复方18甲基炔诺酮透皮控释传递系统的LNG人体药物动力学与药效学评价

复方18甲基炔诺酮/雌二醇透皮控释传递系统(LNG/E_2 TCDS)能同时恒速释放低剂量的LNG和E_2,在1周内维持一个平稳而有效的LNG血药浓度。药动学与药效学研究证明,该系统释放的LNG能达到血清LNG目标水平,产生有效的排卵抑制(6/6)。LNG/E_2 TCDS可望发展成为一种安全、有效、非侵入性的新型生育调节避孕制剂。     

Effects of Progestin and Antiprogestin on the Expression of FSH Receptor and LH Receptor mRNA in Porcine Granulosa and Thecal Cells

In order to investigate the mechanism of progestin and antiprogestin in the regula tion of ovarian steroidogenesis, a dual-chamber culture system was prepared with the amnion membrane of human placenta. Isolated porcine granulosa and thecal cells from 4～6 mm-diameter follicles were grown on both sides of the amnion, respectively, and co-cultured with or without LNG and RU486. After 48 h incubation, the mRNAs of FSH receptor (FSH-R) and LH receptor (LH-R) of both cells were observed by in situ hybridization. The results showed that granulosa cells expressed both FSH-R mR NA and LH-R mRNA, while thecal cells expressed LH-R mRNA only. Under the stimulation of FSH, both LNG and RU486 increased FSH-R mRNA expression of granulosa cells. Under the stimulation of LH, LNG enhanced LH-R mRNA expres sion of thecal cells; while RU486 decreased its expression. When granulosa and thecal cells were exposed to FSH and LH both, the actions of LNG and RU486 in thecal cells showed the same result as that stimulated by LH alone. In granulosa cells LNG de creased LH-R mRNA expression, while RU486 increased its expression. These data suggest that: (1) granulosa cells expressed FSH-R mRNA significantly;(2) both the progestin and antiprogestin directly acted on the mRNA expression of gonadotropin re ceptors of ovarian cells, but effects were different; (3) the response of granulosa or thecal cells to the action of LNG and RU 486 was not the same. The mechanism needs to be further investigated.     

国产长效皮下埋植剂和Norplant的药物体外释放比较

本文研究了国产18-甲基炔诺酮硅橡胶长效皮下埋植剂的药物体外释放,并与进口Norplant进行了比较。释放试验采用水平振荡法,实验条件符合“漏槽”状态的要求。用紫外分光光度法在240 nm波长处测定18-甲基炔诺酮每天的体外释放量。二年多体外释放试验的实验结果表明:国产埋植剂的药物体外释放无爆破效应,释药速度稳定,为零级速度。平均每天释放量为85μg。体外释放的重现性好。进口Norplant则有明显的爆破效应,经10天释放,才趋于稳定,平均每天释药量为68μg。     

十八甲基炔诺酮透皮控释传递系统在人体不同部位皮肤的药物动力学

6名健康妇女分别于上臂、臀部和腹部三部位经皮给予合LNG的透皮控释传递系统（TCDS）后，用放射免疫法测定LNG血清浓度，计算其主要药物动力学参数。结果表明：在TCDS用药期间，三部位的C（max）、T（max）及AUC（0～168h）基本接近，部位间无显著性差异（P＞0．05）；TCDS揭除后，AUC（168～204h）及消除相半衰期T（1／2）（Ke）均以腹部最大，臀部次之，上臂最小，在腹部与上臂间有显著性差异（P＜0．05）。上述结果可归因于TCDS对LNG的控释和人体皮下脂肪的“贮库效应”。     

左炔诺孕酮宫内缓释系统联合宫腔镜治疗子宫内膜息肉临床分析

目的以子宫内膜息肉(EMP)为基础病,探究宫腔镜子宫内膜切除手术后安置左炔诺孕酮宫内缓释系统在治疗该病中的应用。方法选取2011年1月～2012年1月在我院治疗的子宫内膜息肉患者113例,进行回顾性研究,研究组患者68例采用宫腔镜手术联合左炔诺孕酮宫内缓释系统治疗,对照组45例采用宫腔镜治疗。比较两组患者6个月、12个月、24个月后月经量以及子宫内膜等指标。结果研究组与对照组的总有效率分别为88.23%、68.89%,两组差异有统计学意义(P<0.05);两组患者治疗12个月、24个月后月经量以及内膜厚度指标存在明显差异(P<0.05);研究组患者EMP复发6例,复发率为8.82%,对照组患者EMP复发9例,复发率为20.00%,两组差异有统计学意义(P<0.05)。结论宫腔镜联合左炔诺孕酮宫内缓释系统是治疗子宫内膜息肉患者较好的选择,适宜临床推广。     

Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: A randomized,double‐blind,placebo‐controlled study

This randomized, double‐blind, placebo‐controlled, two‐way crossover study aimed to assess the pharmacokinetic interactions between brivaracetam 100 mg/day and a combination oral contraceptive (OC) containing 30 μg ethinylestradiol and 150 μg levonorgestrel. The study was performed in 28 healthy women over five 28‐day menstrual cycles: baseline (OC only), two treatment cycles with brivaracetam (50 mg b.i.d.) or placebo coadministered with OC separated by a wash‐out cycle (OC only), and a follow‐up cycle (OC only). The OC was administered on days 1–21 of each cycle, and brivaracetam or placebo on days 1–28 of the treatment cycles. Pharmacokinetics of ethinylestradiol and levonorgestrel were determined on day 20; brivaracetam morning trough levels on days 20 (with OC) and 29 (without OC) were compared. C_max (maximum plasma concentration) and AUC (area under the plasma concentration versus time curve) ratios for brivaracetam versus placebo (90% confidence interval [CI]) were 0.96 (0.88–1.04) and 0.90 (0.86–0.95) for ethinylestradiol, and 0.95 (0.91–0.99) and 0.92 (0.88–0.97) for levonorgestrel, within predefined bioequivalence limits (0.80–1.25). Brivaracetam trough levels were similar on days 20 and 29 (ratio 1.08; 90% CI 0.98–1.18). No differences in breakthrough bleeding were seen across the five cycles. It was concluded that there were no interactions between brivaracetam 100 mg/day and the OC. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Short term suppression of follicular recruitment and spontaneous ovulation in the cat using levonorgestrel versus a GnRH antagonist

Suppression and subsequent rebound of ovarian activity using a progestin (levonorgestrel; Norplant) versus a GnRH antagonist (antide) was assessed in the domestic cat via fecal estradiol and progesterone metabolite analyses. Following an initial dose-response trial, queens were assigned to one of four treatments: (1) antide, two 6 mg/kg injections 15 days apart (n = 8 cats); (2) levonorgestrel, six silastic rods (36 mg levonorgestrel/rod) implanted for 30 days (n = 8); (3) control injections (n = 5); and (4) control implants (n = 5). Steroid metabolites were quantified from daily fecal samples for 90 days before, 30 days during, and 90 days after treatment. Antide and levonorgestrel inhibited estrous cyclicity in contrast to continued cyclicity in controls. Cats already at estradiol baseline in antide (n = 7) and levonorgestrel (n = 4) groups remained inhibited during treatment. In females with elevated estradiol levels at treatment onset (Day 0), a normal estradiol surge was completed before concentrations declined to baseline (∼Days 5-7) and remained suppressed throughout the remaining treatment period. Additionally, 56% of treatment animals exhibited at least one spontaneous ovulation during the pre-treatment period, but no female ovulated during treatment with levonorgestrel or antide. Antide-treated cats exhibited lower (P < 0.05) baseline estradiol concentrations during treatment compared to pre- and post-treatment. In contrast, levonorgestrel induced elevations in baseline estradiol following treatment compared to pre- and during treatment intervals. Control females showed no change (P > 0.05) in baseline estradiol throughout the study period. All levonorgestrel and antide cats returned to estrus after treatment withdrawal. Results demonstrate that: (1) both antide and levonorgestrel are effective for inducing short-term suppression of follicular recruitment and ovulation in the cat; (2) inhibition is reversible; and (3) GnRH antagonists and progestins differentially regulate basal estradiol secretion. This study also confirmed a relatively high incidence of spontaneous ovulation in the cat, a species generally considered to be an induced ovulator.     

培坤丸联合左炔诺孕酮治疗围绝经期功能失调性子宫出血的疗效观察

目的探讨培坤丸联合左炔诺孕酮治疗功能失调性子宫出血患者的安全性与有效性。方法选取2013年2月—2018年2月在自贡市妇幼保健院诊治的功能失调性子宫出血患者78例,根据用药差别分成对照组(39例)和治疗组(39例)。对照组患者口服左炔诺孕酮片,2片/次,2次/d,待阴道停止流血3 d后,药量改为1次/d,1片/次,维持治疗14 d,1个月经周期为1个疗程。治疗组患者在对照组基础上口服培坤丸,9g/次,2次/d。两组患者均连续治疗3个疗程。观察两组患者临床疗效,同时比较治疗前后两组患者血红蛋白水平、经期天数、WHOQOL-BREF评分及性激素水平。结果治疗后,对照组和治疗组临床有效率分别为76.92%和94.87%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者血红蛋白水平和WHOQOL-BREF评分均显著升高(P0.05),经期天数均显著减少(P0.05),且治疗组上述指标明显优于对照组(P0.05)。治疗后,两组患者雌二醇、卵泡刺激素和促黄体生成素均显著降低(P0.05),且治疗组雌二醇、卵泡刺激素和促黄体生成素水平明显低于对照组(P0.05)。结论培坤丸联合左炔诺孕酮治疗功能失调性子宫出血疗效显著,不良反应少,且能够显著提升排卵率,具有一定的临床推广应用价值。     

Effect of Extended 30 μg Ethinyl Estradiol with Continuous Low-Dose Ethinyl Estradiol and Cyclic 20 μg Ethinyl Estradiol Oral Contraception on Adolescent Bone Density: A Randomized Trial

Study ObjectiveTo compare changes in lumbar spine bone mineral density after 12 months of a 91-day extended regimen or 28-day combined oral contraceptive with those in a healthy reference group not using hormonal contraceptives.DesignPhase 2, multicenter, open-label, randomized, controlled study.SettingForty-five academic centers, clinical research centers, and community practices in the United States.ParticipantsEight hundred twenty-nine postmenarcheal adolescent girls aged 12-18 years.InterventionsAdolescents were randomly assigned to 91-day levonorgestrel (LNG)/ethinyl estradiol (EE) extended regimen (84 days of LNG 150 μg/EE 30 μg with 7 days of EE 10 μg [LNG/EE extended regimen]) or 28 days of LNG/EE (21 days of LNG 100 μg/EE 20 μg with 7 days of placebo [LNG/EE 21/7]) for 12 months. A reference group not seeking hormonal contraception was also evaluated.Main Outcome MeasuresThe primary end point was mean percent change in lumbar spine bone mineral density measured using dual-energy x-ray absorptiometry.ResultsOf 1361 adolescents randomized/enrolled, 829 were included in the primary analysis. Mean changes in lumbar spine bone mineral density were +2.26% with LNG/EE extended regimen, +1.45% with LNG/EE 21/7, and +2.50% in the reference group. Noninferiority of the LNG/EE extended regimen compared with the reference group was shown. A statistically significant treatment difference was found between LNG/EE 21/7 and the reference group (1.05%; 95% confidence interval, 0.61%-1.49%) but not between LNG/EE extended regimen and the reference group (0.23%; 95% confidence interval, −0.20% to 0.67%). No new safety signals were noted.ConclusionCompared with the reference group, bone accrual was statistically significantly lower among LNG/EE 21/7 users but not among LNG/EE 30-μg extended regimen users. Additional research is needed to clarify the clinical relevance of these findings.