左炔诺孕酮宫内节育器的制备及药物释放研究

采用改性乙烯-醋酸乙烯共聚物(mEVA)作为控释材料制备释放左炔诺孕酮(LNG)4μg/d,预期使用寿命为5年的钥匙形宫内节育器(IUD)。本IUD在体外和在人及动物子宫内均为零级释药。释药速度与释药管管壁厚度或管外内径比的对数成反比,提示本释药体系的释药模武符合膜控制释药的特性。动物血药浓度测定结果表明,家兔子宫内植入IUD 2d后,血中LNG浓度趋于稳定。     

服用左炔诺孕酮滴丸和妈富隆1年对血压、血糖和血脂的影响

目的：观察第二、三代口服避孕药(COC)对育龄妇女体重指数、血压、血糖和血脂的影响。方法：将自愿服用COC避孕1年的妇女105例随机分为两组，其中54例给予第二代COC(EE／LNG组)，51例给予第三代COC(EE／DG组)。并对研究前后所有病例的体重指数(BMI)、血压、血糖和血脂代谢指标进行比较分析。结果：EE／LNG组：BMI、收缩压、舒张压、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)和载脂蛋白B(ApoB)水平均升高，高密度脂蛋白(HDL)水平下降，血糖、载脂蛋白AI(ApoAI)水平无明显改变。EE／DG组收缩压、TG、HDL水平升高，BMI、舒张压、血糖、TC、LDL、ApoAI和ApoB均未发生显著变化。以上所有测量指标均未超出正常范围。结论：使用1年第二、三代COC对妇女BMI、血压和血脂代谢都有微弱的影响，对空腹血糖无明显影响。第三代COC对妇女BMI、收缩压、舒张压、TG、TC、LDL、HDL水平和ApoB的不利影响小于第二代，更加安全可靠。     

尼尔雌醇和左炔诺孕酮对人成骨肉瘤 MG-63细胞株雌激素受体亚型的作用

目的：观察不同浓度的尼尔雌醇(NYL)和左炔诺孕酮(LNG)对人成骨肉瘤MG-63细胞株ERα和ERβ表达的作用，探讨旁分泌效应对ERα和ERβ基因表达的影响。方法：人成骨肉瘤MG-63细胞株分为（1）空白对照组：用含1% BSA无血清MEM培养液培养48 h；（2）阳性对照组：培养液中加入10-8 mol/L的17β-estradiol (E2) 培养48 h；（3）药物处理组：培养液中分别加入10-10，10-8，10-6 mol/L的NYL或LNG培养48 h；（4）药物处理+换液组：培养液中分别加入10-10 mol/L的NYL或10-8 mol/L LNG培养48 h，每12 h更换新的含有相应药物的培养液。用半定量RT-PCR检测各组细胞ERα和ERβmRNA的表达。结果：NYL及LNG均能诱导ERα和ERβ亚型mRNA表达上调，诱导ERαmRNA表达的最强作用浓度均为10-6 mol/L。NYL，LNG对ERβ mRNA表达最强作用浓度分别为10-10，10-8 mol/L。每12 h更换干预培养液对ERα表达无影响，但可抑制ERβ的表达。结论：NYL和LNG均可诱导MG-63细胞株ERα和ERβ mRNA表达上调，且2种亚型的表达存在相互制约关系；在NYL和LNG诱导ER亚型表达上调过程中ERβ的表达可能受到旁分泌作用的影响。     

Transdermal Dual-Controlled Delivery of Contraceptive Drugs: Formulation Development,in Vitro and in Vivo Evaluations,and Clinical Performance

Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17-estradiol (E₂), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E₂ from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia–Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45°C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm²). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.     

A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception

A prospective randomized study was conducted at the Family PlanningAssociation of Hong Kong to compare the efficacy of the Yuzperegimen and levonorgestrel (0.75 mg for two doses 12 h apart)in post-coital contraception. A total of 424 subjects were recruitedinto the Yuzpe group and 410 subjects into the levonorgestrelgroup; 77 subjects in the Yuzpe group and 79 subjects in thelevonorgestrel group had further acts of intercourse duringthe treatment cycle. Fifteen pregnancies (3.5%) occurred inthe Yuzpe group and 12 pregnancies (2.9%) in the levonorgestrelgroup. After excluding the patients who had further acts ofintercourse, the failure rates in the Yuzpe group and the levonorgestrelgroup were 2.6 and 2.4% respectively. The incidence of nausea,vomiting and fatigue in the Yuzpe group was significantly higherthan those in the levonorgestrel group. We conclude that levonorgestrelis an effective drug for post-coital contraception with a lowerincidence of side-effects than the Yuzpe regimen.     

长效抗生育埋植剂CaproF体内药物释放的研究

目的对可降解长效抗生育埋植剂CaproF的体内药物释放动力学进行评价。方法将CaproF植入Wister大鼠皮下。每隔一定时间处死动物,取出埋植剂,用紫外分光光度法测药物残留量,计算单位长度埋植剂平均每日药物释放量。放射免疫法测定左炔诺孕酮(LNG)血药浓度。结果CaproF埋植剂在60、120、180、360、720d药物平均释放速率分别为(11.0±3.0)、(11.7±3.7)、(8.0±1.2)、(7.3±0.4)、(9.3±0.9)μg/(d·cm),并可维持基本恒定的血药浓度。结论左炔诺孕酮CaproF埋植剂植入体内后,平均药物释放速率达到7.6μg/(d·cm),并可维持2年的基本稳定释放。     

Contraception: Contraception with NORPLANT(R) implants

NORPLANT^® progestogen-only implant contraception providesseveral years of effective protection against pregnancy followinga single application. It is reversible whenever desired, withreturn to normal fertility. Drug release and concentrationsare maximal in the first month of use, when a set of six capsulesreleases 85/µg/day of levonorgestrel. Release is 25–30/µg/dayat 60 months. Circulating drug concentrations and pregnancyrates vary inversely with body weight at placement, but evenamong heavier women, failure rates are below those of oral contraceptivesin the general population. Side-effects are most marked at theinitiation of use. Disruption of normal menstrual patterns occursin 70–80% of recipients initially. Menstrual blood lossis decreased, however, and most women experience modest increasesin haemoglobin. Headache, acne, other skin or hair problems,changes of weight and of mood and abdominal pain, are the mostcommon side-effects attributed to NORPLANT^® contraception.The frequency of occurrence of side-effects diminishes withincreased duration of use. The comparative paucity of majorside-effects, coupled with the method‘s convenience andeffectiveness and its very long action have made NORPLANT^®implants highly acceptable in both developing and developedcountries.     

Mainstreaming of Emergency Contraception Pill in India: Challenges and Opportunities

Background:

Emergency Contraception Pill (ECP) is an essential intervention to prevent unwanted pregnancies. However, its use has remained low due to various barriers including reservations among medical fraternity.

Materials and Methods:

This paper presents findings on barriers to ECP''s easy access for potential users from (i) a cross-sectional survey of providers'' attitudes, beliefs, and practices and interviews with key opinion leaders, (ii) three consultations organized by Population Council with policymakers and public health experts, and (iii) evidence from scientific literature.

Results:

The major barriers to easy access of ECP include misconceptions and reservations of providers (disapproval of ECP provision by CHWs, opposition to its being an OTC product, and myths, misconceptions, and moral judgments about its users) including influential gynecologists.

Conclusion:

For mainstreaming ECP, the paper recommends educational campaign focusing on gynecologists and CHWs, relaxing restrictive policy on advertisement of ECP, involving press media and strengthening supply chain to ensure its regular supply to ASHA (CHW).     

LNG-IUS 12: a 19.5 levonorgestrel-releasing intrauterine system for prevention of pregnancy for up to five years

Introduction: Globally, intrauterine devices (IUDs) are the second most commonly used form of reversible contraception because of their high efficacy, safety, convenience and cost effectiveness. The levonorgestrel releasing intrauterine system with daily average release of 20 mcg (LNG-IUS 20) is the popular choice because of its favorable bleeding patterns and many noncontraceptive benefits. A three year (LNG-IUS 8) became available three years ago. More recently, the LNG-IUS 12 was added. This new IUD shares a smaller frame, narrow inserter and lower rate of amenorrhea with the LNG-IUS 8, but it offers the five years of contraceptive protection of the LNG-IUS 20.

Areas covered: This article provides information on the contraceptive efficacy, safety and tolerability of this new IUS based on approximately 60,000 cycles of use. Where available, the impacts of subject age, parity and body mass index (BMI) on study outcomes are reported.

Expert opinion: This new LNG-IUS 12 with mid-dose hormone levels, smaller frame and longer effective life fills a niche that may better meet the needs of women who might appreciate the narrow insertion tube and/or the lower rates of amenorrhea. Cost will ultimately help determine success.     

宫腔镜电切术后左炔诺孕酮宫内缓释系统预防子宫内膜息肉复发的研究

目的探讨左炔诺孕酮宫内缓释系统（LNG-IUS）预防子宫内膜息肉宫腔镜电切术后复发的临床疗效。方法采用前瞻性随机对照研究,将99例宫腔镜子宫内膜息肉切除术（TCRP）患者分为两组,治疗组48例,TCRP后月经来潮第3~5天放置LNG-IUS,其中单发性息肉10例,多发性息肉38例;对照组51例,TCRP术后无任何处理措施,其中单发性息肉11例,多发性息肉40例;门诊随访12个月,观察子宫内膜息肉复发及月经量情况。结果治疗组中无一例复发;对照组中单发性息肉有1例复发,多发性息肉有6例复发,复发率为13.73%（7/51）,两组复发率差异有统计学意义（P〈0.05）。治疗组月经量少于对照组,差异有统计学意义（P〈0.05）。结论 LNG-IUS能有效地预防子宫内膜息肉切除术后的复发并明显减少月经量。