左旋18—甲基炔诺酮事后药的药物动力学及药效学研究

本研究为6例健康妇女,在月经周期排卵前后,口服左旋18-甲基炔诺酮(简称18-甲)0.75mg/天,连续七天的药物动力学和药效学。服药期间,每日在服药前取血,此外在第一和第七天服药后1,2,4,8,12和24小时取前臂静脉血,放射免疫法测定血中18-甲水平。药—时曲线表明所有受试者均为开放二室模型,药时方程为C(t)=Ae~(-αt)+Be~(-βt)-(A+B)e~(-kat)。第一天服药后药物动力学参数:达峰时间T_(max)3.74±1.06h,峰值C_(max)=8.91±2.25ng/ml,消除半寿期t_(1/2)β=11.98±2.99h,K_a=0.476±0.1202h,表观分布容积V_d=102.8±35.81L,体内总廊清率Cl=6.34±2.37L/h,血药浓度—时间曲线下面积Auc=136.91±50.58ng/ml/h;第七天药物动力学参数:T_(max)=3.46±1.12h,C_(max)=6.92±2.39ng/ml,t_(1/2)β=14.45±4.55h,K_a=0.4584±0.1640h,V_d=147.81±76.01L,Cl=6.95±4.21L/h,Auc=134.25±56.29ng/ml/h。比较服药第一天和第七天的药物动力学参数经(?)t-test 计算,两者之间无统计学差异。服药期间,每日血标本用RIA法测定雌二醇E_2,孕酮P,促黄体生长激素LH,促卵泡激素FSH,和促泌乳激素PRL。结果发现血内FSH 水平明显偏低,6例中4例LH 峰偏低或消失;有两例孕酮峰消失;E_2及PRL 的变化较小,其值在正常范围内。     

左旋18-甲基炔诺酮两种产品的药代动力学比较

本文报告两种均含0.75mg左旋18-甲基炔诺酮(LNG)的事后片的药代动力学研究。每例对象服药后0～24小时的血清LNG浓度以放射免疫法进行测定;药—时曲线由微机以迭代法进行拟合,均符合二室开放模型。结果显示口服Postinor和国产片以后,血清LNG峰值,C_(max)分别为11.25±3.39(X±SD,下同)和5.89±1.72ng/ml(P<0.001);达峰时间T_(max)分别为1.9l±0.58 和3.08±1.24h,吸收半寿期T_(1/2a)分别是0.88±0.23和1.38±0.69h,服药后0～24h的药-时曲线下面积AUC_(0～24)分别为92.19±34.34和64.40±21.97ng/ml(P<0.05),两者亦均有明显差异。提示口服Postinor以后,LNG的吸收更迅速,更完全。然而服药后分布半寿期T_(1/2α)、消除半寿T_(1/2β)和总廓清率CL在统计学上无显著差异。故提示两种制剂经口服以后在体内的分布和消除过程较为相似。本文结果表明Postinor中LNG剂量可适当减少,而国产事后片若能改进制剂工艺,提高生物利用度也可适当减少剂量。     

米索前列醇阴道重复给药的药代动力学研究

目的:探索米索前列醇重复给药终止孕9～12周妊娠的药代动力学变化。方法:研究共纳入受试者11例,米索前列醇600μg(3片)阴道给药,间隔6h,继续给药1次(400μg)。采集不同时点血液样本,采用液相色谱-串联质谱法(LC/MS/MS)法测定受试者血浆中活性代谢物米索前列酸(MPA)浓度,并计算相关药代参数。结果:米索前列醇片阴道给药后其活性代谢产物米索前列酸血浆浓度在2h左右达峰值,半衰期约为5h,重复给药后血药浓度略有升高,差异无统计学意义。结论:米索前列醇阴道用药产生较高浓度的MPA,且在妊娠妇女体内维持较长时间,有较高的生物利用度,重复给药后血药浓度略有升高,无明显药物蓄积,安全性好。     

新型左炔诺孕酮/炔雌醇复方避孕贴剂的家兔药代动力学研究

目的:探讨新型左炔诺孕酮(levonorgestrel,LNG)和炔雌醇(ethynylestradiol,EE)在家兔体内的药物动力学特征,评价多次给药后是否出现药物蓄积情况。方法:家兔在单次和多次给药及停止给药后不同时间点耳缘静脉采血,选择放射免疫分析(radioimmunoassay,RIA)法测定各时间点各组家兔雌/孕激素的血药浓度,使用药物动力学软件计算各药物动力学参数并对其进行统计分析。结果:单次给药后受试贴剂低(10cm2)、中(20 cm2)和高剂量(40 cm2)组血清LNG峰浓度(Cmax)分别为1.04±0.12 ng/ml、2.42±0.60 ng/ml和4.90±1.39 ng/ml,3组间有显著差异(P<0.05)。血药浓度-时间曲线下面积(AUC)分别为49.93±9.79h.ng/ml、115.14±34.25 h.ng/ml和251.22±80.55 h.ng/ml,3组间有显著差异(P<0.01);血清EE峰浓度(Cmax)分别为112.00±45.50 pg/ml、139.23±28.23 pg/ml和290.26±66.62 pg/ml,中、高剂量组间有显著差异(P<0.05),而中、低剂量组间无统计学差异(P>0.05)。EE血药浓度-时间曲线下面积(AUC)分别为4.70±1.34 h.ng/ml、6.59±1.23h.ng/ml和16.59±2.33 h.ng/ml,中、高剂量组之间有显著差异(P<0.01)。Evra参比避孕贴剂组血清LNG浓度的Cmax为3.16±1.00 ng/ml,AUC为155.29±46.14 h.ng/ml,与LNG/EE避孕贴剂中剂量组(拟采用的临床试验剂量)相比,两者无显著差异(P>0.05)。中剂量组血清EE浓度与Evra避孕贴剂的相比显著降低(P<0.05)。多次给药后LNG/EE避孕贴剂10 cm2组和20 cm2组在重复给药10次的过程中未出现LNG和EE血药浓度蓄积现象,Evra贴剂组在重复给药4次的过程中未出现LNG和EE血药浓度蓄积现象。结论:中剂量的LNG/EE避孕贴剂具有良好的避孕效果,同时其副作用可能小于Evra。     

预痫时硫酸镁静脉给药法和肌肉给药法的比较

不经肠道应用硫酸镁在阻止子痫和防止预痫时的抽搐非常有效.作者对32例预痫病人进行前瞻性研究,比较连续静脉输入与肌注硫酸镁的血镁水平.32例轻度预痫(血压至少140/90mmHg、蛋白尿)和重度预痫病人(间隔6小时两次血压至少160/110mmHg、蛋白尿)中14例连续静脉内给与,50%硫酸镁4g溶于5%葡萄糖250ml在15分钟内滴完,再用1g/dl/hr或2g/dl/hr的维持量维持各7例;另18例肌注,对重度预痫用20%硫酸镁20ml(4g)于4～5分钟输完,再肌注50%硫酸镁溶液10ml(5g)于臀部外上1/4处,然后每4小时肌注50%硫酸镁溶液10ml(5g),只要膝腱     

~(125)I-α-苦瓜子蛋白的大鼠药代动力学研究

本文采用同位素示踪技术对~(125)Ⅰ-α-苦瓜子蛋白进行药代动力学研究。药物经小鼠腹腔内吸收较快,给药后2h 吸收82.3%。大鼠静脉给药后的主要药代参数T_1/2α=1.61±0.41(h),T1/2β=48.98±8.02(h),V_c=30.94±4.18(dpm/kg),K_(21)=0.084±0.032(1/h),K_(10)=0.072±0.020(1/h),K_(12)=0.23±0.08(1/h)。消除相半衰期较长,说明药物排除缓慢。药物生物利用度76.6%,提示α-苦瓜子蛋白在体内易吸收。大鼠静脉注入~(125)Ⅰ-α-苦瓜子蛋白后,血中放射性-时间数据经拟合符合二室开放动力学模型。放射性分布结果证实,最高是肾,其次为胚胎、卵巢、子宫、肝、脂肪等组织。药物主要经尿排泄,给药24h 后,排出剂量的67.3%。胆汁排泄证实此药不易形成肠肝循环。用Sephadex G-75柱层析方法证实,代谢产物仍保持原有分子大小,未被降解。     

左旋18-甲基炔诺酮经阴道给药的药代动力学和药效学研究

本文比较了左旋18-甲基炔诺酮(LNG)制剂Postinor单剂量(0.75mg)口服和阴道给药的药代动力学,并研究了这种制剂经阴道多次给药的药代动力学及对卵巢功能的影响。征集6例月经规则的健康育龄妇女。第一周期,每例对象每次于阴道深处放置一片Postinor,共8次,每2次间隔为48小时;第二周期,每例对象口服一片相同的LNG制剂,放免测定血清LNG、雌二醇和孕酮水平。结果表明在第一周期,除1例对象在中期有一较高的雌二醇峰以外,其余雌、孕激素水平均呈明显低平状态;口服和阴道放置相同的单剂量LNG以后血清LNG浓度时间曲线分别符合二室与一室开放模型。由此提示与口服相比,Postinor经阴道给药后吸收缓慢,且血清LNG峰值低,而消除过程则两种给药途径较为相似;Postinor经阴道给药可明显抑制排卵。     

左炔诺孕酮口崩片的人体药代动力学及相对生物利用度研究

目的:比较左炔诺孕酮口崩片和市售口服片的人体药代动力学及相对生物利用度。方法:20名健康女性志愿者随机双交叉单剂量服用左炔诺孕酮口崩片和市售口服片,剂量均为0.75 mg,分别于服药前和服药后72 h内不同时间点抽取静脉血,清洗期为2周,以放射免疫分析(radioimmuno-assay,RIA)法测定血清中左炔诺孕酮的浓度,并利用SAS软件计算口崩片与市售口服片的药代动力学和相对生物利用度。结果:采用RIA测定左炔诺孕酮的最低检测限为10 pg/ml,低、中、高(300 pg/ml、2 000 pg/ml、6 000 pg/ml)3种浓度左炔诺孕酮标准质控血清的日内精密度分别为12.4%、9.3%、3.1%(n=5),日间精密度分别为4.3%、11.7%、5.7%(n=5)。口崩片和市售口服片的主要药代动力学参数分别为:tmax1.6±0.2 h、tmax1.7±0.3 h;Cmax6.2±0.8 ng/ml、Cmax6.5±1.0 ng/ml;AUC0～72 h 85.5±24.4 h.ng/ml、AUC0～72 h 90.8±27.1 h.ng/ml;AUC0-inf96.8±27.9 h.ng/ml、AUC0-inf 101.2±30.8 h.ng/ml;t1/2 25.3±3.5 h、t1/224.2±3.1 h。口崩片的AUC0～72 h、AUC0-inf和Cmax的90%置信区间分别为市售口服片相应参数的87.72%～101.87%、89.01%～103.73%和89.80%～101.75%。口崩片tmax与市售口服片相比无显著差异(P>0.05)。口崩片的相对生物利用度为96.1±18.3%。结论:建立的分析方法准确灵敏,可用于左炔诺孕酮血药浓度的测定;左炔诺孕酮口崩片与市售口服片的生物利用度无显著性差异,2种制剂具有生物等效性。     

高效液相色谱分析人血中RU486及其代谢产物

本文采用HPLC分析RU 486及其代谢产物。分析用200mm×3.5mm ODS/YWG柱(青岛海洋化工厂担体),流动相为甲醇:乙腈:水42:28:30(V:V:V),pH4.7,流速1ml/min,紫外检测为302nm。在此色谱条件下,能使RU 486及其三种代谢产物得到很好分离。四种化合物的标准曲线在100～2800ng/ml浓度范围内,线性的相关系数为0.999。RU 486和其代谢产物去单甲基衍生物(RU 42633),丙炔醇衍生物(RU 42698)不同浓度的回收率均达90%左右,另一代谢产物去双甲基衍生物(RU 42848)的回收率为60%左右,本方法已用于RU 486及其代谢产物的临床药代动力学研究。     

黄体酮阴道环在家兔的药代动力学研究

目的:提供研制可供哺乳期妇女避孕的黄体酮阴道环的药理学依据。方法:将18只去卵巢后2周的新西兰雌兔随机分为3组:阴道环低剂量组(175mg,A组)、高剂量组(350mg,B组)及肌注组(C组),分别在放置阴道环及肌注黄体酮前后不同时点取静脉血,用磁性分离酶联免疫法测定兔血清中黄体酮的浓度,用PK-Graph程序计算药代动力学参数。结果:黄体酮阴道环和黄体酮注射剂在兔体内的药代动力学符合二室开放模型。主要药代动力学参数分别是A组:Tmax:2.23±1.3h,Cmax:47.64±23.58ng/ml,T1/2:818.08±511.77h,AUC:16115.11±8398.88ng·ml·h-1;B组:Tmax:2.03±1.33h,Cmax:74.04±24.57ng/ml,T1/2:730.31±306.49h,AUC:28751.95±7151.95ml·h-1;C组:Tmax:1.54±0.77h,Cmax:138.88±60.96ng/ml,T1/2:2.55±0.89h。其中A组的AUC(56d)明显低于B组,二者有显著性差异(P<0.05);A组和B组的Cmax均低于C组,差异显著(P<0.05);A组和B组的T1/2均明显高于C组(P<0.01),但A、B组间无差异。结论:与传统的黄体酮注射剂相比,黄体酮阴道环的药代动力学参数呈现明显的长效缓释特征。应可成为安全长效且使用方便的哺乳期避孕药具。     

RU 486处理后大鼠垂体前叶对GnRH反应的影响

本实验选用动情前期的雌性Sprague-Dawley 大鼠在GnRH 刺激之前不同时间(0,0.5,1,2,24,48h)先肌肉注射RU 486,剂量为2mg/kg 体重,大鼠麻醉后由外颈静脉插入套管,从套管中分两次(0及1h)注入GnRH 各100ng,随后分别不同时间采血,用放射免疫法测定血浆中的LH 含量。实验结果显示在GnRH 诱导后LH 分泌出现两次高峰,正常对照组大鼠与注射RU 486的实验组大鼠作比较,实验组的LH 分泌量在0,0.5,1,2h 与对照组比有明显的降低,P<0.05;24和48h 实验组与对照组比P>0.05无明显差异;实验进行到4h 后血浆中LH 的浓度都逐渐恢复到起始基准线所需的时间,RU 486实验组与正常对照组无显著性差异(P>0.05)。以上实验表明RU 486处理后会显著降低大鼠垂体对GnRH 的反应,而对LH 水平的恢复无明显影响。     

The value of an antiprogesterone steroid in the treatment of extra-uterine pregnancy. Preliminary results

The aim of this work is to study the effects of an antiprogesterone drug (RU 486) on extrauterine pregnancy and to draw from it possible inferences for therapy. The study was carried out on 28 patients presenting an extrauterine pregnancy, the levels of plasma chorionic gonadotrophins of whom were higher than or equal to 250 mIU/ml. Different modes of administration were employed and a coelioscopic salpingotomy was carried out for a pathological study.     

The effect of cis-platinum (CDDP) on methotrexate-resistant choriocarcinoma cell line

Cis-platinum (CDDP) was investigated in vitro and in vivo for its ability to inhibit the growth of Methotrexate (MTX)-resistant choriocarcinoma cell line (BeWo) and was compared with the effect of MTX and Actinomycin D (ACD). Each drug was added into medium (RPMI 1640 containing 10% FBS) for 1 hr. at the concentration of peak plasma level in clinical use (CDDP 7 X 10(-6)M, MTX 10(-6)M, and ACD 8 X 10(-8)M), or for 48 hrs. at one-tenth of the level. CDDP inhibited the cell growth to 40% of control at 7 X 10(-6)M for 1 hr., and 25% at 7 X 10(-7) M for 48 hrs. And ACD suppressed the cell growth to 10% at both 8 X 10(-8)M for 1 hr. and 8 X 10(-9)M for 48 hrs. But MTX did not inhibit the cell growth at 10(-6)M for 1 hr., and inhibited to 60% of control at 10(-7)M for 48 hrs. On the other hand, BeWo transplanted to athymic nude mice (CD-1(ICR) nu/nu) was treated with intraperitoneal injections of CDDP (1.4 mg/kg/day for 4 consecutive days in a week and repeated for 2 and 4 weeks), MTX (2mg/kg/day for 4 consecutive days in a week and repeated for 2 weeks), and ACD (90 micrograms/kg/day for 4 consecutive days in a week and repeated for 2 and 4 weeks). The suppression of the tumor growth was seen in CDDP-treated group (TRW/CRW = 6.5%) and ACD-treated group (TRW/CRW = 29%) after 2 courses of treatment, but no apparent suppression was shown in the MTX-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

国产半合成米非司酮临床药代动力学

２４例早孕妇女分别口服不同剂量的国产半合成米非司酮（ＲＵ４８６），以ＨＰＬＣ测定其血清母药及其代谢产物（ＲＵ４２６３３，ＲＵ４２８４８和ＲＵ４２６９８）浓度，并以免疫火箭电泳测定α－酸糖蛋白（ＡＡＧ）血清水平。结果显示米非司酮吸收和代谢均很迅速，口服２０ｍｉｎ后可测得母药．２ｈ以后ＲＵ４２６３３水平开始超过母药水平。母药峰浓度（ＣＭＡＸ）与剂量不成比例。按二室开放模型和非空模型计算，母药消除半衰期均随剂量而变化。但在６００ｍｇ组，ＣＭＡＸ与０、２４和４８ｈ的ＡＡＧ平均水平呈显著正相关（ｒ＝０．９２９９，Ｐ＜０．０１），结果提示米非司酮在人体内代谢里非线性过程，ＡＡＧ在一定程度上影响该化合物血清浓度与代谢过程。     

The effect of the anti-progestin mifepristone (RU 486) on plasma prostaglandin metabolite levels in early pregnancy and its influence on pregnancy termination

The effect of a single dose of RU 486 (600mg) on prostaglandin metabolite levels has been studied over a 48 h period in 20 women undergoing medical termination of early pregnancy. The results were compared with controls of similar gestation who were treated surgically. The mean (SD) PGEM levels at 0 and 48 h in the RU 486 group were 13.7 (2.7) and 13.2 (2.2) pg/ml respectively, which was not significantly different from the values of 11.7 (1.1) and 11.3 (0.4) pg/ml measured in the control patients. Similarly the mean (SD) PGFM values of 22.3 (14.7) and 17.0 (7.2) pg/ml at 0 and 48 h were not significantly different from the corresponding control values of 21.9 (13.8) and 23.8 (7.2) pg/ml. In 10 of the study patients, there were no significant changes in PGEM and PGFM concentrations prior to and at 4, 24 and 48 h after RU 486 administration. Although all pregnancies were successfully terminated with the combination of RU 486 and subsequently a vaginal pessary containing PGE1, no stimulation of prostaglandin production could be demonstrated.     

The effect of progesterone and RU486 on progesterone production in the ovulatory process of rats

To clarify the autoregulatory mechanism of progesterone (P) production in the ovulatory process, we examined the ovarian concentration of P 46 hrs after PMSG and the effects of P and RU486 (RU) injected 4-2 hrs before hCG administration on the serum concentrations of P and estradiol (E2), and ovarian 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activities in PMSG/hCG treated immature rats. The effect of RU on the number of ovulated ova was also studied. The ovarian concentration of P 46 hrs after PMSG was 0.96 +/- 0.03,ng/mg protein (mean +/- SEM). When P (100,mg/kg) was injected 2 hrs before hCG, ovarian 3 beta-HSD activities had significantly increased by 4 hrs after hCG. However, P at a dosage of 10 and 20,mg/kg had no effect on ovarian 3 beta-HSD activities. The administration of RU (20,mg/kg) 2 hrs before hCG significantly inhibited ovarian 3 beta-HSD activities measured 4 and 6 hrs after hCG (p less than 0.01 and p less than 0.05, respectively). In addition, the serum P concentration 4 hrs after hCG was significantly lower than that of the control (p less than 0.01). However, RU (20 mg/kg) in concomitant with hCG had no effect on ovarian 3 beta-HSD activities within 6 hrs after hCG. The suppression of ovarian 3 beta-HSD activities by RU was the concomitant reversed by the concomitant treatment with P (10 mg/kg). RU (10, 20, or 40 mg/kg) injected 2 hrs before hCG significantly reduced the number of ovulated ova (p less than 0.01, p less than 0.01 and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of gossypol on immature male rats

In immature male rats the body growth rate, the testis and epididymis weight were not affected by gossypol treatment (4, 8 and 40 mg/kg body weight/24 hrs. for 30 days). There was however a marked reduction in the weight of the prostate after high dose gossypol administration. Furthermore gossypol treatment did not show any effect on the histoarchitecture of the testis nor did the drug treatment have any effect on sperm motility. The plasma levels of testosterone, LH and FSH in gossypol treated animals were no different from those on the controls.     

Antiprogesterone steroid RU486. Pharmacokinetics and receptor binding in humans

A researcher in Helsinki, Finland conducted laboratory research on the pharmacokinetics, tissue distribution, serum binding properties, and binding affinities of RU-486 and its major metabolites. After oral administration of different single doses, absorption was rapid. RU-486 levels packed around 1 hour. Serum levels plateaued at 2.5 umol/1 for 24-48 hours and could still be measured for 5-7 days. There existed highly significant correlations between alpha1-acid glycoprotein (AAG), the main serum transport protein for RU-486, and serum concentrations of RU-486. As concentrations of RU-486 climbed from 2.5 umol/1, the available RU-486 for excretion or tissue distribution increased rapidly. Hence, AAG saturation may account for the similar serum concentrations of RU-486 following various doses. This also occurred following multiple doses of 50 mg RU-486. This phenomenon may explain why no correlation exists between the administration of RU-486 and clinical outcome when it is used to induce an abortion. RU-486 was detected in the myometrium at levels about 1/3 of those in serum, in fat at levels similar to those in serum, and in the enterohepatic cycle. The major metabolites retained moderate affinities of 9.21% to the progesterone receptor when compared with RU-486 (=100%). The inability of various doses to affect the clinical performance of RU-486 and the actions of RU-486 and its metabolites after oral intake suggest that the metabolites insignificantly affect the antiprogesterone action of RU-486. The affinities of these metabolites for the glucocorticoid receptor were higher (45-61%), however, perhaps causing the antiglucocorticoid effects of RU-486 at high oral doses. Based on these results, low doses of RU-486 (20-50 mg) could effectively terminate an early pregnancy.     

孕妇及非孕妇口服不同剂量RU 486后的药物动力学研究

非孕妇(n=9)及早孕妇(n=36)口服不同剂量RU 486后,以HPLC测定服药后RU486及其代谢产物RU 42633、RU 42848和RU 42698的血浆浓度,结果显示不论妊娠与否,药物的吸收及代谢都很迅速;服药后20 min 即可测得血浆中的RU 486及其代谢产物;母药达峰时间Tmax 均为1～2h,其峰浓度Cmax 对数与剂量对数之间呈显著正相关。服相同剂量后,非孕组药-时曲线水平及药时曲线下面积AUC 大于早孕组,但两组间并无显著性差异(P>0.05)。无论非孕组及早孕组,口服25 mg、100 mg 和200 mg后,RU 486代谢符合二室开放模型,口服400 mg 和600mg 后则呈非线性动力学过程。