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。     

RU486对OHSS模型大鼠血管内皮生长因子产生的作用

目的:探讨RU486对卵巢过度刺激综合征(OHSS)模型大鼠血管内皮生长因子(VEGF)产生的作用。方法:30只22日龄雌性大鼠,从22日龄起每天皮下注射10IUPMSG连续4d,26日龄时皮下注射100IUhCG,建立OHSS模型。在27日龄将上述大鼠随机分成5组,每组6只。其中4组(A-D组)为实验组,分别皮下注射不同剂量(1mg/kg、5mg/kg、10mg/kg、20mg/kg)的RU486;另一组为对照组不给药。RU486注射48h后,采用酶联免疫吸附试验方法测定血清和腹腔冲洗液中VEGF水平;采用免疫组织化学法和逆转录聚合酶链反应技术检测卵巢组织VEGF蛋白质和mRNA的表达。结果:B组和C组的血清VEGF水平分别为55.00±14.13pg/ml和49.67±17.44pg/ml,均显著低于对照组(76.17±18.19pg/ml)(P<0.05)。同样,B组和C组的腹腔VEGF水平分别为10.43±6.80pg/ml、10.30±5.82pg/ml,也均显著低于对照组(17.12±1.71pg/ml)(P<0.05)。B组和C组的卵巢组织VEGF蛋白质和mRNA的表达显著低于对照组(P<0.05)。结论:适当剂量的RU486能够降低OHSS模型大鼠VEGF的产生。     

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。     

Trem-1在子宫内膜异位症中的表达

目的:研究髓样细胞触发受体(Trem-1)在子宫内膜异位症(endometriosis,EMs)中的表达和作用。方法:应用实时定量RT-PCR方法检测EMs患者外周血白细胞膜表面的Trem-1mRNA表达;同时收集血清及腹腔液,应用ELISA法检测其中可溶性Trem-1(sTrem-1)水平。并以正常妇女为对照,进行比较。结果:EMs组β-actin/Trem-1Ct值为0.77±0.02,正常对照组为0.70±0.04。在EMs组中,Trem-1mRNA表达明显高于对照组(P<0.05)。EMs组血清中sTrem-1的浓度为22.16±5.37ng/ml,正常对照组为9.78±0.84ng/ml,EMs组腹腔液中sTrem-1水平为33.60±5.14ng/ml,正常对照组为14.60±3.13ng/ml,二组均具有显著差异(P<0.01),且腹腔液中的浓度明显高于血清中的浓度(P<0.05)。结论:Trem-1可能在子宫内膜异位症的发生发展过程中具有重要的作用。     

氧化应激在高氧肺损伤发生中的作用及N乙酰半胱氨酸的干预效果

目的探讨氧化应激在高氧肺损伤发生机制中的作用,并观察N乙酰半胱氨酸(N-ace-tylcysteine,NAC)的干预效果,以期为临床防治高氧肺损伤提供一条新的有效途径。方法光镜观察肺组织病理形态学;ELISA方法检测各亚组大鼠血浆8异前列腺素F2α含量,并比较高氧模型组与空气组及不同剂量NAC组大鼠血浆8异前列腺素F2α含量之间的差别。结果高氧模型组第3、7天,肺泡大小不等,肺泡内有出血和炎症细胞浸润;第14、21天肺泡间隔增厚。高氧+大剂量NAC组第3、7天肺泡内极少量红细胞渗出;第14、21天肺泡间隔无明显增厚。各时间点血浆8异前列腺素F2α含量高氧模型组分别为(28.33±5.57)pg/ml、(51.21±15.01)pg/ml、(84.54±14.85)pg/ml、(43.14±11.37)pg/ml,空气组为(19.09±5.57)pg/ml、(18.24±5.91)pg/ml、(17.00±5.58)pg/ml、(17.85±5.00)pg/ml,高氧+大剂量NAC组为(20.90±4.33)pg/ml、(37.30±12.86)pg/ml、(51.99±11.91)pg/ml、(29.37±9.41)pg/ml。高氧模型组各时间点血浆8异前列腺素F2α含量与空气组、高氧+大剂量NAC组比较差异均有统计学意义(P<0.05),与高氧+小剂量NAC组比较差异无统计学意义(P>0.05)。结论氧化应激与高氧肺损伤密切相关,NAC对高氧肺损伤的氧化应激作用具有明显的干预作用,其作用具有剂量依赖性。     

妇女血清可溶性Fas/FasL与反复自然流产的关系初探

目的:探讨妇女血清可溶性Fas/FasL(sFas/sFasL)在反复自然流产(RSA)发病中的作用。方法:采用ELISA法检测62例RSA妇女(RSA组)、34例正常妊娠妇女(正常妊娠组)和34例正常非孕妇女(对照组)血清sFas/sFasL水平。结果:RSA组sFas含量(1051.44±420.87pg/ml)高于对照组(529.49±241.01pg/ml),差异有显著性(P<0.05);正常妊娠组sFas含量(520.19±253.82pg/ml)与对照组相比差异无显著性(P>0.05)。RSA组、正常妊娠组、对照组sFasL含量分别为1.29±0.82ng/ml、1.20±0.85ng/ml、1.32±1.01ng/ml,3组间比较,差异无显著性(P>0.05)。结论:反复自然流产的发生可能与血清sFas水平升高有关,而与血清sFasL无明显相关。     

卵巢过度刺激综合征患者血管内皮生长因子的变化

目的:探讨卵巢过度刺激综合征(OHSS)发病过程中血管内皮生长因子(VEGF)的作用机理。方法:ELISA法测定hCG注射日、胚胎移植日血清及取卵日卵泡液VEGF浓度;半定量RT-PCR技术检测取卵日颗粒细胞VEGF mRNA的表达。结果:OHSS组与非OHSS组血清VEGF浓度相比,hCG注射日未见显著性差异(102.5±40.8比90.23±34.62 pg/mL,P>0.05),胚胎移植日则差异显著(150.93±59.91,104.18±20.76 pg/mL,P<0.01);两组卵泡液相比有显著性差异(782.86±136.87比362.5±231.85 pg/ml,p<0.05)。OHSS组hCG注射日与胚胎移植日血清VEGF浓度有显著性差异,而对照组则未见差异。半定量RT-PCR结果显示,两组VEGF/β-actin之比有显著差异(0.54±0.24比0.27±0.12,P<0.01),OHSS组VEGF mRNA表达明显增强。结论:VEGF在OHSS发病机理中起一定作用。卵泡液及胚胎移植日血清VEGF浓度与OHSS的发生有着密切的关系。     

血清前列腺素E_2预测左炔诺孕酮缓释系统治疗子宫腺肌病痛经效果的价值探讨

目的:探讨子宫腺肌病(adenomyosis,ADS)患者血清前列腺素E2(prostaglandin E2,PGE2)水平预测左炔诺孕酮缓释系统(levonorgestrel-releasing intrauterine system,LNG-IUS)治疗ADS痛经效果的可能性。方法:因ADS痛经放置LNG-IUS的患者41例,根据痛经缓解情况分为治疗有效组(n=32)和治疗无效组(n=9)。ELISA法测定放置LNG-IUS前及放置后6个月血清PGE2水平并进行组内、组间比较,分析LNG-IUS对ADS痛经患者血清PGE2水平的影响以及血清PGE2水平与LNG-IUS治疗痛经效果的相关性。结果:有效组血清PGE2水平治疗前为20.95±3.07 pg/ml,治疗6个月后为5.56±1.72 pg/ml,差异有统计学意义(P<0.05)。无效组血清PGE2水平治疗前为5.74±1.12 pg/ml,治疗6个月后为4.95±1.39 pg/ml,两者无统计学差异(P>0.05)。治疗前有效组血清PGE2浓度显著高于无效组(P<0.05)。患者放置LNG-IUS 6个月后视觉模拟评分(visual ana-logue scale,VAS)变化与放置前血清PGE2水平呈正相关,血清PGE2浓度越高,VAS下降越明显(P<0.05)。结论:PGE2可能与部分ADS患者痛经的发生有关,LNG-IUS通过降低PGE2浓度而缓解痛经,因此高水平PGE2患者可选择LNG-IUS治疗痛经,低水平PGE2患者则建议选择其他方式治疗痛经。     

血小板活化因子和卵巢过度刺激综合症发病的关系

目的 :建立过度刺激卵巢模型 ,探讨血小板活化因子 ( PAF)在卵巢过度刺激综合症( OHSS)发病中的变化。方法 :未成年 Wistar雌鼠 ,连续 4d皮下注射 PMSG1 0 IU,d5注射 h CG 3 0 IU,48h后取腹腔灌洗液 ,用分光光度计测腹腔和卵巢的血管通透性。取尾静脉血测 PAF含量、血浆血小板活化因子乙酰水解酶 ( PAF-AH)活性及血小板聚合功能。另设生理盐水对照组。结果 :PMSG+h CG组腹腔灌洗液中美兰的含量为 5.6 1 8±1 .1 3 3μg/1 0 0 g体重 ,显著高于对照组的 0 .976± 0 .2 2μg/1 0 0 g体重 ( P<0 .0 1 )。卵巢PAF含量 PMSG+h CG组为 1 1 .3 51± 0 .46 9pmol/卵巢 ,显著高于对照组的 1 .0 0 0±0 .1 0 8pmol/卵巢 ( P<0 .0 1 )。PAF-AH活性 :PMSG+h CG组 d5和 d7分别为 40 .0 2 7±1 3 .791 pmol/min· ml和 1 8.90 9± 9.783 pmol/min· ml,显著低于对照组的 57.875±1 4 .2 2 8pmol/min· ml和 53 .82 1± 1 6 .71 4 pmol/min· ml( P<0 .0 1和 P<0 .0 0 1 )。结论 :注射 PMSG和 h CG后 ,雌鼠卵巢 PAF含量增高 ,并使腹腔和卵巢血管通透性增高 ,导致 OHSS。血浆 PAF-AH在 OHSS发病中可能通过调节 PAF的水平而发挥作用。     

Transfer of drospirenone to breast milk after a single oral administration of 3 mg drospirenone + 30 μg ethinylestradiol to healthy lactating women

Drospirenone (DRSP) is a synthetic progestogen which has been developed in combination with ethinylestradiol (EE) for use as an oral contraceptive (Yasmin^®, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of DRSP were evaluated in serum and breast milk from lactating women who received a single oral dose of 3 mg DRSP + 30 μg EE, to determine the fraction of the dose of DRSP which transfers to breast milk. Nine healthy, lactating women were included into the present study and pharmacokinetic data were obtained from six participants. The maximum DRSP concentrations (data given as mean ± standard deviation) were reached on average 2.5 ± 1.2 and 2.8 ± 1.3 h in serum and breast milk, respectively after oral administration of 3 mg DRSP + 30 μg EE, and amounted on average to 30.8 ± 14.4 and 13.5 ± 11.7 ng DRSP/ml in serum and breast milk. The mean breast milk versus serum concentration ratios of DRSP increased from 0.16 to 0.57 within 2 h after dosing and decreased to 0.16 after 24 h. The average ratio of AUC_{0-48 h} values in breast milk versus serum was 0.23 ± 0.09. The mean DRSP concentration in breast milk over the 24-h period after dosing was 3.7 ± 1.9 ng/ml. The amount of DRSP measured to be transferred into breast milk in the six women participating in the present study was, on average, 635 ng (range 256.2–1357.9 ng) within 24 h, corresponding to about 0.02% of the maternal dose. Based on the average concentration of the drug in breast milk over 24 h and assuming a daily ingestion of approximately 800 ml breast milk, the daily dose that reaches an infant via breast milk is estimated to be approximately 3 μg DRSP. The subjective and objective tolerances of 3 mg DRSP + 30 μg EE were good, with no adverse events reported.     

Transdermal contraception: evaluation of three transdermal norelgestromin/ethinyl estradiol doses in a randomized, multicenter, dose-response study.

OBJECTIVE: The objective of this study was to identify the dose for a contraceptive patch that provides a predetermined level of ovulation suppression and cycle control and that is well tolerated. STUDY DESIGN: In this randomized study, 610 subjects received 10-, 15-, or 20-cm(2) patch dose sizes (20-cm(2), Ortho Evra/Evra) (Janssen Pharmaceutica, NV Belgium) or Ortho-Cyclen/Cilest (Janssen Pharmaceutica, NV Belgium) for up to 4 cycles. As with Ortho-Cyclen, patch regimens included 21 dosing days (3 consecutive 7-day patches) followed by 1 dose-free week. RESULTS: The patch regimens demonstrated a dose-response for ovulation suppression and cycle control. Presumed ovulation, determined on the basis of serum progesterone concentrations > or = 3 ng/mL in cycles 1 and 3, occurred in 6.2% (Ortho Evra) and 7.2% (Ortho-Cyclen) of subjects. At cycle 3, breakthrough bleeding/spotting was reported by 10.5% and 15.0% of subjects, respectively. Compliance with each patch was superior to that with Ortho-Cyclen (all P <.001). All regimens had safety profiles typical of oral contraceptives. CONCLUSION: The 20-cm(2) patch (Ortho Evra) provided ovulation suppression, cycle control, and safety similar to that of Ortho-Cyclen, with significantly better compliance.     

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五年内血清雌二醇、孕酮、左旋18甲基炔诺酮水平

５例使用国产长效避孕皮埋剂（Ｓｉｎｏ－Ｉｍｐｌａｎｔ，以下简称为Ｓｉｎｏ）长达五年以上的妇女，每年末抽血一个周期（即连续４～５周，每周定时抽血一次）。用ＲＩＡ测定血清中雌二醇（Ｅ２），孕酮（Ｐ）和左旋１８甲基炔诺酮（ＬＮＧ）水平。研究结果显示：长期使用Ｓｉｎｏ未出现相似的卵巢内分泌反应。８４％（２１／２５）抽血周期血清Ｅ２水平出现峰值（Ｅ２＞１５０ｐｇ／ｍｌ），以例数计，埋植后１～４年内每年有８０％（４／５）抽血周期血清中Ｅ２显示峰值，第五年为１００％（５／５）。４０％（１０／２５）抽血周期显示黄体活性（Ｐ＞３ｎｇ／ｍｌ），以例数计，埋植第一年为０％（０／５）；第二年为４０％（２／５）；３～５年每年６０％（３／５）表现黄体活性。５例对象中有２例埋植后五年内未见血清Ｐ＞１ｎｇ／ｍｌ，而且这２例分别在埋植后１～２年及３～４年未见Ｅ２峰（Ｅ２＜１５０ｐｇ／ｍｌ）。５例对象埋植前对照周期均有正常的Ｅ２峰和黄体活性。在用Ｓｉｎｏ的５年内抽血周期血清Ｅ２和Ｐ的均值都低于对照周期。在用Ｓｉｎｏ期间，有黄体活性的周期均伴有Ｅ２峰。然而，并非所有有Ｅ２峰的周期都表现黄体活性。在埋植第一年，除第一个月外，血清ＬＮＧ水平低而相对?     

Transfer of drospirenone to breast milk after a single oral administration of 3 mg drospirenone + 30 microg ethinylestradiol to healthy lactating women.

Drospirenone (DRSP) is a synthetic progestogen which has been developed in combination with ethinylestradiol (EE) for use as an oral contraceptive (Yasmin, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of DRSP were evaluated in serum and breast milk from lactating women who received a single oral dose of 3 mg DRSP + 30 microg EE, to determine the fraction of the dose of DRSP which transfers to breast milk. Nine healthy, lactating women were included into the present study and pharmacokinetic data were obtained from six participants. The maximum DRSP concentrations (data given as mean +/- standard deviation) were reached on average 2.5+/-1.2 and 2.8+/-1.3 h in serum and breast milk, respectively after oral administration of 3 mg DRSP + 30 microg EE, and amounted on average to 30.8+/-14.4 and 13.5+/-11.7 ng DRSP/ml in serum and breast milk. The mean breast milk versus serum concentration ratios of DRSP increased from 0.16 to 0.57 within 2 h after dosing and decreased to 0.16 after 24 h. The average ratio of AUC0-48 h, values in breast milk versus serum was 0.23+/-0.09. The mean DRSP concentration in breast milk over the 24-h period after dosing was 3.7+/-1.9 ng/ml. The amount of DRSP measured to be transferred into breast milk in the six women participating in the present study was, on average, 635 ng (range 256.2-1357.9 ng) within 24 h, corresponding to about 0.02% of the maternal dose. Based on the average concentration of the drug in breast milk over 24 h and assuming a daily ingestion of approximately 800 ml breast milk, the daily dose that reaches an infant via breast milk is estimated to be approximately 3 microg DRSP. The subjective and objective tolerances of 3 mg DRSP + 30 microg EE were good, with no adverse events reported.