triglycerides with long-chain fatty acids in the 2 position.     

Synthesis and anticonvulsant properties of new acetamide derivatives of phthalimide, and its saturated cyclohexane and norbornene analogs

The synthesis and anticonvulsant properties of new piperazine or morpholine acetamides derived from 2-(1,3-dioxoisoindolin-2-yl)-, 2-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl-) and (3,5-dioxo-4-azatricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)-acetic acid were described. Initial anticonvulsant screening was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective in the MES screen. The most active was 2-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindoline-1,3-dione (12) that revealed protection in the electrically induced seizures at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration in mice respectively. This molecule given orally in rats at a dose of 30 mg/kg was more potent than reference anticonvulsant--phenytoin.