人粒细胞—巨噬细胞集落刺激因子转移表达及对慢性乙型肝炎细胞免…

为了探讨人ＧＭ－ＣＳＦ基因转移表达对慢性乙型肝炎患者细胞免疫功能的影响，运用携带人ＧＭ－ＣＳＦ基因的重组腺病毒转染慢性乙型肝炎患者ＰＢＭＣｓ，表明以重组腺病毒为载体的人ＧＭ－ＣＳＦ基因在转染细胞中，可持续表达１．２６±０．０６５￣２．０９±０．１１ｎｇｓ·ｍｌ＾－１·２４ｈ＾－１水平２６天左右。通过观察慢性乙型肝炎患者ＰＢＭＣｓ在ＧＭ－ＣＳＦ基因转染前后及分泌ＧＭ－ＣＳＦ细胞和慢性乙型肝炎患者ＰＢ     

盐酸伪麻黄碱在人体中的药物动力学

采用反相高效液相色谱外标法测定人血清中伪麻黄碱浓度，并测定８例志愿受试者伪麻黄碱血药浓度，并计算分析药物动力学参数，结果单剂量口服９０ｍｇ盐酸伪麻黄碱后，药时曲线呈一室模型。Ｔｍａｘ＝１．７±１．１ｈ，Ｃｍａｘ＝３６４±９４ｎｇ·ｍｌ－１，ＡＵＣ（０～∞）＝２６６２±３０３（ｎｇ·ｈ·ｍｌ－１），Ｔ１／２＝４．０±１．０ｈ，Ｋａ＝２．４±１．４ｈ－１，Ｋｅ＝０．１９±０．０４ｈ－１，Ｖｄ＝０．１９±０．０５ｍｇ，Ｃｌ＝０．０３±０．０１ｍｇ·ｈ－１。     

高效液相色谱法测定盐酸氟桂利嗪血浆浓度及其药物动力学

以高效液相色谱法测定血浆中的盐酸氟桂利嗪浓度。色谱条件：紫外检测波长２１０ｎｍ；柱ＳｐｈｅｒｉｓｏｒｂＣ８１５０×４．６ｍｍ；流动相：甲醇（８０％）∶水（１５％）∶（０．０５ｍｏｌ·Ｌ－１ＮＨ４Ｈ２ＰＯ４＋０．０２５ｍｏｌ·Ｌ－１Ｈ３ＰＯ４）缓冲液（５％）。最低检测限１０ｎｇ·ｍｌ－１。药物动力学为一室模型，其参数（Ｔ１／２（Ｋ）２．３８～２．６４ｈ，Ｔｍａｘ２．３０～２．４３ｈ，Ｃｍａｘ１３５．１３～１４３．９６ｎｇ·ｍｌ－１。     

Pharmacokinetics of recombinant human granulocyte macrophage colony-stimulating factor in Macaca mulata

目的：研究重组人粒细胞巨噬细胞集落刺激因子（ｒｈＧＭＣＳＦ）在恒河猴体内的药物动力学．方法：用酶连接免疫吸附测定法检测血浆中ｒｈＧＭＣＳＦ的含量．结果：ｉｖｒｈＧＭＣＳＦ后血药浓度时间曲线符合三房室模型．第１，２和３相的Ｔ１２分别为００５－００７ｈ，０１４－０５８ｈ和１４－４１ｈ．ＡＵＣ随剂量成比例增加．ｉｖ高剂量和低剂量的Ｃｌ和Ｋ１０都相似．ｓｃｒｈＧＭＣＳＦ后血药浓度的峰值为０９３±０１６μｇ·Ｌ－１，达峰时间为２６５±０１４ｈ，生物利用度为０６１．结论：恒河猴ｒｈＧＭＣＳＦ药物动力学数据为临床试验提供有用参考．     

盐酸特拉唑嗪胶囊人体生物利用度及药物动力学研究

目的：对盐酸特拉唑嗪胶囊的人体内生物利用度进行研究。方法：单剂量口服盐酸特拉唑嗪胶囊和片剂２ｍｇ。血药浓度采用ＨＰＬＣ测定，数据用３Ｐ８７计算药动学参数。结果：盐酸特拉唑嗪胶囊剂的药动学参数：Ｋａ为８．２±４．０ｈ－１，Ｔ１／２为８．２±２．５ｈ，Ｔｍａｘ为０．６１±０．１１ｈ，Ｃｍａｘ为４３．５±８．５ｎｇ·ｍｌ－１，ＡＵＣ为３６７．４±３４．６ｎｇ·ｈ·ｍｌ－１；盐酸特拉唑嗪片剂的药动学参数：Ｋａ为６．４±７．４ｈ－１，Ｔ１／２为７．４±２．１ｈ，Ｔｍａｘ为０．９±０．４ｈ，Ｃｍａｘ为４３．１±４．８ｎｇ·ｍｌ－１，ＡＵＣ为３７１．３±４４．４ｎｇ·ｈ·ｍｌ－１。结论：两种剂型的药物动力学参数之间差异均无显著性（Ｐ＞０．０５），胶囊剂的相对生物利用度为９９．８８％。     

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

健康志愿者１０名，随机交叉口服硫酸吗啡控释片（ＣＲＭＳ）３０ｍｇ（３０ｍｇ×１）和硫酸吗啡普通片（ＩＲＭＳ）２０ｍｇ（１０ｍｇ×２），分别于服药前后各时点取静脉血，用ＧＣＭＳ测定血浆中吗啡含量。以药代软件程序处理，分别求得ＣＲＭＳ和ＩＲＭＳ的Ｃｍａｘ为１９．３８±３．８０和２１．２７±６．２１ｎｇ／ｍｌ；ｔｍａｘ为２．３６±０．３７ｈ和０．５５±０．１６ｈ；ｔ１／２β为３．５３±０．８７ｈ和３．０３±０．７４ｈ，曲线下面积ＡＵＣ为１４５．１５±１７．６５和９３．０８±１６．６５ｎｇ·ｈ／ｍｌ。癌症病人多次口服硫酸吗啡至稳态，ＣＲＭＳ和ＩＲＭＳ的峰浓度分别为２７．４３±０．３３ｎｇ／ｍｌ，２２．６８±０．１６ｎｇ／ｍｌ；谷浓度分别为１９．４５±１．４４ｎｇ／ｍｌ；１８．１４±０．４９ｎｇ／ｍｌ。     

高效液相色谱法测定人体地尔硫及其主要代谢物的药物动力学

用高效液相色谱法（ＨＰＬＣ）测定人血清中地尔硫（ＤＺ）及去乙酰地尔硫（Ｍ１）浓度。以ＳｐｈｅｒｉｓｏｒｂＯＤＳ，５μｍ为层析柱，流动相：甲醇∶乙腈∶水（６０∶１０∶３０），检测波长２３７ｎｍ，以盐酸普罗帕酮为内标。检测范围：ＤＺ为５．４５～２７２．５ｎｇ·ｍｌ－１，Ｍ１为５．８５～２９２．５ｎｇ·ｍｌ－１。最低检测浓度：ＤＺ为２．８７ｎｇ·ｍｌ－１，Ｍ１为１．９９ｎｇ·ｍｌ－１。平均回收率ＤＺ为１０１．８８％，Ｍ１为１０１．７２％，ＲＳＤ均在１２％以内。并对４名受试者口服９０ｍｇ盐酸地尔硫片后，其药时曲线经微机用ＰＫＢＰ－Ｎ１程序拟合，ＤＺ为一房室开放模型，Ｍ１为二房室开放模型，求得ＤＺ和Ｍ１的Ｔ１／２分别为５．６±１．５ｈ和１４±７ｈ。     

常咯啉在实验性心律失常狗的药代动力学－药效动力学分析

用Ｈａｒｒｉｓ冠脉结扎法诱发的心律失常狗研究常咯啉药代动力学－药效动力学。７只狗按８３．３３μｇ·ｋｇ￣（－１）·ｍｉｎ￣（－１）静脉滴注６０ｍｉｎ，在给药期间和停药后不同时间记录ＥＣＧ及测定血药浓度。Ｃ－Ｔ数据用药代程序计算药代参数；药效数据用药代－药效同步分析模型计算药效动力学参数，Ｋ１０，Ｔ１／２，Ｖｄ，Ｃｌ分别为０．００８７ｍｉｎ￣（－１），７８．０３ｍｉｎ，４０．５５ｍｌ·ｋｇ￣（－１）和０．４２１ｍｌ·ｋｇ￣（－１）·ｍｉｎ￣（－１）；Ｋｅ０和Ｃｅ（５０）分别为０．００４８ｍｉｎ￣（－１）和２．０１μｇ·ｍｌ￣（－１）.     

舌下片与硝苯地平片血药浓度测定与药物动力学研究

本文用毛细管气相色谱法（ＧＣ─ＥＣＤ）测定了血清中硝苯地平浓度。并对９名受试者服２０ｍｇ硝苯地平舌下片和国产普通片的药物动力学进行了比较研究。舌下片、普通片主要动力学参数为：Ｋａ（ｈ￣－１）＝７．５５、２．０８；ｋｅ（ｈ￣－１）＝０．３１、０．２１；Ｖ／Ｆ［ｍｇ／（ｎｇ／ｍｌ）］＝０．１６、０．２９；Ｔ＿ｐｅａｋ（ｈ）＝１．６８、２．２７；Ｃ＿ｍａｘ（ｎｇ／ｍｌ）＝１００．０５、５８．０８。结果舌下片吸收快、峰浓度高、起效时间明显提前。     

盐酸特拉唑嗪在健康人体内的药物动力学

目的：在８名健康志愿者体内研究了国产盐酸特拉唑嗪胶囊和进口片剂的药物动力学和生物利用度。方法：受试者交叉口服单剂量（２ｍｇ）盐酸特拉唑嗪胶囊和片剂后,采用高效液相色谱法和荧光检测器测定血药浓度。结果：胶囊和片剂的药时曲线均符合二室模型,其Ｔｍａｘ分别为１．３±０．６ｈ和１．３±０．４ｈ,Ｃｍａｘ分别为４９．５±８．６ｎｇ·ｍｌ－１和５０．３±５．２ｎｇ·ｍｌ－１,ＡＵＣ０→∞分别为５３６．５±３９．８ｎｇ·ｍｌ－１和５８６．６±５２．８ｎｇ·ｍｌ－１·ｈ,测试药品的相对生物利用度为９２．３０％±１２．９１％。结论：经方差分析两药药物动力学参数间差异均无显著性（Ｐ＞０．０５）;结果表明两药具有生物等效性。     

alpha-glucosidase (CHO) (Genzyme)

Genzyme General is developing recombinant human alpha-glucosidase, produced in mammalian cell culture, as a potential treatment for Pompe disease. By July 2004, enrollment was completed in two clinical trials and an observational study in adults. Genzyme was planning to file for regulatory approval in Europe during 2004, followed by filings in the US and Japan in mid-2005.     

(S)-oxybutynin (Sepracor)

Sepracor is developing (S)-oxybutynin, a single-isomer version of Alza's Ditropan (racemic oxybutynin), a muscarinic acetylcholine receptor antagonist, as a potential treatment for urinary incontinence.     

Allosteric interaction of zinc with recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) GABA(A) receptors

In a recent study we have provided evidence that inhibition of native GABA(A) receptors by zinc depends primarily on the allosteric modulation of receptor gating. Both the kinetics and the sensitivity of the GABA(A) receptor to zinc depend on subunit composition, especially on the presence of the gamma(2) subunit. To analyze the mechanism of action of zinc its effects have been tested on recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors expressed in HEK 293 cells. The currents produced by ultrafast application of GABA have been measured to assess the impact of zinc ions on GABA(A) receptor gating with resolution corresponding to the time scale of synaptic currents. While, as expected, zinc markedly reduced the peak amplitude of alpha(1)beta(2)-mediated currents, its effect on kinetics was significantly different from that observed for alpha(1)beta(2)gamma(2). In particular, unlike alpha(1)beta(2)gamma(2), zinc did not affect the onset of alpha(1)beta(2)-mediated responses. Moreover, zinc increased the extent of desensitisation of alpha(1)beta(2)gamma(2) receptors and reduced desensitisation of alpha(1)beta(2) ones. Quantitative analysis suggests that zinc exerts an allosteric modulation on both alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors. Zinc effects on alpha(1)beta(2)gamma(2) were qualitatively similar to those reported for native receptors.     

Di(isononyl) phthalate (DINP) and di(isodecyl) phthalate (DIDP) are not mutagenic

Recently there have been reports of liver and kidney tumors in rodents following long-term exposure to di(isononyl) phthalate (DINP). Mechanistic studies suggested that the liver tumors were a consequence of peroxisomal proliferation, whereas the kidney tumors (found only in male rats) were associated with induction of alpha(2u)-globulin. Because both peroxisomal proliferation and alpha(2u)-globulin are considered to be non-genotoxic carcinogenic processes, it seemed appropriate to investigate the genotoxic potential of DINP. Additional studies were also conducted on di(isodecyl) phthalate (DIDP), a structurally related substance that also induces peroxisomal proliferation, although it has not been tested in a carcinogenicity bioassay. The DINP was tested in Salmonella, in vitro cytogenetics and mouse micronucleus assays, whereas DIDP was evaluated in a mouse micronucleus test. All of these tests produced negative results, i.e. neither phthalate was mutagenic in any of the test systems. These data are consistent with results of other published and unpublished genotoxicity tests and provide support for the hypothesis that the liver and kidney tumors induced by DINP were the result of non-genotoxic processes.     

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.     

4（R）—（6—氨基—9H—嘌呤—9—基）—2（R）—（羟甲基）四氢呋喃—3（R）—醇的合成

为寻找抗HIV化合物,我们以D－核糖为原料,经甲基化、硅烷基化、还原裂解反应制得重要中间体1－脱氧核糖（5）,再通过形成环状亚砜化合物,与NaN3发生反应后,经过还原、缩合、环合、氨化、脱保护基反应制得异脱氧腺嘌呤核苷（1）,各步反应收率均超过70％。其抗HIV活性测定尚在进行中。     

Two-generation reproduction toxicity studies of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.     

1,2-环己二胺柠檬酸铂(Ⅱ)及异柠檬酸铂(Ⅱ)的合成和抗癌活性

报道了1,2-环己二胺异柠檬酸铂(Ⅱ)及1,2-环己二胺柠檬酸铂(Ⅱ)的合成及鉴定方法。抗癌试验表明前者在40及80mg/kg 剂量下对小鼠 L1210、P388及S180均有明显的抑瘤作用,且有部分动物可治愈;后者对 L1210也有明显的抑瘤作用,但较前者为弱。     

4（R）—（6—氨基—9—嘌呤基）—2（R）—（羟甲基）四氢呋喃—3（R）—醇的合成

为寻找抗免疫缺陷病毒化合物,以D－核糖为原料,经甲基化、硅烷基化、还原裂解反应制得重要中间体1－脱氧核糖（5）,再通过形成环状亚砜化合物,与NaN3发生反应后,经过还原、缩合、环合、氨化、脱保护基反应制得异脱氧腺嘌呤核苷（1）,各步反应收率均超过70％。