长效避孕皮下埋植剂体外缓释行为研究

本文对以加成型硅橡胶为基质的左旋18—甲基炔诺酮长效避孕埋植剂的体外释放行为及对可能影响其释放量的诸因素,进行了观察与研究,结果表明:此长效避孕皮下埋植剂的体外释药行为,符合零级释药动力学规律。释药量受控释膜厚度,控释膜交联密度及释药面积的影响。体外释放药物曲线无明显爆破峰。     

缓释18-甲基炔诺酮宫内节育器对大鼠子宫及主要脏器的影响

本文研究新制缓释18-甲基炔诺酮宫内节育器(LNGR-IUD)对大鼠子宫及主要脏器的影响。实验分四组:1.含药IUD组;2.不含药硅橡胶IUD组;3.手术对照组;4.正常对照组。结果表明,含药IUD组子宫内膜早期(15及30天时)有轻度炎症反应,60天时炎症反应逐渐消退,90天恢复正常。与不含药IUD组及手术对照组无差异。含药组子宫内膜呈乳头状增生与分泌,亦随时间延长而渐减轻。内膜血管仅早期呈现充血反应,30天后逐步消失。各组全身主要脏器皆未见病变,含药IUD组各期卵巢中见到正常卵泡发育及黄体形成。     

日释10μg18－甲基炔诺酮钥匙形宫内节育器和TCu200对比性临床研究

日释１０μｇ１８－甲基炔诺酮（ＬＮＧ）钥匙形宫内节育器（ＩＵＤ）进行临床初试１０１例，观察５７８．５个妇女月与ＴＣｕ２００对照。未发现失败，续用率为９３．０７％，无宫外孕发生，闭经率很低（０．９９％），且能自然恢复月经。主要副反应为经期延长和月经淋漓。经３例置器前后月经中期连续测定晨尿ＬＨ和宫颈粘液，提示对排卵可能无影响。使用者经血量明显减少．血红蛋白相应上升，痛经改善。本器使用５年或５年以上。为月经过多、贫血和痛经妇女提供了合适的ＩＵＤ，为我国计划生育提供了一种新的工具。     

Contraception and treatment in the perimenopause with a novel "frameless" intrauterine levonorgestrel-releasing drug delivery system: an extended pilot study

The objective of the study was to evaluate the contraceptive performance, acceptability, side effects, and adverse events of a novel "frameless" intrauterine drug delivery system (IUS), FibroPlant-levonorgestrel (LNG) releasing 14 microg of LNG/day, in perimenopausal women. An ancillary objective was to evaluate the effect of the new IUS on menstrual blood loss in women with or without fibroids.The study, consisting of 109 women, suggests that FibroPlant-LNG IUS is an effective contraceptive. No pregnancies occurred with the FibroPlant-LNG IUS. The total use-related discontinuation rate at 1 year is low (1.9) and results in a high rate of continuation of use (98.1). In addition, the FibroPlant-LNG IUS demonstrated a high level of effectiveness in reducing bleeding in women with excessive menstrual flow even when medium or large fibroids were present. However, an effect on the size of the fibroids could not be demonstrated.Patient satisfaction with the method is high, which is a prerequisite for continuance of the method, and may be linked with the advantageous design characteristics of the FibroPlant-LNG IUS, the virtual absence of hormonal side effects, and the low incidence of irregular bleeding and spotting even during the first 3 months after insertion of the FibroPlant IUS. Counseling remains important though to explain to women about the possible occurrence of changes in their menstrual pattern that may sometimes be annoying but harmless.It is concluded that many women over age 40 years could substantially benefit from the advantages of this intrauterine drug delivery technology which provides contraception and treatment of a possible associated condition such as menorrhagia. The treatment also creates the opportunity to pass through the transitional perimenopausal period smoothly and to benefit fully from the advantages hormone replacement therapy offers in terms of treatment of short-term symptoms and long-term prevention by gradually replacing the waning estrogens.     

A randomized study of metabolic effects of four low-estrogen oral contraceptives: I. Results after 6 cycles

Healthy, non-smoking, normotensive, well-motivated young women were assigned at random to one of four different, commercial, low-estrogen, oral contraceptive products. Measurements of biochemical parameters were made on blood specimens collected from fasting subjects twice during the late pretreatment cycle, then again during each late treatment cycle for six months. All women assigned to one product (0.5mg NET + 35 microgram EE) dropped out of the study before the end of the fifth cycle, but discontinuations with the other three products were few. While numbers of subjects are small, the groups are closely matched and most metabolic differences are statistically significant. Products containing EDA and NET were associated with increases in serum total cholesterol and triglycerides, but decreases in HDL-cholesterol. In contrast, the LNG-containing preparation produced significantly less effect on these tests. A similar pattern was seen with a range of blood coagulation and fibrinolytic factors, Minimal alterations were seen with the LNG preparation, while those containing NET or EDA showed marked increases in factors I. VII, VIII, X and plasminogen, associated with a decrease in antithrombin III. It is suggested that differences in the metabolic impact of the various commercially available low-estrogen preparations, combined with effects on intermenstrual bleeding, allow a choice of the progestogen component most suitable for general use.     

Biodegradation and biocompatibility of contraceptive-steroid-loaded poly (DL-lactide-co-glycolide) injectable microspheres: in vitro and in vivo study

PURPOSE: A controlled-release drug delivery of contraceptive steroids levonorgestrel (LNG) and ethinyl estradiol (EE) has been developed by successful encapsulation of LNG and EE in poly (lactide-co-glycolide) (PLG) microspheres. MATERIALS AND METHODS: Smooth, spherical, steroid-loaded PLG microspheres with a mean size of 10-25 microm were prepared by using the water/oil/water double-emulsion solvent evaporation method. RESULTS: In vitro release profiles showed an increased burst release of LNG/EE on Week 1; thereafter, the release was sustained. At the end of Week 7, the release of LNG/EE from 1:5 and 1:10 PLG microspheres was 75.64% and 62.55%. respectively. In vitro degradation studies showed that the PLG microspheres maintained surface integrity up to Week 8 and then eroded completely by Week 20. In an in vivo study, the serum concentration of LNG/EE in rats showed a triphasic release response, with an initial burst release of 8 ng/mL LNG and 14 pg/mL EE on Day 1; thereafter, a controlled release of the drugs to the systemic circulation was maintained until Week 15, maintaining constant drug levels of 2 ng/mL LNG and 3-4 pg/mL EE in the blood. Histological examination of steroid-loaded PLG microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that contraceptive-steroid-loaded microspheres were biocompatible. CONCLUSION: This controlled-release and biocompatible nature of the PLG microspheres may have potential application in contraceptive therapy.     

Long-term administration with levonorgestrel decreases allopregnanolone levels and alters GABA(A) receptor subunit expression and anxiety-like behavior

Fluctuations in the concentrations of the neuroactive steroid allopregnanolone are thought to influence γ-amino-butyric acid type A (GABA_A) receptor gene expression and function. Long-term treatment with ethinyl estradiol (EE) plus levonorgestrel (LNG), two of the most widely used steroids in the hormonal contraceptive pill, decreases allopregnanolone levels in rat cerebral cortex and plasma, alters GABA_A receptor expression and induces anxiety-like behavior. We evaluated which component of the hormonal contraceptive pill is responsible for the aforementioned changes. Female rats were injected subcutaneously (s.c.) with EE (0.030 mg) or LNG (0.125 mg) once a day for 4 weeks. Compared to the respective vehicle-treated control groups, EE decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively and hippocampal levels by 52, 56 and 50%, respectively. Likewise, LNG decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively, and hippocampal levels by 55, 65 and 60%, respectively. Administration of LNG, but not EE, increased the abundance of the γ2 subunit peptide in cerebral cortex and hippocampus by 38 and 59%, respectively. Further, LNG, but not EE, decreased the time spent and the number of entries into the open arms of the elevated plus maze by 56 and 43%, respectively, an index of anxiety-like behavior. These results suggest that alterations in GABA_A receptor subunit expression and anxiety-like behavior induced by long-term treatment with combined EE/LNG appear to be caused by LNG. Given that both EE and LNG decrease allopregnanolone levels in a similar manner, these results further suggest that changes in allopregnanolone levels are not associated with GABA_A receptor expression.