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。     

左旋18—甲基炔诺酮经阴道给药避孕效果的临床研究

<正> 为了进一步改善甾体避孕药的有效性、安全性和可接受性,近年来有人进行了关于甾体避孕药直接经阴道给药的临床研究,结果令人满意。阴道作为性激素的靶器官之一,存在着雌、孕激素受体,能有效地吸收天然和合成的雌、孕激素。有关的动物实验结果显示把含孕激素的硅橡胶埋植剂放人大鼠、家兔的阴道,则孕激素的效能比相同剂量的注射剂至少大6～25倍,比灌饲给药大13～26倍。在妇科临床上常用雌激素制剂直接经阴道给药来治疗因雌激素水平低下所致的各种症状,也有人用孕激素制成阴道坐药来治疗黄体功能不足。含有甾     

阴道使用小剂量OC对人体排卵的影响

把20名计划生育门诊中的育龄妇女分为2组。试验周期内每天分别由阴道置入每片含左旋18甲孕酮0.15mg和已烯雌酚0.03mg的复方口服避孕片(OC)1片或2片。每个试验周期连续放药21天。在本项研究前的3个月内,所有观察对象均不曾使用过任何激素制剂。观察追随每人2个周期,对部     

达那唑经小鼠阴道和回服给药后血药浓度及子宫内含量的比较

本文采用ＨＰＬＣ法，比较小鼠阴道给药后达那唑血浆浓度及子宫组织内分布与口服给药的差异。结果是：相同剂量（１００ｍｇ／ｋｇ）的达那唑，阴道给药后在小鼠吸收入血的药量明显较口服给药的少。然而，子宫组织中的含量，在给药１ｈ内阴道给药比口服给药明显较高，１ｈ后两者含量相近。     

米非司酮阴道给药对血清雌孕激素及输卵管生理状态的影响

目的:探讨米非司酮不同给药方式对血清雌孕激素及输卵管生理状态的影响。方法:新西兰大白兔米非司酮阴道给药(6ml/kg,1mg/ml)以及灌药口服给药(6mg/kg)后不同时间,利用高效液相色谱法;放射免疫分析法;结合化学分离与原子吸收分光光度法等方法,研究血清米非司酮浓度和雌二醇、孕酮浓度以及输卵管内分泌液、输卵管组织中Ca2+浓度。结果:灌药口服给药组的各时间点血清米非司酮浓度均明显低于阴道给药组,1h,2h时间点两组有显著差异(P<0.05);两种给药方式均可使血清孕酮水平降低,雌二醇浓度明显增加。阴道给药组孕酮的浓度最低值以及雌二醇浓度的最高值均明显早于口服给药组,0.5h,1h,2h时间点两组对比之间有显著差异(P<0.05);米非司酮阴道给药与灌药口服给药对Ca2+含量的影响无明显差异(P>0.05)。结论:米非司酮两种给药方式对输卵管生理状态的影响无显著差异,阴道给药对血清孕酮、雌二醇的影响明显大于口服给药。     

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。     

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。     

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。     

氟康唑单纯口服及联合硝呋太尔片治疗外阴阴道假丝酵母菌病合并需氧菌性阴道炎的疗效观察

目的:比较口服氟康唑胶囊与口服氟康唑胶囊联合阴道放置硝呋太尔片治疗外阴阴道假丝酵母菌病(VVC)合并需氧菌性阴道炎(AV)混合感染的疗效,探讨VVC合并AV的合适治疗方案。方法:收集2014年1月至2016年11月天津医科大学总医院收治的VVC合并AV患者173例。将患者随机分为两组:89例给予口服氟康唑治疗(单药组),84例给予口服氟康唑胶囊联合阴道放置硝呋太尔片治疗(双药组),统计两组的治愈率、有效率及复发率。结果:173例患者中,91.9%为VVC合并轻、中度AV患者。单、双药组中,VVC合并轻、中度AV患者的治愈率、有效率均高于合并重度AV患者。单、双药组间比较,VVC合并轻、中度AV的治愈率(轻度:76.4%vs 73.5%,中度:77.3%vs 90.5%)、有效率(轻度:94.5%vs 93.9%,中度:95.5%vs 100.0%)差异均无统计学意义(P0.05)。结论:对于VVC合并轻、中度AV的患者,单纯口服氟康唑可取得氟康唑与硝呋太尔联合用药相同的治疗效果。     

A pharmacokinetic study with a low-dose oral contraceptive containing 20 microg ethinylestradiol plus 100 microg levonorgestrel.

This study investigated the pharmacokinetics of a dose-reduced oral contraceptive containing 20 microg ethinylestradiol (EE) + 100 microg levonorgestrel (LNG) in 18 young, healthy females. Serum levels of EE and LNG were determined after single and repeated daily oral administration over three treatment cycles, each consisting of 21 treatment days followed by a 7-day treatment-free period. Additionally, the time courses of sex hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and total and free testosterone serum levels were analyzed. Both active ingredients were rapidly absorbed and maximum concentrations in serum were reached between, on average, 1 and 2 h after single and multiple administrations, respectively. Concentrations of EE increased during repeated daily administration. An approximate two-fold accumulation was calculated based on the comparison of EE area under the curve (AUC) (0-24 h) values determined after the first and the last tablet administration within a treatment cycle. LNG serum concentrations also increased during repeated daily administration, reaching steady-state levels after about 11 days. Based on the comparison of AUC (0-24 h) values determined after the first and the last tablet administration, LNG accumulated approximately by a factor of 3 within a treatment cycle. Steady-state pharmacokinetics of LNG were similar at the end of the first and the third treatment cycles, indicating no further accumulation of LNG beyond a treatment cycle under long-term use of this combined oral contraceptive. The clearance and volume of distribution of LNG decreased and the terminal half-life increased after repeated daily administration, compared with single administration. These effects have also been reported for other LNG/EE combinations. SHBG serum concentrations increased during repeated daily intake by, on average, 1.5-1.6-fold, and for CBG, an average increase of 1.4-1.8-fold was found. Although free testosterone concentrations declined during repeated daily administration by about 40%, total testosterone remained relatively unchanged at a low level. In conclusion, the pharmacokinetics of EE and LNG determined in the present study were in good agreement with those previously reported for 30 microg EE + 150 microg LNG, taking the 33% dose reduction into account.     

使用国产长效避孕皮下埋植剂妇女第一年血清中左旋18甲基炔诺酮、雌二醇及孕酮水平

10例妇女在月经周期开始的7天内,皮下埋植国产长效避孕埋植剂。埋植后第一年内每周定时抽血一次,用RIA 测定血清中左旋18甲基炔诺酮(LNG),雌二醇(E_2)和孕酮(P)的浓度。血清中LNG 浓度在埋植后开始两周内下降较快,随后两周较缓慢地下降,在埋植后第一年内LNG 浓度几乎呈平稳状态,但显示有明显的个体差异。血清中E_2峰值频繁出现,但随后未见典型的黄体期P 值升高,在高的E_2峰值突然下降时,常伴随阴道流血出现。干扰月经是此埋植剂的主要副反应。     

Blood levels of levonorgestrel in women following vaginal placement of contraceptive pills

6 healthy women aged 25-38 years, attending a family planning clinic in the Dominican Republic, participated in an experiment to determine blood levels of levonorgestrel (1Ng) resulting from daily vaginal placement of contraceptive pills containing .5 mg dl-norgestrel and .05 mg ethinyl estradiol and to evaluate the effect on ovulation. Subjects were observed for 3 cycles. Blood samples were taken on days 14, 18, 23 and 27 following the 1st day of menses on a pretreatment cycle. In 1 cycle the pill was taken daily for 21 days by the oral route, and in another it was placed in the vagina on the same schedule. Blood samples were taken frequently during the 1st 24 hours and subsequently on days 5, 8, 12, 15, 18, and 21 of experimental cycles. Plasma levels of 1Ng reached a peak of 3-4 ng/ml 1-4 hours after oral administation of dl-norgestrel and fell slowly thereafter to a level slightly over 1 ng at 24 hours after ingestion. Plasma concentrations of 1Ng rose at a slower rate and reached a lower peak value after vaginal placement. After 4 hours the 2 curves were approximately parallel. The mean 1Ng plasma concentration 24 hours after vaginal insertion was less than 1/2 the value after oral administration. The differences in plasma levels were statistically significant for each of the times studied. Differences were most pronounced in the 1st 2 weeks. In each pretreatment cycle, progesterone levels reached a peak above 4 ng/ml, indicating ovulation. All but 1 treatment cycle by either route had progesterone values suggesting anovulation; the exception was a vaginal administration cycle. 4 of the 6 women maintained low estradiol levels, mostly between 20-40 pg/ml, during treatment cycles by either route. The lower plasma levels of 1Ng after vaginal insertion of pills may reflect inefficient absorption of steroids within the vagina, or a difference in metabolic degradation when the drug is administered parenterally via the vaginal blood supply. It was still possible to suppress ovulation in 5 of the 6 vaginal cycles without attempting to adjust the dose.     

A clinical study on the contraceptive effect of vaginal application of levonorgestrel]

50 healthy women aged 27-39 were screened and participated in an clinical study on the vaginal application of levonorgestrel (LNG) as a contraceptive. Among the 50 women, 27 had live births and 23 had abortions as the result of their last pregnancy within 5 years. They had regular menstruation for the past 3 months, and no disease of the liver, heart, or urinary system. 0.75 mg LNG tablets produced by Beijing Pharmaceutical Manufacturers were chosen for the study. All the participants were instructed to put one tablet into the upper end of vagina every other day from the seventh day of the menstrual cycle with 8 tablets per cycle. 258 cycles of pills were used by the 50 participants. 953 acts of sexual intercourse were recorded during the study with 3.69 per cycle on average. Even though pills were missed in 28 cycles, there was only 1 case of pregnancy. The pill use affected the duration of the menstrual cycle, with mean duration of 27.8 days + or - 4.1 days. Vaginal bleeding occurred in 13 cycles (4.06). Side effects including sickness, backache, breast pain, and increased vaginal secretion occurred only in 3.89% of the cycles, which was much lower than in oral administration. No vaginal infection occurred in any of the cases. 10 participants dropped out before the end of study, including 1 who became pregnant. 44 participants, including 4 drop-outs, wanted to continue with the method. Vaginal application of progesterone is a promising means of contraception. But, as the study has a small sample size and short duration, is further research to prove the advantage of vaginal application over oral administration in terms of effectiveness, side effects, longterm safety, an acceptability.     

Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women

OBJECTIVE: To investigate the pharmacodynamic effects and plasma pharmacokinetics of single subcutaneous doses of cetrorelix acetate in healthy premenopausal women. SETTING: Phase I clinical research unit. PATIENT(S): Healthy, premenopausal women aged 19 to 35 years. INTERVENTION(S): Single subcutaneous morning doses of cetrorelix acetate (1, 3, or 5 mg peptide base) were investigated in a randomized, single-blind, placebo-controlled, parallel-group design. After a control cycle, 36 women received cetrorelix acetate (12 per dose) and 12 received placebo on the eighth individual cycle day. Transvaginal ultrasound was performed, and blood samples for LH, FSH, E2 were collected during both cycles and for pharmacokinetics up to 168 hours after dosing. The serum hormone levels were determined by electrochemicoluminescence immunoassay and plasma cetrorelix concentrations by radioimmuno assay. RESULTS: Cetrorelix acetate administration led to a rapid, marked, and reversible suppression of serum LH, E2, and to a lesser extent FSH concentrations. The median intra-individual shifts between treatment and control cycle were -1.0, 4.0, 8.0, and 9.5 days for serum LH maximum and -1.0, 4.5, 7.0, and 10.0 days for ovulation following placebo or 1, 3, and 5 mg cetrorelix acetate, peptide base, respectively. The area under the concentration-time curve (AUC) and peak cetrorelix concentrations in plasma (Cmax) increased proportionally with dose. CONCLUSIONS: Cetrorelix acetate showed pronounced and reversible LH and E2 suppression and a dose-dependent postponement of LH surge and ovulation after single subcutaneous administrations to healthy premenopausal women. Dose proportionality over the range of 1 mg to 5 mg cetrorelix acetate, peptide base was demonstrated.     

New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea.

OBJECTIVE: To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. DESIGN: This was an open-label study. PATIENTS: Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. MAIN OUTCOME MEASURES: Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. RESULTS: Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. CONCLUSIONS: The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.     

RU486合并前列腺素终止早孕的效果及对性激素影响的研究

4O例早孕妇女,停经49天以内,给予RU 486合并前列腺素(Sulprostone)终止早孕。对象随机分为两组(每组20例)。组Ⅰ,口服RU 486 25mg2次/日×4天,在第四天上午肌注Sulprostone 0.25mg;组Ⅱ,RU 486 25mg2次/日×3天,在第三天上午肌注Sulprostone 0.25mg。对象必须从服药的第一天起连续四天(组Ⅱ三天)上午来门诊,此外第8、15及43天亦须来门诊,接受访视及取血,用以测定B-hCG、E_2、P、PRL及Cortisol等。检测结果,血清B-hCG及E_2水平在服药期间继续上升,但流产后迅即下降;PRL及Cortisol在服药期间及服药后,血清水平上下波动不大;P在服药期间水平未见上升,但流产后迅即下降。40例对象,不论服药三天或四天,均发生完全流产,无一例需要刮宫或输血。     

Serum progesterone levels following vaginal administration of progesterone during the luteal phase

We measured serum progesterone (P) levels after administration of 400 mg P vaginal suppositories to women during the luteal phase of the menstrual cycle. Blood samples were obtained before suppository insertion and at five intervals up to 8 hours after insertion. On the first day of treatment with P suppositories, there was a substantial elevation in serum P above baseline after insertion. However, on subsequent days of administration a smaller increment in serum P was observed. In 4 women studied on days 1 and 8 of the same treatment cycle in the luteal phase, a smaller rise in serum P following suppository administration on day 8, compared with day 1, was found. Overall, a highly significant negative correlation between change in serum P from baseline and duration of vaginal suppository treatment was found. This observation does not appear to be related to the achievement of a pharmacokinetic steady state. Possible mechanisms for this observation are discussed.     

卵泡刺激素刺激后血清抑制素B和雌二醇预测体外受精周期中卵巢的反应性及其相关性

目的 探讨以经重组卵泡刺激素（rFSH）刺激后体外受精（IVF）周期中不同时间血清抑制素B（INHB）、雌二醇（E2）的动态变化,预测不孕患者卵巢的反应性,为选择最佳的超促排卵方案提供理论依据。方法 采用酶联免疫吸附试验,测定57例不孕患者（年龄〈40岁）于IVF周期中的不同时问,即月经第3天、注射rFSH前、注射rFSH后1d,及注射rFSH后5d的血清INHB、E2水平,并与反映卵巢反应性的2个指标——获卵数／rFSH总量、（卵泡数／rFSH总量）的平方根进行相关性分析。根据本研究中卵泡数及获卵数、是否发生卵巢过度刺激综合征（OHSS）的情况,将57例患者分为低反应组、过度刺激组及正常反应组,比较3组注射rFSH后INHB及E2水平的变化。结果 （1）注射rFSH后1、5d,其血清INHB及E：水平均与卵巢反应性呈显著正相关（INHB：rS=0．69—0．73,E2：rS=0．60～0．73;P=0．000）。（2）低反应组、正常反应组及过度刺激组注射rFSH后5d,患者血清INHB水平分别为164．7、696．2及1263．5ng／L,E2水平分别为303．2、1709．5及4261．0pmol／L,低反应组明显低于正常反应组,正常反应组明显低于过度刺激组,3组分别比较,差异均有统计学意义（P（0．01）。结论 经rFSH刺激后,血清INHB及E2水平能较敏感地预测卵巢对rFSH刺激的反应性,且INHB比E2更敏感。INHB及E2水平降低,可预测卵巢的低反应性;反之,可预测发生OHSS。