~(19)F体内核磁共振技术观测5-氟尿嘧啶在小鼠植入肿瘤中的摄取与代谢

应用体内１９ＦＮＭＲ谱观察并定量评价了５－氟尿嘧啶（５－ＦＵ）在荷Ｓ１８０瘤和Ｂ１６瘤小鼠肿瘤内的摄取和代谢动力学过程．５－ＦＵ２００ｍｇ·ｋｇ－１ｉｖ后，药物在Ｓ１８０和Ｂ１６瘤内的主要产物为其活性产物氟代核苷／核苷酸（ＦＮＵＣ），同时可检测到少量的降解产物α－氟－β－丙氨酸（ＦＢＡＬ）和α－氟－β－脲基丙酸（ＦＵＰＡ）．在Ｓ１８０瘤内，５－ＦＵ摄取，消除以及ＦＮＵＣ的生成有较大的个体变异，５－ＦＵ的消除半衰期ｔ１／２ｋｅ为４１．５－８４．８ｍｉｎ，ＦＮＵＣ生成ｔ１／２ｒ为２６．０－９１．９ｍｉｎ．当甲氨蝶呤（ＭＴＸ）与５－ＦＵ合用时，５－ＦＵ在Ｓ１８０瘤内的活化代谢过程明显加快，ｔ１／２ｋｅ缩短为２９．９－４３．４ｍｉｎ，ＦＮＵＣ的生成速率显著提高，生成量增加．５－ＦＵ在Ｂ１６瘤内的摄取及代谢过程的个体波动较小，其ｔ１／２ｋｅ为３９±５ｍｉｎ，ＦＮＵＣ的生成ｔ１／２ｒ为６０±７ｍｉｎ，在Ｂ１６瘤内，ＭＴＸ的合用不能明显加快５－ＦＵ转化为ＦＮＵＣ的反应，也不改变５－ＦＵ在瘤内的消除模式．上述结果表明，５－ＦＵ对肿瘤的化疗作用与肿瘤灌注５－ＦＵ在瘤组织内的摄取和活化代谢过程密切相关，亦可受到合用药物的影响．     

Detection of DNA damage in peripheral lymphocytes by 7 compounds using comet assay

目的：检测过氧化氢（Ｈ２Ｏ２）、甲磺酸乙酯（ＥＭＳ）、丝裂霉素Ｃ（ＭＭＣ）、二甲基亚硝胺（ＤＭＮＡ）、苯并（ａ）芘（ＢａＰ）、２氨基芴（２ＡＦ）和环磷酰胺（ＣＰ）诱发小鼠、大鼠及人外周血淋巴细胞ＤＮＡ单链断裂．方法：体外单细胞微量凝胶碱性电泳试验（慧星试验）．结果：除ＥＭＳ０９７ｍｍｏｌ·Ｌ－１在小鼠淋巴细胞，ＭＭＣ３０μｍｏｌ·Ｌ－１在小鼠、人淋巴细胞中呈阴性外，其余均为阳性．最低可检测浓度分别为Ｈ２Ｏ２１μｍｏｌ·Ｌ－１，ＥＭＳ０４８ｍｍｏｌ·Ｌ－１，ＢａＰ５０μｍｏｌ·Ｌ－１，ＣＰ２０ｍｍｏｌ·Ｌ－１，ＭＭＣ１０μｍｏｌ·Ｌ－１，ＤＭＮＡ２７３ｍｍｏｌ·Ｌ－１，２ＡＦ６２５μｍｏｌ·Ｌ－１．ＣＰ、ＢａＰ、２ＡＦ需经Ｓ９Ｍｉｘ代谢活化才显示毒性．结论：彗星试验检测出ＭＭＣ诱导大鼠，ＥＭＳ诱导大鼠和人，以及Ｈ２Ｏ２、ＤＭＮＡ、ＢａＰ、ＣＰ和２ＡＦ诱导小鼠、大鼠和人外周血淋巴细胞ＤＮＡ单链断裂损伤．     

2，4，5－三氯苯胺体外代谢生成一氧化碳的途径与三卤苯胺的构效关系研究

实验证明，２，４，５－三氯苯胺（ＴＦＡ）与大鼠肝微粒体、ＮＡＤＰＨ和分子氧共存时可经历脱氟、对位羟化和氧化释放一氧化碳（ＣＯ）等代谢过程。与对照组（Ｃｏｎｔｒｏｌ）微粒体相比，苯巴比妥（ＰＢ）或地塞米松（ＤＥＸ）诱导的微粒体，使２，４，５－ＴＦＡ代谢降解为ＣＯ的速度分别提高３～８倍，脱氟速度提高１～４倍，对位羟化速度提高１．９～１．５倍，底物消失速度提高２～２．５倍。而２，４，６－ＴＦＡ，２，４，５－与２，４，６－三氯苯胺（ＴＣＡ）和１，２，４－三氟苯（ＴＦＢ）等经一般代谢几乎不产生ＣＯ，ＰＢ或ＤＥＸ诱导的微粒体使其转化为ＣＯ的能力也低至可忽略不计。同时，在Ｃｏｎｔｒｏｌ或ＰＢ微粒体中，２，４，５－ＴＦＡ的底物消失与脱氟两种速度比平均约为１：１，在ＤＥＸ微粒体中，两种速度比则为１：２，而２，４，６－ＴＦＡ在ＰＢ微粒体中的两种速度比为１：０．６。两个ＴＦＡ的对位羟化速度相对较慢，而两个ＴＣＡ几乎不能进行对位羟化。     

2,4,5—三氟苯胺体外代谢生成一氧化碳的途径与三卤苯胺的构…

实验证明，２，４，５－三氟苯胺（ＴＦＡ）与大鼠肝微粒体、ＮＡＤＰＨ和分子氧共存时可经历脱氟、对位羟化和氧化释放一氧化碳（ＣＯ）等代谢过程。与对照组（Ｃｏｎｔｒｏｌ）微粒体相比，苯巴比妥（ＰＢ）或地塞米松（ＤＥＸ）诱导的微粒体，使２，４，５－ＴＦＡ代谢降解为ＣＯ的速度分别提高３－８倍，脱氟速度提高１－４倍，对位羟化速度提高１．９－１．５倍，底物消失速度提高２－２．５倍，而２，４，６－ＴＦＡ，２，４，     

四甲基吡嗪对内毒素血症小鼠的保护作用及其与血小板活化因子的关系(英文)

研究四甲基吡嗪（ＴＭＰ）对内毒素血症小鼠的保护作用及其与血小板活化因子（ＰＭ）的关系．方法：给 ＴＭＰ处理的小鼠 ｉｖ　 ＬＰＳ,观察其存活率及血清ＰＡＦ水平．体外用ＬＰＳ刺激小鼠ＰＭφ,测定 ＰＭ及 ＰＬＡ２和乙酰辅酶 Ａ乙酰基转移酶的活性．结果：ＴＭＰ明显提高小鼠存活率和降低血清ＰＡＦ水平．体外,ＴＭＰ（０．０５－５０μｍｏｌ· Ｌ－１）剂量依赖性减少ＰＭφ释放ＰＡＦ［１２．７±１．６）,（８．９±１．２）,（６．９±０．８）,（５．５±１．０）μｇ·Ｌ－１,Ｐ＜０．０１］,降低ＰＬＡ２活性肝（１４９．９±２．８）（１１７．５±２．０）,（８９．６±２．０）,（７５．０±２．８） Ｕ,Ｐ＜０．０１］和乙酰辅酶Ａ乙酰基转移酶活性［ＰＡＦ（９．５±０．７）,（５．２± ０．７）,（２．９±０． ３）,（２．５±０． ３）μｇ· ｇ－１（ｐｒｏｔｅｉｎ）·ｍｉｎ－１, Ｐ＜０．０１］．结论： ＴＭＰ对内毒血症小鼠有保护作用,其机制是通过抑制 ＰＬＡ２和乙酰辅酶Ａ乙酰基转移酶的活性而抑制ＰＡＦ的合成。     

用兔血小板膜受体筛选血小板激活因子（TAF）拮抗剂

在兔血小板膜中，血小板激活因子（ＰＡＦ）结合部位显示高度亲合性（Ｋｄ＝０．１±０．００７ｎｍｏｌ／Ｌ）、饱和性、显著的药理学特异性，其最大结合容量为２．８９±０．３２ｐｍｏｌ／ｍｇ蛋白。３Ｈ－ＰＡＦ饱和结合浓度为０．２ｎｍｏｌ／Ｌ。等温线表明为单一结合位点。红曲霉（Ｍｏｎａｓｃｕｓｓｐ．Ｆ４００）代谢产物中的小成份Ｄ（２Ａ）和Ｃ（４Ａ）与ＰＡＦ竞争受体结合部位，它们是ＰＡＦ的拮抗剂。Ｄ２Ａ的ＩＣ５０为３．１６×１０－５ｍｏｌ／Ｌ，Ｃ４Ａ的ＩＣ５０为３．０３×１０－５ｍｏｌ／Ｌ。     

家兔静注水杨醛-N'-(2-呋喃硫羰基)腙铜配合物的药物动力学

目的：研究水杨醛－Ｎ′－（２－呋喃硫羰基）腙铜配合物（ＣＳＦＣ）在兔体内的药物动力学。方法：１０只家兔静脉注射ＣＳＦＣ５ｍｇ·ｋｇ－１，用反相ＨＰＬＣ法测定血清药物浓度。结果：ＣＳＦＣ的血药浓度－时间曲线符合二室开放模型，主要药动学参数为：Ｔ１２α＝３．４±１．７ｍｉｎ，Ｔ１２β＝６５．５±１４．６ｍｉｎ，Ｋ１２＝０．１１８３±０．０６６９ｍｉｎ－１，Ｋ２１＝０．０２２８±０．００６５ｍｉｎ－１，Ｋ１０＝０．１２０２±０．０４０７ｍｉｎ－１，Ｖ０＝０．３０５±０．１８４Ｌ·ｋｇ－１，ＣＬ＝１．８９６±０．４７０Ｌ·ｋｇ－１·ｈ－１，ＡＵＣ＝１７０．１±５７．０ｍｇ·ｍｉｎ－１·Ｌ－１。结论：ＣＳＦＣ在兔体内分布迅速而广泛，消除也较快。家兔静注５ｍｇ·ｋｇ－１，可维持抗结核杆菌有效血浓度６ｈ。     

4，5－二氢－6－［（苯乙酰基－哌嗪基）苯基］－5－甲基－3（2H）－哒嗪酮对血小板聚集，花生四烯酸代谢及cAMP含量的影响

４，５－二氢－６－［（苯乙酰基－哌嗪基）苯基］－５－甲基－３（２Ｈ）－达嗪酮（ＳＭＤ。）０．１一２．５ｐｍｏｌ·Ｌ能使血小板激活因子（ＰＡｎ及血栓素Ａ，类似物Ｕ４６６１９诱导的兔血小板聚集剂量一效应曲线不移且最大反应降低。其ｐＤ２分别为６．０±ｓ０．４及６．１±ｓ０．３ＳＭⅡ４还能抑制ＡＤＬ花生四烯酸（ＡＡ）及Ｕ４６６１９诱导的人血小板聚集，其ＩＣ（５０）分别是１２，１３及１．６μｍｏｌ．Ｌ．用放射性薄层层折及放射免疫测定法分别检测血小板ＡＡ代谢产物及ｃＡＭＰ含量表明，ＳＭⅡ４对血小板ＡＡ代谢没有显著影响，但能剂量依赖性地升高血小板内ｃＡＭＰ含量，ＰＡＦμｍｏｌ·Ｌ不能改变此作用     

2，4，5－三氟苯甲酸合成路线图解

２，４，５－三氟苯甲酸合成路线图解张跃臻（阜新市化工研究所，辽宁１２３０００）ＧＲＡＰＨＩＣＡＬＳＹＮＴＨＥＴＩＣＲＯＵＴＥＳＯＦ２，４，５－ＴＲＩＦＬＵＯＲＯＢＥＮＺＯＩＣＡＣＩＤ￥ＺＨＡＮＧＹｕｅｎ－Ｚｈｅｎ（ＦｕｘｉｎＩｎｓｔｉｔｕｔｅｏｆＣｈ...     

没食子酸丙酯在麻醉大鼠体内的药物代谢动力学

用高效液相色谱（ＨＰＬＣ）测定大鼠给予没食子酸丙酯（ＰＧ）３０ｍｇ·ｋｇ－１后０．５，１．５，３．５，７．０，１０．０和３０．０ｍｉｎ的血浆浓度，分析所得血药－时浓度曲线符合二室开放性模型。大鼠ｉｐ双－对硝基苯磷酸酯钠（ＢＮＰＰ）３．４ｍｇ·ｋｇ－１，再ｉｖＰＧ３０ｍｇ·ｋｇ－１，所测ＰＧ血浆浓度与对照组有显著不同，其药物代谢动力学参数ｔ１／２α，ｔ１／２β，ｋ１０，ＡＵＣ以及ＭＲＴ（０－Ｉｎ）均较对照组延长或增加，两组间各参数比较均有显著或非常显著性差异；而ＣＬ也较对照组降低１倍；并且于ｉｖＰＧ５，１０及２０ｍｉｎ后其肝脏及血浆中ＰＧ含量也较对照组增高，两组之间比较均有显著性差异。结果表明ＢＮＰＰ对ＰＧ在大鼠体内的代谢速度有显著影响．     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Polymorphisms in genes involved in neurotransmission in relation to smoking

Smoking behavior is influenced by both genetic and environmental factors. The genetic contribution to smoking behavior is at least as great as its contribution to alcoholism. Much progress has been achieved in genomic research related to cigarette-smoking within recent years. Linkage studies indicate that there are several loci linked to smoking, and candidate genes that are related to neurotransmission have been examined. Possible associated genes include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D₁, D₂, and D₄ receptors, dopamine transporter, and serotonin transporter genes. There are other important candidate genes but studies evaluating the link with smoking have not been reported. These include genes encoding the dopamine D₃ and D₅ receptors, serotonin receptors, tyrosine hydroxylase, trytophan 2,3-dioxygenase, opioid receptors, and cannabinoid receptors. Since smoking-related factors are extremely complex, studies of diverse populations and of many aspects of smoking behavior including initiation, maintenance, cessation, relapse, and influence of environmental factors are needed to identify smoking-associated genes. We now review genetic polymorphisms reported to be involved in neurotransmission in relation to smoking.     

Genotoxic effects of chlorophenoxy herbicide diclofop-methyl in mice in vivo and in human lymphocytes in vitro

Diclofop-methyl (DM) is a chlorophenoxy derivative used in large quantities for the control of annual grasses in grain and vegetable crops. In this study, the genotoxic effects of DM were investigated by measuring chromosomal aberrations (CAs) in mouse bone-marrow cells and CA and the comet assay in human peripheral lymphocytes. Mice were treated with 15.63, 31.25, 62.5, and 125?mg/kg body weight of DM intraperitoneally for 24 hours, and 15.63-, 31.25-, 62.5-, 125-, and 250-µg/mL concentrations were applied to human lymphocytes for both 24 and 48 hours. In in vivo treatments, DM significantly, but not dose dependently, increased the total chromosome aberrations, compared to both negative and solvent controls. Cell proliferation was significantly, but not dose dependently, affected by all doses. In in vitro treatments, DM (except 15.63 µg/mL) significantly and dose dependently increased the frequency of chromosome aberrations. Also, 250 µg/mL of 48-hour treatment was found to be toxic. Cell proliferation was significantly and dose dependently affected by DM applications, when compared to negative control. In in vitro treatments, DM significantly decreased the mitotic index only at the highest concentration for 24 hours, and 62.5- and 125-µg/mL concentrations for 48 hours. In the comet assay, a significant and dose-dependent increase in comet-tail intensity was observed at 62.5-, 125-, and 250-µg/mL concentrations. The mean comet-tail length was significantly increased in all concentrations. Our results demonstrate that DM is genotoxic in mammalian cells in vivo and in vitro.     

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood–brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.     

2010调脂治疗领域进展

2010年在调脂治疗领域针对他汀治疗心血管病的防治又进行了许多探索。本文通过综述他汀类药物的国际大规模临床试验结果,重新评价了他汀类药物在冠心病一级预防和冠心病二级预防中的地位,阐明了强化他汀治疗的意义;对他汀的心肾保护作用和安全性新证据进行了说明。