左旋18-甲基炔诺酮肟与左旋18-甲基炔诺酮的抗生育作用比较

本文比较了LNGO和LNG对大鼠的抗生育作用,结果表明,LNGO在剂量为10mg/kg·d时可以完全抑制大鼠着床,剂量为40,60mg/kg·d时有明显抗早孕作用。光电镜观察提示,剂量为10mg/kg·d时,对大鼠子宫内膜间质细胞和上皮细胞均有影响。组织培养研究发现,对体外人胎盘滋养层细胞有直接损伤作用。LNG对大鼠未见抗着床及抗早孕作用,对大鼠子宫内膜和体外人胎盘滋养层细胞也均未见明显作用。     

溶剂系统对18-甲基炔诺酮渗透皮肤的影响

本文对乙醇、水、油酸等溶剂系统对左旋18-甲基炔诺酮(简称LNG)及消旋18-甲基炔酮(简称NG)渗透皮肤的影响进行了研究。实验采用Vaila-Chien双室扩散池及成人离体皮肤。结果表明,在80%乙醇水溶液中,LNG与NG的皮肤渗透速率比用生理盐水提高5～6倍,其中NG的皮肤渗透速率比LNG高1～2倍.含水乙醇与油酸复合使用时,对LNG通透皮肤具有明显的协同促进作用。当油酸—80%乙醇(0.75:9.25v/v)作为复合溶剂时。所获得的LNG皮肤渗透速率为0.53μg/cm²·h,分别比油酸或80%乙醇单独使用时提高29倍和3倍。提示正确地采用复合溶剂系统,能有效地提高LNG或NG透皮速率。     

α-苦瓜籽蛋白对体外培养人胚泡滋养层和蜕膜细胞的影响

通过观察α-苦瓜籽蛋白对体外培养的人胚泡滋养层细胞形态、HCG分泌功能的影响,以及对人蜕膜细胞形态改变,探讨了α-苦瓜籽蛋白抗早孕的细胞学作用机理。0.13,0.50,2.00,8.00 μg/mlα-苦瓜籽蛋白对滋养层细胞形态有不同程度的损伤,时间越长、浓度越大则损伤越重;滋养层细胞分泌HCG功能受到明显抑制,同时对蜕膜细胞也有一定的毒性作用。实验证明:α-苦瓜籽蛋白具有直接损伤滋养层细胞以及毒害蜕膜细胞而达到抗早孕的作用。     

氯丙嗪对大鼠卵巢颗粒细胞损伤及其作用机制

目的 通过氯丙嗪染毒体外培养的大鼠卵巢颗粒细胞,研究其对卵巢颗粒细胞的毒性作用,并初步探讨可能的作用机制.方法 对未成熟的Wistar大鼠卵巢颗粒细胞进行原代培养,用不同浓度的氯丙嗪(0、0.1、1和10μmol/L)染毒24 h.MTT法检测细胞相对活力,ELISA法检测培养液中孕酮(P)和雌二醇(E<,2>)的含量...     

氟西汀对大鼠肺动脉平滑肌细胞体外增殖的影响

目的观察氟西汀对大鼠肺动脉平滑肌细胞体外增殖的影响并探讨其可能的机制。方法采用肺动脉平滑肌细胞(PASMC)体外培养的方法,观察氟西汀对PASMC增殖及细胞周期的影响。实验细胞分为4组:①正常对照组(Control):培养液含10%胎牛血清的高糖DMEM;②5-HT组:培养液含10%胎牛血清的高糖DMEM,其中加入终浓度为5μg/mL的5-HT的培养液100μL;③Flu组:培养液含10%胎牛血清的高糖DMEM,其中加入终浓度为10μg/mL的Flu的培养液100μL;④5-HT+Flu组:培养液含10%胎牛血清的高糖DMEM,其中加入培养液100μL(其中5-HT终浓度为5μg/mL,Flu终浓度为10μg/mL)。4组细胞均在常规条件下培养,分别于实验第24、48及72小时采用MTT法测定各组细胞的吸光度值(A490),并采用流式细胞周期分析方法测定各组细胞不同时间点细胞周期分布的特点。结果 PASMC离体干预实验结果表明,5-HT+Flu组细胞随着氟西汀浓度增高或时间延长,A490较对照组逐渐降低。细胞周期分析显示,氟西汀作用于PASMC 72 h后,细胞周期分布表现为S期细胞比例下降,G0/G1期细胞比例上升。结论氟西汀可有效拮抗5-HT刺激所致的PASMC增殖,且这一作用可能与氟西汀阻碍PASMC向DNA合成期转化有关。     

N-(3’,4’,5’-三甲氧基肉桂酰)邻氨基苯甲酸对抗原诱发的离体豚鼠回肠收缩、大鼠肥大细胞脱颗粒及组胺释放的影响

实验证明 N-(3′,4′,5′-三甲氧基肉桂酰)邻氨基苯甲酸(TOA)管内浓度80μg/ml 能明显抑制抗原诱发的主动致敏豚鼠离体回肠收缩。TOA 管内浓度25和50μg/ml 能显著抑制亲同种细胞抗体介导的大鼠肠系膜肥大细胞脱颗粒和腹腔肥大细胞组胺释放。     

牛膝总皂甙对大鼠离体子宫兴奋作用机理的研究

以子宫收缩面积(UCA)为指标,用消炎痛与氯丙嗪等作阻断剂,分析牛膝总皂甙(ABS)对大鼠离体子宫兴奋作用的机理。结果表明,实验前给大鼠用消炎痛(75mg/只)灌胃或浴槽内加消炎痛(20μg/ml),均可明显减弱ABS对大鼠离体子宫的兴奋作用。前列腺素E_2200ng/ml可明显增强ABS兴奋大鼠子宫作用。氯丙嗪0.5μg/ml也可明显减弱ABS对已,未孕大鼠子宫的兴奋作用,而阿托品10μg/ml对ABS所致大鼠子宫兴奋无明显影响。     

N—（3′，4′，5′—三甲氧基肉桂酰）邻氨基苯甲酸对抗原诱发的离体豚鼠回肠收缩、大鼠肥大细胞脱颗粒及组胺释放的影响

实验证明N－（3′，4′，5′－三甲氧基肉桂酰）邻氨基苯甲酸（TOA）管内浓度80μg/ml能明显抑制抗原诱发的主动致敏豚鼠离体回肠收缩。TOA管内浓度25和50μg/ml能显著抑制亲同种细胞抗体介导的大鼠肠系膜肥大细胞脱颗粒和腹腔肥大细胞组胺释放。     

7α-和7β-甲基-10β,17β-二乙酰氧基-△~4-雌甾烯-3酮的抗早孕作用

7α-和7β-甲基-10β,17β-二乙酰氧基-△~4-雌甾烯-3酮(简称7α-和7β-甲-乙氧雌酮)对小鼠抗早孕ED_(50)分别为1.6和5.5 mg/kg。7α-甲-乙氧雌酮在大鼠也有抗早孕作用并使血浆孕酮浓度降低,应用10 μg/ml浓度能抑制离体妊娠大鼠卵巢孕酮合成。7α-和7β-甲-乙氧雌酮与兔子宫胞浆雌二醇受体的相对结合亲和力(RBA)分别为10.8和1.5,与孕酮受体的RBA均<1.7α-和7β-甲-乙氧雌酮都有较弱的雌激素和抗雌激素活性。     

全反式维甲酸联合猪胆酸钠对人卵巢癌细胞生长抑制作用的影响

目的 探讨维甲酸（ATRA）及猪胆酸钠（SBANa)联合反应对人卵巢癌细胞生长的抑制作用。方法 实验共分为三组：单用ATRA组、单用SBANa组及ATRA＋SBANa联合用药组。应用MTT比色法、流式细胞仪对COC1、COC2、CAOV3三种卵巢癌细胞系在不同浓度的ATRA及SBANa下进行检测。结果 ATRA及SBANa联合应用后，能增强抑制卵巢癌细胞生长作用，当达到ATRA10μmol/L SBANa 100μg/ml浓度时，G0、G1期细胞比例增加，G2M、S期细胞比例下降，细胞增殖速度较单独用药组减缓。MTT检测提示在联合用药浓度达到ATRA 10μmol/L SBANa 100μg/ml时，癌细胞抑制率最佳。结论 ATRA及SBANa联合应用可增强对卵巢癌细胞增殖的抑制作用，并在ATRA 30μmol/L SBANa 100μg/ml浓度时，促进癌细胞凋亡。     

Investigations on the in vitro metabolism of five synthetic 19-norprogestins using hepatocyte suspensions isolated from five laboratory animal species

Five synthetic progestins of the 19-nortestosterone type (norethisterone, NET; levonorgestrel, LN; gestodene, GEST; NET-3-oxime, NETO; norgestimate, NGM) were investigated in the in vitro hepatocyte model. Radiolabelled progestins were added to hepatocyte suspensions (3 x 10(6) cells/ml) freshly prepared from female rat, guinea pig, rabbit, dog (beagle) and cynomolgus monkey. Drug level decreases (NET, LN, GEST) and prodrug conversions (NETO, NGM) were followed by radiochromatography (HPLC) for 60 min. In the case of NET and NETO the conversion into ethinyl estradiol (EE2) was quantified by RIA after HPLC separation. Half-lives of drug level decreases (t1/2), areas under the curves (AUC) and metabolic clearance rates (MCR) were estimated for all progestins. For NETO and NGM the percentages of conversion into NET and LN were calculated, respectively, and levels of EE2 determined in the case of NET and NETO. Rat hepatocytes showed an extremely high metabolic activity towards NET, LN and GEST resulting in t1/2 values of below 2 min. Respective values for rabbit hepatocytes ranged from 5-8 min, whereas half-lives calculated for liver cells from guinea pig, dog and monkey were generally above 30 min. A drastic increase in t1/2 was found for NETO (as compared to NET) in hepatocytes from rat, rabbit and monkey but not from guinea pig. Dog hepatocytes degraded NETO about 3 times more rapidly than NET. NGM was degraded much faster than LN in hepatocytes from all species except the rat. Liver cells from guinea pig and dog seem to be able to metabolize the 3-oxime group much more rapidly than hepatocytes from the other animal species. The lowest degree of prodrug conversion of 4% was observed for NGM and dog hepatocytes. Elevated EE2 levels were found in all experiments with NET and NETO. Results of NET, LN and GEST were compared with published in vivo experiments. No correlations were found for t1/2, MCR, and AUC.     

炔诺酮肟抗着床作用与雌激素活性关系探讨

本文报道炔诺酮肟、炔诺酮及炔雌醇对大鼠抗着床作用和雌激素活性的比较研究。炔诺酮肟的抗着床活性、子宫增重活性和阴道细胞角化活性分别为炔诺酮的25,26和21倍。炔诺酮肟抗着床活性与阴道细胞角化活性的比率比炔雌醇强14倍。说明炔诺酮肟比母体化合物炔诺酮有更高的抗着床活性,与其具有更强的雌激素活性有关,但尚存在除雌激素活性外的其它作用机理。     

蛹虫草提取物对高糖诱导内皮细胞衰老的影响

目的：探讨蛹虫草乙酸乙酯提取物（CME）对高糖诱导人脐静脉内皮细胞（HUVECs）衰老的影响。方法：用高糖（40mmol／L）诱导建立HUVECs衰老体外模型,以冬虫夏草提取物（CSE）（50μg／mL）为阳性对照,观察CME（12．5～100μg／mL）对内皮细胞衰老的干预作用。四甲基偶氮唑蓝（MTT）比色法检测细胞增殖;SA—β-半乳糖酐酶（SA—β—gal）染色法检测细胞衰老特异性的SA—β—gal活性;流式细胞术检测细胞周期分布和细胞内活性氧（ROS）含量。结果：经高糖干预24、48、72h后,HUVECs增殖活性OD值明显低于对照组;而且在高糖孵育96h后,SA—β-gal染色阳性细胞率明显增加;孵育48h后,处于G0／G1期细胞的百分率和ROS相对水平明显增加（P〈0．01）。与高糖组相比,CME（25～50μg／mL）孵育48和72h后细胞OD值显著提高（P〈0．05）;CME（12．5～100μg／mL）孵育96h后SA-β-gal染色阳性细胞率显著降低（P〈0．01）;孵育48h后Go／G1期的细胞百分率（P〈0．01）、细胞内ROS水平显著降低（P〈0．05）;CME25、50／μg／mL效果优于CME12．5、100〉g／mL（P〈0．05）,且与CSE50ptg／mL作用相近（P〉0．05）。结论：蛹虫草乙酸乙酯提取物可促进内皮细胞生长增殖,可能与其降低细胞内ROS水平,减轻细胞氧化应激损伤有关,从而减轻内皮细胞衰老。     

Distribution of norethisterone and ethinylestradiol in the gravid rat and in the feto-placental unit of rhesus monkeys following intragastric administration of norethisterone acetate in combination with ethinylestradiol. I. Direct determinations

The time course of the concentration of the 14C- and 3H-labelled substances and of unchanged norethisterone was determined in maternal plasma and selected tissues of the feto-placental unit after intragastric administration of a combination of 14C-norethisterone acetate (NET-Ac) and 3H-ethinylestradiol (EE2), respective commercial formulation: Ostro - Primolut , to pregnant rats. When given intragastrically in doses of 1 mg NET-Ac/kg and 0.002 mg EE2/kg both synthetic steroids were rapidly and completely absorbed. Highest concentrations of 14C-labelled substances were measured 0.5 h p. admin . in maternal and fetal tissues. Only approximately 1% of total radioactivity in maternal plasma (= 30 ng NET/ml) corresponded to unchanged norethisterone. Less than 1% of the dose administered passed the placental barrier. The maximum NET-levels in the fetuses amounted to 4 ng NET/g tissue. The highest levels of EE2-metabolites in the fetuses were found 2-5 h after administration with 34 pg EE2-equiv./g corresponding to only 0.15% of the dose administered in total fetuses. 14C- and 3H-radioactivity was eliminated from the fetuses with a similar or only a slightly lower rate than from the maternal organism. When administered intragastrically the twofold dose (2 mg NET-Ac/kg plus 0.004 mg EE2/kg) to pregnant rhesus monkeys maximum NET plasma levels of 40 ng/ml were observed after 2 h. Thereafter the NET plasma levels decreased with a half-life of 1.4 hours. The time course of NET concentrations in ovary and pituitary mirrored plasma levels whereas that in placenta and amniotic fluid paralleled plasma levels at a 30-50% and 3-15% niveau , respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antitumor and Cytotoxic Investigation of Amoora Rohituka

Abstract

An ethyl acetate extract derived from the stem bark of Amoora rohituka exhibited antitumor activity on mice inoculated with Dalton's lymphoma ascites cells (DLA). Intraperitoneal administration of the extract at doses of 10 or 20 mg/kg/day prolonged the median survival time of the animals. It showed cytotoxicity against Dalton 's lymphoma ascites cells with a 50% inhibitory concentration (IC₅₀) of 9 μg/ml, with no activity against Hep-2 cells from a tumor of the larynx.     

LOX-1对氧化低密度脂蛋白所诱导的PAI-1基因表达的影响

目的探讨血凝素样氧化型低密度脂蛋白受体(LOX)-1对氧化低密度脂蛋白(ox-LDL)所诱导1型纤溶酶原激活物抑制剂-1(PAI-1)表达的影响。方法不同浓度ox-LDL培养人脐静脉内皮细胞(HUVECs),采用倒置显微镜观察内皮细胞形态变化,通过反转录-聚合酶链反应(RT-PCR)测定LOX-1、PAI-1mRNA表达,Westernblot、酶联免疫吸附试验(ELISA)分别测定LOX-1、PAI-1蛋白的表达。结果不同浓度ox-LDL组,LOX-1和PAI-1mRNA和蛋白的表达明显增加,且呈浓度依赖性(P<0.01);用250μg/mLPoly(Ⅰ)与HUVECs预先作用2h后,再加入50μg/ml的ox-LDL培养24h,与未加Poly(Ⅰ)相比,LOX-1和PAI-1mRNA和蛋白的表达明显减少(P<0.05)。结论ox-LDL可以调节培养的脐静脉内皮细胞LOX-1和PAI-1表达;LOX-1作为ox-LDL特异性受体,介导了ox-LDL诱导脐静脉内皮细胞表达LOX-1。同时该实验提示了ox-LDL诱导脐静脉内皮细胞表达PAI-1是通过LOX-1介导的。     

Cytotoxic Effects of Tris (2,3-dibromopropyl) phosphate and 2,4-diaminoanisole

Abstract The flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and the hair-dye component 2,4-diaminoanisole (2,4-DAA) were studied for possible cytotoxic effects in rat hepatoma cells grown in culture and in suspensions of isolated rat hepatocytes. Cell growth of Reuber cells was inhibited by 50% at 50 μg/ml Tris-BP and 20 μg/ml 2,4-DAA, respectively. At 200 μg/ml Tris-BP protein synthesis in Reuber cells was reduced by 40%, whereas 50% inhibition of protein synthesis in isolated hepatocytes was seen at 100 μg/ml. IC50 of 2,4-DAA with respect to protein synthesis was found at 400 μg/ml in Reuber cells and at 3600 μg/ml in MH₁C₁ cells, whereas in the isolated hepatocytes IC50 was 650 μg/ml. DNA synthesis was inhibited by 50% at 225 μg/ml Tris-BP in Reuber cells. At 500 μg/ml 2,4-DAA DNA synthesis in Reuber and MH₁C₁ cells was inhibited by more than 80%.     

The effect of rifampicin on norethisterone pharmacokinetics

Summary The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450–600 mg/day). Rifampicin caused a significant reduction in the A. U. C. of a single dose of 1 mg norethisterone from 37.8±13.1 to 21.9±5.9 ng/ml X h (p<0.01). The plasma norethisterone half life (-phase) was also reduced from 6.2±1.7 to 3.2±1.0 h (p<0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/ml. Rifampicin caused a significant increase in antipyrine clearance, 6-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there were no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A. U. C. during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin.     

Pharmacokinetics, hydrolysis and aromatisation of norethisterone-3-oxime in female cynomolgus monkey.

Norethisterone-3-oxime (NETO) was administered to 3 female cynomolgus monkeys intragastrically and, after a wash-out period of 2-5 weeks, intravenously at a dose of 1 mg/kg. The radioactive dose of tritiated NETO was 20 microCi/kg for both treatments. For i.v. injection, a 30% propylene glycol/water solution and for i.g. administration an aqueous microcrystalline suspension was used. Excretion of radiolabel in urine and feces was followed for 5 days and plasma samples were obtained up to 2 days after administrations. In all samples (urine, feces and plasma) radioactivity was determined. Extracts from plasma samples were subjected to HPLC separation of drug and metabolites, as well as NETO and NET (metabolite of NETO after hydrolysis of the oxime group) levels were determined. In addition, EE2 (ethinylestradiol, A-ring aromatised metabolite of NET) levels were estimated using a specifically designed HPLC system for separation. Quantification of EE2 was achieved by radioimmunoassay (RIA) of specific eluate fractions. The results demonstrate that [3H]-NETO was absorbed completely at a dose level of 1 mg/kg, and excreted predominantly via the kidneys. A urinary to fecal excretion ratio of 1.5 (i.v.) or 1.0 (i.g.) was found. Renal excretion of total radiolabel proceeded with a half-life of about 0.8 (i.v.) or 1.1 (i.g.) days. Balances were incomplete, probably due to technical reasons. Orally administered NETO was highly bioavailable (84.0 +/- 16.9% of dose) but rapidly cleared from plasma (total clearance corresponded to 97% of plasma liver flow). The clearance from plasma is equivalent to the metabolic clearance because almost no unchanged NETO is excreted. Extensive metabolism of the parent drug was observed leading to at least two pharmacologically active metabolites (NET, EE2). The main progestogenic metabolite was NET reaching similar high plasma levels as NETO. EE2 turned out to be a metabolite of NETO and a conversion rate of below 0.5% of dose was estimated. However, due to its high estrogenic potency EE2 might contribute to the overall pharmacological pattern of NETO in the cynomolgus monkey.