醋炔诺酮肟的抗着床作用原理的研究

醋炔诺酮肟(2.5～5.0毫克/公斤/日)于妊娠第2天单次或第2、3天连续二次灌胃,可使小鼠卵子在输卵管(42.6～67.8%)运行提前一天进入子宫;但在妊娠第1天给予2.5毫克/公斤,则有76.6%卵子滞留于输卵管内,其中17.2%孕卵出现滞育现象(2细胞期)或异常。卵子移植实验表明,该药主要是抑制内膜分化,直接损伤胚泡作用较小。以醋炔诺酮肟1毫克/公斤/日给予妊娠第2和3天大鼠,第4天血清雌二醇峰、孕酮和子宫胞浆雌二醇受体水平均显著地受到抑制。提示醋炔诺酮肟可能通过加速小鼠卵子转运、干扰大鼠着床的激素平衡和抑制内膜分化,导致孕卵与内膜发育不同步,从而达到抗着床作用。     

醋炔诺酮丙酰肟对鼠的抗生育作用研究

醋炔诺酮丙酰肟在大鼠和小鼠妊娠1～5天口服的抗着床ED_(50)分别为0.068±0.02和0.31±0.1mg/kg,大鼠妊娠第2天单次肌注或口服的抗着床ED_(50)分别为0.53±0.1和3.5±0.7mg/kg。大鼠妊娠7～8天肌注5～10mg/kg醋炔诺酮丙酰肟有明显的终止早孕作用。醋炔诺酮丙酰肟在终止早孕剂量时,明显抑制假孕大鼠的蜕膜反应且使早孕大鼠的血清孕酮浓度明显下降。提示:醋炔诺酮丙酰肟的终止早孕作用可能与其抑制孕激素活性有关。     

甲孕环酯的药理学研究

本文报道了我国合成的一种长效孕激素化合物、甲地孕醇-3-环戊烷丙酸酯(简称甲孕环酯,曾称孕素1号)的药理学研究。生物检定表明该化合物具有一定的孕激素活性与雌激素活性。对家兔有显著的抗排卵与抗着床作用。实验表明药物的抗着床效果与投药时间有一定关系:交配前3天给家兔灌服单次剂量(1.5毫克/公斤)时显示100%抗着床效果;而交配当天(配前1小时)或交配后次日投药均无抗着床作用。此外,交配前连续3天(-2,-1,0天)投药、达100%抗着床效果的总剂量为0.6毫克/公斤,较单次剂量)1.5毫克/公斤)低2.5倍。狗的毒性实验表明,每次剂量相当于临床剂量250倍的甲孕环酯,在投药8次后(每二周一次),未引起性器官或其他脏器的明显病理变化,对胃肠道也无明显的副反应。本文还结合复方甲孕环酯片的临床应用,以及如何发展以孕激素为主要成分的长效避孕药进行了讨论。     

庚炔诺酮肟对小鼠的抗生育作用和家兔的抗排卵作用研究

小鼠妊娠第1天起,给予庚炔诺酮肟1.25～10mg/kg 灌胃,每天1次,连续5天,有显著的抗着床作用,其ED_(50)为0.765±0.15mg/kg。给小鼠灌胃或皮下注射庚炔诺酮肟50～100mg/kg,有明显的避孕作用,给家兔肌注庚炔诺酮肟25mg/kg,抑制排卵作用可维持2周。小鼠一次灌胃庚炔诺酮肟1g/kg,无明显毒性。     

醋酸棉酚在雌性大鼠的抗着床作用及其机理分析

本工作观察了醋酸棉酚对大鼠早期妊娠的影响。于大鼠妊娠的第1—5天,每鼠每天灌服一次醋酸棉酚混悬液(100毫克/公斤体重),对照组灌服等量蒸馏水。于妊娠第10天处死,处死前取血测定血清孕酮,处死后取卵巢测定⊿~5-3β-羟甾脱氢酶活性并记录妊娠动物数及正常着床胎数。结果表明,醋酸棉酚对大鼠具有明显的抗着床作用,抗着床率达85.7%,同时伴有血清孕酮水平下降。若同时皮下注射5毫克孕酮或是同时皮下注射50国际单位的hCG 均能有效地对抗醋酸棉酚的抗着床作用,而同时注射20微克的LH-RH 类似物并不能对抗醋酸棉酚的抗着床作用。在延缓着床的大鼠,醋酸棉酚不能对抗外源性雌二醇的致着床作用。以上结果提示,对抗LH 对黄体功能的支持有可能是醋酸棉酚抗着床作用的机理之一。     

甾体酮肟化合物的研究(Ⅰ)——43个化合物的合成和抗生育活性

本文报道一些甾体酮肟化合物的合成及其在实验动物中的抗着床、抗早孕效果。其中炔诺酮肟(33),醋炔诺酮肟(36),炔诺酮肟三甲硅醚(35),R-2010酮肟(57),R-2323酮肟(65)以及苯丙酸诺龙酮肟对大鼠具有显著的抗早孕作用,炔诺酮肟(33)以及苯丙酸诺龙酮肟(48)对金黄色地鼠也有抗早孕作用。炔诺酮肟(33),醋炔诺酮肟(36),炔诺酮肟三甲硅醚(35)以及R-2323酮肟(65)亦具有很强的抗着床作用。此类化合物的活性分析表明:“非纯孕激素”酮肟,如炔诺酮肟(33)、醋炔诺酮肟(36),R-2323酮肟(65)等具有很强的抗着床、抗早孕作用,而“纯孕激素”酮肟则无效。苯丙酸诺龙酮肟(48)的作用可能有别于“非纯孕激素”酮肟。     

棉酚抑精种属差异的原因初探

<正> 王月娥等报道,饲料中若含5%棉子粉,5周后大鼠附睾尾内均为死精子;然而给兔连续喂饲含10%棉子粉的饲料,历时9周,对精子活力仍无影响。张明觉等报道,雄兔服1.25—10毫克/公斤的醋酸棉酚,每周5次,历时5—14周,精子发生依然正常;但大鼠与仓鼠服棉酚5或10毫克/公斤,12周后,即出现死精和不正常的精子。本实验室曾以10毫克/公斤/天剂量的棉酚给大鼠灌服,每周6次,5周后附睾尾内全为死精;而以20毫克/公斤/天的棉酚灌服小鼠,历时60天,亦未见附睾尾内有死精子出现。Nieschlag认为,大鼠、仓鼠、猴和人对棉酚敏感,而小鼠、豚鼠、兔、猪、山羊、绵羊和牛则不然。棉酚抑精作用为何有如此明显的种属差异?为了探讨其     

炔诺酮肟对家兔孕卵运行及发育的影响

本实验以生理盐水分段冲洗家兔输卵管及子宫,收集孕卵并作形态学观察。结果表明,给药后24～48小时孕卵在输卵管内的运行稍有加快,以后明显减慢以致大多数孕卵滞留在输卵管内。孕卵发育受阻,其外周粘蛋白层变薄,部分孕卵出现退行性变化。以上各种改变证实炔诺酮肟的抗着床作用是干扰了孕卵的运行及发育。由于这些变化与外源性雌激素作用相似,提示在家兔实验中炔诺酮肟抗着床作用可能与它具有的雌激素活性有关。     

棉酚对大鼠血睾屏障影响的研究

本实验采用辣根过氧化物酶、硝酸镧和氯化锂示踪观察成年大鼠灌服棉酚后血睾屏障的变化。成年雄性大鼠连续灌服醋酸棉酚30毫克/公斤/日2周、4周和6周后,血管内分别灌流0.75M 氯化锂溶液、2%硝酸镧溶液和睾丸内注射辣根过氧化物酶。结果表明,大鼠灌服棉酚达抗生育效果时,并未显示血睾屏障通透性损伤。因此,可以排除棉酚作用于支持细胞或血睾屏障继而间接影响生精细胞的可能性。     

莪术止孕作用的实验研究

本文报告应用小白鼠、大白鼠及家兔进行止孕作用筛选实验,发现4种药物有止孕作用,其中莪术油止孕效果较显著。小白鼠经腹腔和皮下注射600～900毫克/公斤莪术油,其抗着床与抗早孕效果为70～90%;大白鼠腹腔注射复方莪术油的抗早孕效果为77%;家兔腹腔注射80毫克/公斤莪术油的抗着床效果为80%,经阴道注药400毫克/公斤的抗着床效果为100%。     

Azastene对大鼠止孕作用的研究

妊娠第10天大鼠单次灌胃24mg/kg azastene全部达到终止妊娠作用,12或6mg╱kg azastene达到部分终止妊娠作用,3mg/kg azastene则对大鼠终止妊娠无显著作用。妊娠第10天和第11天是azastene对大鼠止孕作用的最佳给药时间。孕酮和消炎痛在妊娠大鼠上均能明显阻断12mg/kg azastene对大鼠的终止妊娠作用。灌胃6mg/kg azastene与肌肉注射0.1mg/kg 15-甲基前列腺素F_(2α)合并用药,其止孕效果较单用azastene或15-甲基前列腺素F_(2α)更为满意。     

十一酸睾酮与棉酚合用对雄大鼠生育力的影响

本研究探讨十一酸睾酮(TU)与醋酸棉酚(G)序列使用对雄大鼠生育力的影响。SD 雄大鼠肌注TU 12mg/kg 共3次,9/10鼠生育力下降至零(P<0.001),附睾精子密度和活率明显下降(P<0.001);然后胃饲G 12mg/kg·d,每周6日,共3个月。使雄鼠可维持在不育状态,无论在注射TU 或胃饲G 期间,大鼠体重增长如常。停用棉酚3周后,10鼠中6只生育力恢复,停用5周后10鼠生育力全部恢复。二药合用可减少各自的用药量,因TU 所致睾丸体积缩小及单用棉酚引起的不良反应的均可有所减轻,为降低二药的副作用提供了一条可能的途径。     

环氧司坦对大鼠止孕作用的药理研究

本文研究了环氧司坦(epostane)对妊娠大鼠的止孕作用。环氧司坦48mg/kg灌胃给药,最佳给药时间为妊娠第10～11天。大鼠妊娠第10天,环氧司坦以48mg/kg灌胃给药或96mg/kg肌肉注射给药,均可使大鼠完全止孕。灌胃给药的ED_(50)为22.3±0.05mg/kg,95%可信限为17.3～28.8mg/kg;肌肉注射给药的ED_(50)为29.6±0.06mg/kg,95%可信限为22.0～39.5mg/kg。二者之间无显著差异(P>0.05)。环氧司坦对3β-羟甾脱氢酶具有抑制作用,黄体酮或消炎痛均可拮抗环氧司坦对大鼠的止孕作用,绒毛膜促性腺激素(hCG)不能拮抗环氧司坦对大鼠止孕作用。环氧司坦48mg/kg灌胃给药可使血浆孕酮水平下降,但无雌激素活性。     

复方甲地孕酮注射液、醋酸甲地孕酮和雌二醇的生殖毒理研究

本文用新西兰兔和Sprague Dawley大鼠检测了复方甲地孕酮、醋酸甲地孕酮和雌二醇的胚胎毒性和致畸作用。结果表明,复方甲地孕酮低剂量组和高剂量组(即5倍、20倍临床剂量)以及雌二醇低剂量组的兔和大鼠死胎率均为100%,与对照组比较有非常显著性差异(P<0.01)。醋酸甲地孕酮低剂量组和高剂量组的死胎率:兔分别为24.55%和21.43%;大鼠则分别为7.02%和3.42%,与对照组比较无显著性差异(P>0.05)。醋酸甲地孕酮低剂量组兔共有胎仔84只,其中6只畸形胎仔(颅骨缺失或迟化及胸骨缺失或迟化);大鼠114只胎仔未发现畸形。高剂量组兔70只胎仔中有15只为畸形,多见腹裂和骨胳畸形;大鼠无明显畸形胎仔。     

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Serial systolic blood pressure measurements were made in order to assess the effects of pregnancy and estrogen on the angiotensin II pressor response of the rabbit. The systolic blood pressure of the ear in 5 pregnant rabbits did not change throughout the gestational period, being compatible with that in 14 nonpregnant rabbits. However, vascular resistance to infused angiotensin II (over 13.1 ng/kg/min required to elicit a pressor response of 20 mmHg in systolic pressure) was demonstrated as early as the 10th day of pregnancy, and maximum mean resistance occurred on the 20th day: the mean pressor dose required was 34.5 ± 3.6 ng/kg/min (mean ± S.D.). In a separate series, vascular resistance in castrated rabbits was demonstrated as early as the 10th day of estrogen administration, reached a maximum at the 4th week, and then gradually decreased to the control level (pretreatment, 10.5 ± 2.5 ng/kg/min; 10 days, 18.9 ± 2.3 ng/kg/min; 4 weeks, 32.4 ± 5.4 ng/kg/min; 10 weeks, 18.3 ± 3.6 ng/kg/min; and 24 weeks, 11.0 ± 2.0 ng/kg/min). These results indicate that (1) pregnant rabbits have a decreased sensitivity to angiotensin II, (2) estradiol may modulate the angiotensin II pressor response in castrated rabbits, and (3) serial systolic blood pressure measurement may provide an appropriate test for the angiotensin II pressor response in rabbits.     

Effect of shakuyaku-kanzo-to on serum estrogen levels and adrenal gland cells in ovariectomized rats]

The aim of this study is to investigate the effect of the traditional herbal medicine, Shakuyaku-Kanzo-To (SKT) on oophorectomized (OVX) rats. In an in vivo experiment, OVX rats were orally given SKT (low dose group: 45 mg/kg b.w./day, high dose group: 450 mg/kg b.w./day) every day for 2 weeks. Serum dehydroepiandrosterone-sulfate (DHEA-S) and estrone (E1) levels of the low and high dose groups were higher than those of the control given vehicle. Serum 17 beta-estradiol (E2) levels only in the low dose group were higher than those of the control. In an in vitro experiment, adrenal gland cells of OVX rats were incubated with media containing SKT or Shakuyaku(S) or Kanzo(K) for 72-h. DHEA-S production was increased in the SKT 1,000 micrograms/ml and K 500 micrograms/ml group in comparison with the control. At the conclusion of this period, the cells were reincubated for an additional 8-h interval in an androstenedione (delta 4-A, 10(-7) M)-supplemented medium. Aromatase activity assessed by the conversion of delta 4-A to E1 or E2 was not increased in the SKT 1,000 micrograms/ml group. These results indicate that SKT increases DHEA-S, a precursor of estrogen, and brings about an increase in serum estrogen concentrations in OVX rats.     

双酚A对大鼠雌性子代卵巢发育和血管内皮生长因子蛋白表达的影响

目的:探讨大鼠妊娠期接触双酚A(BPA)对雌性子代卵巢发育和血管内皮生长因子(VEGF)蛋白表达的影响。方法:实验组于SD母鼠妊娠第7~20日分别灌胃给予0.005 mg/kg、0.05 mg/kg、0.5 mg/kg、2.5 mg/kg BPA,阴性对照组给予0.5 mg/kg溶剂,阳性对照组给予0.05 mg/kg己烯雌酚,每组8~10只。观察雌性仔鼠的阴道开口时间,分别于出生后30 d、60 d(分别相当于人青春期前和成年期)处死仔鼠,称重卵巢,光学显微镜观察卵巢组织学变化,ELISA检测血清雌、孕激素水平,Western blotting检测卵巢VEGF蛋白的表达。结果:BPA 0.05 mg/kg、0.5 mg/kg、2.5 mg/kg组仔鼠阴道开口时间明显缩短,2.5 mg/kg组青春期前仔鼠卵巢脏器系数明显升高,BPA 0.05 mg/kg、0.5 mg/kg、2.5 mg/kg组卵巢出现多囊样病变,BPA 0.5 mg/kg、2.5 mg/kg组青春期前仔鼠血清雌、孕激素水平明显升高,BPA 2.5 mg/kg可导致青春期前仔鼠卵巢VEGF蛋白表达明显升高。结论:母体妊娠期接触BPA可导致青春期前雌性仔鼠卵巢出现多囊样病变,但对成年雌性仔鼠卵巢无明显影响。     

Extended administration of the association of zidovudine plus ritonavir during rat pregnancy: maternal and fetal effects

The purpose of the study was to evaluate at term, the effects of the association of zidovudine/ritonavir administered during the entire period of rat pregnancy. Forty pregnant EPM-1 Wistar rats were divided randomly into four groups: one control (drug vehicle control, n=10) and three experimental treated with an oral solution of zidovudine/ritonavir (Exp 1 = 10/20 mg/kg bw, n = 10; Exp 2 = 30/60 mg/kg bw, n=10; Exp 3 = 90/180 mg/kg bw, n=10) from day 0 up to day 20 of pregnancy. Maternal body weights were recorded at the start of the experiment and at the 7th, 14th and the 20th day thereafter. At term (20th day) the rats were anesthetized and, upon laparotomy and hysterotomy, the number of implantations, resorptions, living fetuses, placentae and intrauterine deaths were recorded. The collected fetuses and placentae were weighed, and the concepts were examined under a stereoscopic microscope for external malformations. The maternal body gain and the mean fetal weight at term were both significantly lower (p < 0.01 and p < 0.0001, respectively) in the experimental groups compared to the control. The recorded resorptions were higher in Exp 2 and Exp 3 groups than in the control group. The other parameters were not affected. The exposure of pregnant rats at term to a 1:2 association of zidovudine plus ritonavir resulted in a significant reduction in maternal body weight gain and increased rate of fetal resorption.