醋酸棉酚和15甲基PGF2α甲酯对大鼠子宫胞浆雌激素受体的影响

假孕大鼠口服醋酸棉酚40和80 mg/kg连续5天,平均每个子宫的胞浆蛋白和雌激素受体量明显减少。以每mg蛋白计,雌激素受体浓度同对照组差异不显著。幼大鼠口服醋酸棉酚40mg/kg连续8天,作饱和分析测得对照组和给药组K_d值分别为1.04×10^-10和1.09×10^-10mol。最大受体结合数分别为432.0和358.8 fmol/子宫。实验发现棉酚在高浓度时对³H-雌二醇同其受体的结合有抑制作用。15甲基PGF_2α甲酯对假孕大鼠子宫胞浆蛋白水平和雌激素受体均无明显影响。     

2,4-二氨基-5-氯-6-取代苄氨基喹唑啉类化合物的合成及其抗疟、抗肿瘤和抗菌活性

本文报道标题化合物的合成及其抗疟、抗肿瘤和抗菌活性,该类化合物是以5-氯-2,4, 6-三氨基喹唑啉与各种取代苯甲醛缩合成相应的Schiff碱,然后经NaBH₄还原,再甲酰化或亚硝化制得.经对感染伯氏疟原虫(P.berghei)的鼠抑制性治疗筛选,有八个化合物剂量20mg/kg×4d时抑制率100%,Ⅰ₃,Ⅰ₄,Ⅲ₄三个化合物剂量5mg/kg×4d时抑制率在90%以上;体外抗肿瘤试验有4个化合物的活性优于MTX和SIPl759,以Ⅰ₄最佳。对L1210白血病细胞株的IC₅₀为2.20×10^-9 m mol/L;经对18种常用菌株进行体外筛选,发现对肺炎双球菌(D.pneumoniae)有较好的活性。     

粉防己碱,小檗胺等四氢异喹啉类生物碱对大鼠脑内M-胆碱受体的作用

用放射受体结合方法,研究了36种四氢异喹啉类生物碱及其半合成衍生物对大鼠脑内M-胆碱受体的结合特性。实验发现,粉防己碱对M-胆碱受体的亲和力最高,其K_i值为7.3×10^-8mol/L。小檗胺、四氢黄连碱和半合成原小檗碱衍生物B₁亦具有较高亲和力,K_i值分别为1.9×10^-7,6.8×10^-7和8.1×10^-7mol/L。四氢小檗碱半合成原小檗碱衍生物B₂,B₃,B₄,B₅,B₆和半合成小檗胺衍生物E₁及半合成蝙蝠葛碱衍生物D₁对M-胆碱受体的亲和力为中等强度,K_i值在1～2×10^-6mol/L之间。实验结果提示,某些四氢异喹啉类生物碱的药理作用可能与M-胆碱受体有关。     

可乐定镇痛与中枢Ca2+的关系

用大鼠甩尾法和放射配基结合实验,探讨了可乐定镇痛与中枢Ca²⁺的关系。CaCl₂(1μmol/rat,icv)和EGTA(0.2μmol/rat,icv)分别拮抗和增强可乐定(1mg/kg,sc)的镇痛。戊脉安(0.1μmol/rat,icy)对可乐定(1 mg/kg,sc)镇痛无明显影响,但可部分翻转CaCl₂对可乐定镇痛的拮抗。CaCl₂(1×10^-3mol)对[³H]-可乐定结合无明显抑制。结果表明可乐定镇痛与脑室周围组织中Ca²⁺浓度变化密切相关,Ca²⁺至少部分需经对戊脉安敏感的钙通道进入细胞内方可拮抗可乐定镇痛。推沦:可乐定镇痛与神经元内Ca²⁺有关。     

雌激素促进人的类成骨细胞TE85成骨作用的受体机制

目的：研究雌激素促进人的类成骨细胞株TE85细胞骨形成的作用。方法：用³H-胸腺嘧啶、³H-脯氨酸参入法分别测定细胞的增殖和胶原合成; 紫外分光光度法测定细胞内骨碱性磷酸酶（ALP）活性; 放免法测定细胞内骨钙素（BGP）含量; 放射配基法测定细胞核雌激素受体结合。结果：雌激素（E₂, 0.01～1.0 nmol.L^-1）可浓度依赖地刺激TE85细胞的³H-胸腺嘧啶和³H-脯氨酸的参入量; 在相同的时间点和剂量下,可增加成骨细胞内ALP活性和BGP的含量。结论：E₂通过增加成骨细胞数量、促进细胞胶原蛋白及ALP和BGP的合成而促进成骨作用,这些作用是通过雌激素受体介导的。     

某些四氢异喹啉类生物碱对大鼠脑内多巴胺和5-羟色胺受体的作用

本文报道十二种四氢异喹啉类生物碱对大鼠脑内D-2,5-HT₁和5-HT₂受体的结合特性。其中l-千金藤碱(l-STP)对这三种受体均有较高的亲和力,其Ki值分别为1.7×10^-7,9.4×10^-8和1.8×10^-7mol。l-莲碱(l-REM)对5-HT₂受体的亲和力与Z-STP相似(Ki=1.7×10^-7mol)。THB,THC和THJ对D-2受体的亲和力介于l-SPD和l-THP之间。本文报道的多数生物碱能同时影响两种或两种以上受体部位的结合特性,提示它们对单胺神经系统可能有复杂的相互作用。     

四氢异喹啉类生物碱对大鼠脑内α肾上腺素受体的作用

应用放射受体结合法研究了近30种四氢异喹啉类(TIQs)生物碱对大鼠脑内α肾上腺素受体的作用。其中l-CBN,l-THC和l-STP对α₁受体亲和力最高,K_i值为～2.0×10^-7mol/L。其次是DHS,XLP和l-DCT,K_i值分别为4.7×10^-7,6.5×10^-7和7.6×10^-7mol/L。DHS对α₂受体亲和力最高(K_i=1.25×10^-6mol/L),l-REM次之。对α受体亚型亲和力选择比K_i(alpha-2)/Ki(alpha-1)最高的是l-STP(357) 和XLP(154),它们对α₂受体几无亲和力(K_i>10^-4mnl/L)。提示l-STP和XLP对α₁受体有较高的选择性。l-SPD和l-THP对α₁和α₂受体亲和力相近,均为中等强度。THJ,DRC及l-TTD等6种TIQs对α₁和α₂受体均无亲和力(K_i>10^-4mnl/L)。     

抗痫灵的电化学行为及吸附伏安法研究

抗痫灵在0.20 mol/L H₂SO₄底液、富集电位-0.70 V(vs Ag/AgCl)、扫速100 mV/s等条件下,用吸附伏安法得一灵敏的还原峰,峰电位-0.94 V,峰电流与抗痫灵浓度在3.0×10^-9～1.0×10^-8mol/L(富集时间t_ac=120 s),1.0×10^-8～7.0×10^-8mol/L(t_ac=90 s),7.0×10^-8～7.0×10^-7mol/L(t_ac=60 s),7.0×10^-7～3.0×10^-6mol/L(t_ac=45 s)范围内成线性关系,检测限可达1.0×10^-9mol/L,并用于片剂及病人尿样的测定,得到满意的结果。以多种电化学手段研究抗痫灵的电化学行为及反应机理。实验表明属不可逆吸附波。测得扩散系数D为7.7×10^-6cm²/s,电极反应速率常数k₁为1.5×10^-3cm/s,电极反应电子数n为2,电子转移系数α=0.52。抗痫灵的还原基团为分子中碳碳双键。     

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ED₅₀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。     

二氢青蒿素与青蒿琥酯的抗孕作用

研究表明,二氢青蒿素与青蒿琥酯对小鼠、金黄地鼠、豚鼠及兔均有抗孕作用。在金黄地鼠和豚鼠表现为引致流产,在小鼠和兔表现为使胚胎吸收。小鼠妊娠d7、金黄地鼠妊娠d5单次sc二氢青蒿素的抗孕ED₅₀(95%可信限)分别为32.8(27.7～38.9)及6.1(5.6～6.7)mg·kg^-1,豚鼠妊娠d18单次im二氢青蒿素的抗孕ED₅₀为18.3(13.9～24.2)mg·kg^-1,。金黄地鼠妊娠d5单次sc青蒿琥酯的抗孕ED₅₀为12.2(10.3～14.4)mg.kg^-1.以金黄地鼠进行的观察表明二氢青蒿素对胚胎有较高的选择性作用,引起胚胎坏死的剂量对于母体子宫、卵巢和一般健康状况无明显损害。     

18-甲基乙炔雌二醇-3-甲醚的药理

本文报告了18-甲基乙炔雌二醇-3-甲醚的激素活性和避孕作用。18-甲炔雌甲醚在幼年雌性小鼠能明显刺激子宫发育,说明有雌激素活性。经与炔雌醇-3-甲醚作效价比较,结果指出其雌激素活性约为炔雌醇-3-甲醚的1/50。当与雌二醇同时应用时,18-甲炔雌甲醚并不能对抗雌二醇引起的子宫发育,说明没有抗雌激素活性。用Claubcrg方法以及用大鼠蜕膜瘤方法进行的实验说明18-甲炔雌甲醚没有孕激素活性,但有明显的抗孕激素活性。在小鼠妊娠第1、2、3天经口给18-甲炔雌甲醚,每日1 mg/kg小鼠不能怀孕。在妊娠第6、7、8天给18-甲炔雌甲醚,小鼠只有10～20%怀孕。说明有明显的抗着床和抗早孕作用。在小鼠妊娠第1、2两天经口给18-甲炔雌甲醚,有4/10的动物在妊娠第四天输卵管中仍可见到受精卵,而对照组在妊娠第四天输卵管中都没有卵子,可见18-甲炔雌甲醚使受精卵在输卵管中的运行变慢,这一作用也可能是18-甲炔雌甲醚抗着床作用的一个原理。经口给小鼠18-甲炔雌甲醚2 mg/kg,连给2周,对动物体重增长和各主要脏器形态都没有明显影响。经口给狗1 mg/kg,连给两周,狗的血象、心脏和肝、肾功能没有出现异常。     

Anti-implantation effect of droloxifene in rats and its relationship with anti-estrogenic activity

AIM: To investigate the anti-implantation effect of droloxifene and study the possible relationship between the anti-estrogenic activity of droloxifene and its anti-implantation effect. METHODS: Pregnant rats were treated orally with droloxifene at 10:00 AM on d 2 at doses of 1.25-20 mg/kg to observe anti-implantation effects, and then doses of 14 mg/kg or 2.5 mg/kg were given at different time on d 2 to d 5 to determine the optimal administration time for anti-implantation effects. Pregnant rats were treated with a combination of droloxifene (2.5 mg/kg, ig) and E2 (0.5-8.0 microg/kg, sc) on the optimal administration time to observe the antagonistic effect of external estrogen on the anti-implantation effect of droloxifene. Serum estrogen and progesterone levels were measured by carrying out radioimmunoassays on d 1 to d 6 in droloxifene-treated and control rats to determine the surge time for nidatory estrogen and the effect of droloxifene on ovary function. RESULTS: Droloxifene has anti-implantation effects in rats. The optimal oral administration time was at 22:00 PM on d 4, which was after the surge time for nidatory estrogen (on d 4 at 10:00 AM). This suggests that the anti-implantation effect of droloxifene is not attributable to antagonism of the surge in secretion of nidatory estrogen. External estrogen did not antagonize the anti-implantation effect of droloxifene. Droloxifene had no effect on the serum levels of estrogen and progesterone on d 5 or d 6 when administered on d 4 at 22:00 PM. CONCLUSION: Droloxifene has an anti-implantation effect in rats, and the effect appears to be not completely due to its anti-estrogenic activity.     

Antifertility and hormonal properties of flavones of Striga orobanchioides

The two flavones, apigenin and luteolin, isolated from Striga orobanchioides, were investigated for endocrine and contraceptive properties. Graded doses of these compounds (5-25 mg/kg body weight/day) when administered from day 1 to day 4 of pregnancy showed dose-dependent and significant anti-implantation activity. The mean effective Dose 100% (MED(100)) for both compounds was found to be 25 mg/kg body weight. Oral administration of these compounds caused a significant increase in uterine weight in immature ovariectomised rats. It also caused a significant increase in uterine diameter, thickness of the endometrium and its epithelial cell height when compared with those of control rats. The uterotrophic potency was less than that of ethinyl estradiol. Simultaneous administration of these compounds with ethinyl estradiol caused a significant increase in uterine weight, uterine diameter, thickness of the endometrium and height of endometrial epithelium. The extent of these changes was also less than that in only ethinyl estradiol-treated rats. Hence the compounds exhibited estrogenic properties at their contraceptive dose level when given alone. However, along with ethinyl estradiol, they exhibited slight anti-estrogenic activity.     

Contraceptive and Estrogenic Effect of a Methanol Extract of Cassia nigricans Leaves in Experimental Animals

The methanol extract of Cassia nigricans Vadl leaves was investigated for its contraceptive activity in mice and rats. The extract dose-dependently (0.5–1.0 g/kg) protected the animals from conception for 1–4 gestational periods in mice and rats. It inhibited fetal implantation, as was confirmed by laparotomy on day 10 of pregnancy. The pups showed significant change in weight and length (p &lt; 0.01) with 0.75 g/kg, compared to control fetal defects. In ovariectomized immature young rats and mice, there was a dose-dependent increase in uterine wet weight (p &lt; 0.001). The extract induced uterotrophic effects or immature vaginal opening and cornification when compared with estrogen-treated groups. Its anticonceptive effect may be due in part to its anti-implantation, estrogenic and/or direct effect on the uterus.     

Contraceptive Efficacy and Hormonal Profile of Ferujol: a New Coumarin from Ferula jaeschkeana1.

The ethanolic extract of FERULA JAESCHKEANA Vatke as well as its hexane, benzene and chloroform soluble fractions prevented pregnancy in adult female rats when administered orally on days 1-5 POSTCOITUM. Chromatography of these combined fractions, whose TLC pattern was similar, yielded the active compound ferujol. Single oral administration of ferujol on days 1, 2 or 3 POSTCOITUM at 0.6 mg/kg dose prevented pregnancy in rats. None of the fractions nor ferujol, however, exhibited any contraceptive efficacy in hamsters. In ovariectomized immature female rats, ferujol showed potent estrogenic activity at the contraceptive dose, but was devoid of any antiestrogenic activity. Significant uterotrophic effect was discerned even at 1/40th of the contraceptive dose of the compound. Taking 100% increase in uterine weight as the parameter, ferujol was found to be about 10 times less estrogenic than ethynylestradiol. In addition, ferujol induced implantation of blastocysts in mice undergoing experimentally induced delayed implantation, confirming its frank estrogenic activity.     

Octamethylcyclotetrasiloxane exhibits estrogenic activity in mice via ERalpha

Octamethylcyclotetrasiloxane (D4) is a low molecular weight cyclic silicone used in the synthesis of larger silicone polymers and in the formulation of a variety of personal care products. The effects of oral D4 exposure in mice on serum estradiol levels, uterine wet weight, and uterine peroxidase activity were investigated. Additionally, in vitro estrogen receptor binding activity was evaluated. Serum estradiol levels decreased in a dose-dependent manner after exposure to 100 mg/kg to 1000 mg/kg D4. Studies with adrenalectomized animals demonstrated that the decreased serum estradiol levels were not due to elevated serum corticosterone levels. Uterine wet weights in ovariectomized mice were significantly increased in a dose-dependent manner by exposure to 250-1000 mg of D4/kg, but not by exposure to other silicone compounds tested (hexamethylcyclotrisiloxane, decamethylcyclopentasiloxane, decamethyltetrasiloxane, and octaphenylcyclotetrasiloxane). Uterine peroxidase activity, a marker for estrogenic activity, was also significantly increased in D4-exposed mice, but not in mice exposed to the other siloxanes. Pretreating mice with the estrogen receptor antagonist ICI 182,780 completely blocked the D4-induced increase in uterine weight, and ovariectomized estrogen receptor-alpha knockout mice showed no increases in uterine weights when orally exposed to D4 or estradiol. In an in vitro estrogen receptor binding assay, D4 showed significant competition with (3)H-estradiol for binding to estrogen receptor-alpha, but not estrogen receptor-beta. The data presented here indicate that D4 has weak estrogenic activity, and that these effects are mediated through estrogen receptor-alpha.     

二苯乙烯(芪)的一些药理作用

芪(二苯乙烯)通常用于化学工业,对其药理活性的研究很少。通过动物实验我们发现芪能明显保护CCl₄引起的小鼠肝损害,表现在使高的SGPT及SGOT降低、BSP潴留减少、肝组织病变减轻等。芪明显促进肝糖元生成,此作用强度与可的松相近,但芪没有可的松那样的抗炎作用。在去肾上腺小鼠,芪仍能明显促进肝糖元生成,故此作用似乎不通过体内的垂体-肾上腺系统。芪对小鼠戊巴比妥睡眠时间影响不明显。根据实验资料分析,芪对CCl₄肝损害的保护机制大概不是通过酶诱导,也不象某些抗氧化剂那样直接对抗CCl₄的作用,但有可能与其促进肝糖元生成有某种关系。芪有微弱的雌激素作用(约为己烯雌酚的数万分之一)。芪的毒性很低,小鼠一次腹腔注射LD₅₀为6.5 g/kg,灌胃LD₅₀大于8 g/kg,但油溶液毒性较大(灌胃LD₅₀为0.92g/kg)。长期大量给予芪,对雄小鼠的生长及睾丸发育有抑制作用,给狗服芪50 mg/kg/天连续一个月以上未见明显异常反应。     

Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats

The Organization for Economic Cooperation and Development (OECD) is developing a screening and testing method to identify estrogenic/antiestrogenic compounds. Based on these demands, phase 1 study for OECD uterotrophic assay was undertaken. The OECD is in the process of validating the assay results from international participating laboratories, which carried out this study with established environmental estrogenic compounds using designed protocols. The aim of this study was to provide data for validating the OECD uterotrophic assay using Sprague-Dawley immature female rats when testing with weak or partial estrogenic compounds. Ethinyl estradiol (EE) at 0.3 or 1 microg/kg/d, a positive control used in the present study, significantly increased both uterine wet and blotted weights. In the case of weak estrogenic compounds, the uterine wet weights were significantly increased by bisphenol A (BPA) at 300 mg/kg/d, nonylphenol (NP) at 80 mg/kg/d, genistein (GN) at 35 mg/kg/d, and methoxychlor (MXC) at 500 mg/kg/d. In addition, the increase in uterine blotted weights also showed a similar pattern to that of uterine wet weights. However, both 1,1,1-trichloro-2,2-bis(p-chlorphenyl)ethane (o,p-DDT) and dibutyl phthalate (DBP) did not affect uterus (wet and blotted) weights at doses of 100 and 500 mg/kg/d. These results suggest that the increase in uterine weights should be considered useful as a sensitive endpoint for detecting weak estrogenic compounds in 3-d rodent uterotrophic assay. However, further combination studies using surrogate biomarkers may be needed to improve the sensitivity of this assay for the detection of weak estrogenic compounds, such as o,p-DDT.     

怀牛藤总皂甙抗生育作用及其机理

给小鼠灌服怀牛藤总皂甙（ABS）75，150，300mg／kg，表明ABS具有明显的抗着床、抗早孕作用，且呈剂量依赖性关系，其ED50分别为96±27和145±51mg／kg。ABS的抗早孕作用，可被外源性黄体酮、人绒毛膜促性腺激素和泰必利部分拮抗。ABS300mg／kg可显著抑制假孕小鼠和去卵巢小鼠的子宫蜕膜细胞反应，但无雌激素样作用和抗雌激素样作用。     

In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta

The estrogenic activities of bisphenol A (BPA) and its major metabolite BPA glucuronide (BPA-G) were assessed in a number of in vitro and in vivo assays. BPA competed with [3H]-17beta-estradiol (E2) for binding to mouse uterine cytosol ER, a glutathione S-transferase (GST)-human ER D, E, and F domain fusion protein (GST-hERalphadef) and full-length recombinant hERbeta. The IC(50) values for E2 were similar for all three receptor preparations, whereas BPA competed more effectively for binding to hERbeta (0.96 microM) than to either mouse uterine cytosol ER (26 microM) or GST-hERalphadef (36 microM). In contrast, BPA-G did not competitively displace [3H]E2 from any of the ER preparations. In MCF-7 cells transiently transfected with Gal4-hERalphadef or Gal4-hERbetadef, BPA induced reporter gene activity with comparable EC(50) values (71 and 39 microM, respectively). No significant induction of reporter gene activity was seen for BPA-G. Cotreatment studies showed that concentrations of (10 microM) BPA and BPA-G did not antagonize E2-induced luciferase mediated through either Gal4-hERalphadef or Gal4-hERbetadef. In vivo, the uterotropic effect of gavage or subcutaneous (sc) administration of 0.002-800 mg of BPA/kg of body weight/day for three consecutive days was examined in immature rats. Dose-related estrogenic effects on the rat uterus were observed at oral doses of 200 and 800 mg/kg and at sc doses of 10, 100, and 800 mg/kg. These results demonstrate that BPA competes more effectively for binding to ERbeta, but induces ERalpha- and ERbeta-mediated gene expression with comparable efficacy. In contrast, BPA-G did not exhibit any in vitro estrogenic activity. In addition, there was a clear route dependency on the ability of BPA to induce estrogenic responses in vivo.