长效避孕埋植剂的遗传安全性研究

Norplant皮下埋植缓释系统是一种长效、高效、可复性好、低剂量、仅含孕激素的避孕方法，其所含主旋18－甲基炔诺酮通过埋植于皮下的硅橡胶囊缓慢释放，可持续避孕多年，现已在国内外得到广泛应用。WFIO在甾体避孕药安全性准则的改进建议中指出，如能表明药物与释放系统之间没有相互反应，就不必重复毒理学试验，反之则需要再次进行毒理试验[1,2].国内有人发现使用Norplant避孕三年以上妇女，以及埋植左旋18-甲基炔诺酮避孕埋植剂（上海二根型）的动物实验均有明显的细胞遗传学变化。将NorPlant作为一种复合制剂，研究其对妇女的遗传安…     

一根型双烯高诺酮避孕埋植剂研究

用进口和国产医用硅橡胶制成一根型双烯高诺酮(Gestodene)埋植剂,长度为40、20和10mm(合药75、37.5和18.75mg),内填充Gestodene和硅橡胶混炼的药芯,外包裹硅橡胶释药管,两端粘合剂封口.体外释药量测试用紫外分光光度法.三种剂量的埋植剂273天体外释放相当稳定.大鼠10个月药效试验无一例怀孕,大鼠体内平均日释放量为60.7、29.0和13.4μg.经10个月动物试验后取出埋植剂分析其残留药量,10个月内耗药量占总药量的24、23和21%.     

缓释左旋-18甲基炔诺酮皮埋避孕剂对骨密度和骨代谢的影响

对采用 Norplant R埋植剂和仿制 Norplant的国产埋植剂 型避孕的育龄妇女骨密度和骨代谢改变进行了 1年的随机前瞻性临床观察。 6 1例正常妇女被分为两组 :Norplant埋植剂组 30例 ,国产埋植剂组 31例。两组于埋植前和埋植后第 12个月时采用双能 X线骨密度测定仪 (DEXA)分别测定了腰椎 L2 ～ L4、股骨近端骨密度和骨矿含量。两组妇女埋植后第 12个月时腰椎 L2 ～ L4骨密度和骨矿含量均较埋植前明显增加 (P<0 .0 1) ,Norplant组骨密度平均增加2 .40 % ,骨矿含量平均增加 3.34 % ,国产埋植剂组分别增加 2 .75 %和 4.47% ;从年龄分析 ,以 2 5～ 2 9岁组腰椎 L2 ～ L4骨密度埋植后增加最为显著 ,Norplant组 P<0 .0 5 ,国产埋植剂组 P<0 .0 1。国产埋植剂组妇女埋植后第 12个月时股骨大粗隆骨密度和骨矿含量较埋植前明显增加 (P<0 .0 1) ;国产埋植剂组妇女空腹尿羟脯氨酸 /肌酐比值埋植后第 12个月时较埋植前明显下降 (P<0 .0 1) ;对使用妇女腰椎、股骨骨密度和骨代谢生化指标的影响 ,在两种埋植剂之间埋植前后比较均无显著差别 (P>0 .0 5 )。左旋 - 18甲基炔诺酮皮埋避孕剂对绝经妇女的骨骼是非有害的 ,对年轻妇女骨峰值的获得无明显影响。     

Norplant埋植剂可安全避孕五年

<正> Norplant是一种可靠和可逆的避孕埋植剂,它不会损害停用后的生育。最近,芬兰和瑞典已批准将其作为商品供应。这种埋植剂是由6根细小的硅橡胶管囊所组成,每根管囊含有左旋18—甲炔诺酮36毫克。埋植后药物在第一年,以每天约50微克的速度从管壁释出,以后的四年,则每天释放约30微克。在整个五年中,使用者平均血药浓度可达350～290pg/毫升。在最初5年中,每年失败率为千分之4～5,一般到第5年时予以取出。埋植剂的作用机制可能为:(1)抑制排卵,据统计用药者有50%月经周期的排卵受到抑制;(2)宫颈     

缓释左旋-18甲基炔诺酮皮埋避孕剂

时采用NorplantR埋植剂和仿制Norplant的国产埋植剂I型避孕的育龄妇女骨密度和骨代谢改变进行了1年的随机前瞻性临床观察.61例正常妇女被分为两组Norplant埋植剂组30例,国产埋植剂组31例.两组于埋植前和埋植后第12个月时采用双能X线骨密度测定仪(DEXA)分别测定了腰椎L2～L4、股骨近端骨密度和骨矿含量.两组妇女埋植后第12个月时腰椎L2～L4骨密度和骨矿含量均较埋植前明显增加(P＜0.01),Norplant组骨密度平均增加2.40%,骨矿含量平均增加3.34%,国产埋植剂组分别增加2.75%和4.47%;从年龄分析,以25～29岁组腰椎L2～L4骨密度埋植后增加最为显著,Norplant组P＜0.05,国产埋植剂组P＜0.01.国产埋植剂组妇女埋植后第12个月时股骨大粗隆骨密度和骨矿含量较埋植前明显增加(P＜0.01);国产埋植剂组妇女空腹尿羟脯氨酸/肌酐比值埋植后第12个月时较埋植前明显下降(P＜0.01);对使用妇女腰椎、股骨骨密度和骨代谢生化指标的影响,在两种埋植剂之间埋植前后比较均无显著差别(P＞0.05).左旋-18甲基炔诺酮皮埋避孕剂对绝经妇女的骨骼是非有害的,对年轻妇女骨峰值的获得无明显影响.     

Norplant皮下埋植剂对大白鼠肝脏结构与功能的影响

<正> 本文对应用Norplant避孕剂前后的大白鼠肝脏结构与功能进行了研究,旨在进一步为临床安全用药提供实验依据。材料与方法Sprague-Dawley系大白鼠30只:雌性、成熟、健康,体重200 g左右。Norplant胶囊:由芬兰Leiras公司制造。第枚长34 mm,外径2.4mm,内径1.57 mm,两端各有2 mm封闭端,每枚胶囊内含左旋18甲基炔诺酮(LNG)36 mg。在植入皮下后18个月内LNG最大释放量可达每天15 μg,以后逐渐下降。     

国产18甲基炔诺酮皮下埋植剂和Norplant的临床比较性研究——666例4年报告

本文旨在研究国产18甲基炔诺酮皮下埋植剂避孕的有效性及其副反应,与Norplant作比较.666例对象经过4年观察.国产组共发生4例妊娠,4年累积妊娠率为1.07/100妇女,年平均妊娠率为0.27/100妇女,4年累积的续用率为76.6/100妇女.与国外Nor-Plant组相比较,都无统计学差异.两组副反应亦相似,主要均为月经失调,占终止者的半数以上.国产组的左旋18甲基炔诺酮的血药水平下降得较快,2年以后略低于Norplant组,但到48个月时仍在抑制排卵的血药水平.4年临床观察国产组与Norplant相似,都具有长效、高效、可逆、稳定的优点,是可供育龄妇女选用的新避孕法.     

左旋18-甲基炔诺酮硅橡胶阴道药环体外释放量的测定

本文研究了左旋18-甲基炔诺酮避孕药环体外释放量的一种测定方法——升降法。在37℃恒温条件下,药环浸在介质中以恒定的频率和振幅上下振动。介质的体积和搅拌速度都符合“漏槽”状态。用紫外分光光度法测定18-甲基炔诺酮的释放量。测定结果表明,经12～14天的快速释放后可维持稳态释放,释放的重现性较好。确认这一方法可用于18-甲基炔诺酮避孕药环体外释放量的测定。     

皮下埋植避孕剂的避孕效果及不良反应处理原则

皮下埋植避孕剂是自上世纪 80年代初继口服避孕药、避孕针剂后发展起来的一种新剂型避孕药。皮下埋植剂是应用药物缓释系统 ,即一次给药后药物缓慢释放 ,使药物在体内维持在相对恒定的最低有效水平 ,既可维持长效 ,避免了用药初期过高血药峰值引起的不良反应 ,又可避免通过肝脏代谢的首过效应。我国最初引进应用的皮下埋植剂是含左炔诺孕酮的Norplant。目前在中国上市的皮下埋植剂为国产的左炔诺孕酮硅胶棒Ⅰ型 (6根 )和Ⅱ型 (2根 )。这几种埋植剂均为非生物降解 ,在使用年结束后必须取出埋植剂。目前国外尚有单棒皮下埋植剂 ,由欧加农开发…     

皮下埋植避孕技术进展

皮下埋植避孕是指将避孕甾体放在硅橡胶容器中 ,或与硅橡胶混匀 ,植入皮下后药物缓慢、恒定地释放入血而起到长期避孕的作用 ,属于药物控制释放系统。根据携带药物的载体 ,埋植剂分为非生物降解和可生物降解两大类。在临床使用最早和最广泛的是非生物降解的Ｎｏｒｐｌａｎｔ皮下埋植避孕剂。为一组 6支的硅胶囊 ,每支长 3 4 0ｍｍ ,直径 2 4ｍｍ ,含左炔诺孕酮 (ＬＮＧ ,原称左旋 18甲基炔诺酮 ) 3 6 0ｍｇ。一组共含ＬＮＧ 2 16ｍｇ。局麻下将 6支胶囊呈扇形埋入上臂皮下 ,埋植期间每日释放ＬＮＧ平均 3 0～4 0 μｇ ,埋植 1次有效期最少…     

A comparison of levonorgestrel implants with depo-medroxyprogesterone acetate injections for contraception

The Norplant System of levonorgestrel implants and the Depo Provera contraceptive Injection of sterile medroxy progesterone acetate suspension (DMPA) are longterm, progestagen-based contraceptive delivery systems designed to overcome noncompliance which are under review for use in Canada. 150 mg of DMPA, a pregnane compound derived from progesterone, is injected every 3 months. Peak plasma concentrations are reached in 24 hours and plateau for 3-4 months before gradually declining. After termination, ovulation returns on average in 4.5 months, and conception occurs at a median time of 10 months. 90% conceive by 24 months. In the Norplant system, a steady daily supply of 50-80 mcg of levonorgestrel, a gonane progestin derived from the testosterone nucleus which has both progestogenic and androgenic receptor affinity, diffuses from 5 Silastic implants, which must be replaced every 5 years. Ovulation and fertility return rapidly after rod removal. The actual and lowest expected failure rates are equal for both systems. The failure rate for DMPA is .3 pregnancies per 100 women years, while that for levonorgestrel is .4% in 1 year. Although neither method affects blood pressure, DMPA appears to affect carbohydrate metabolism by impairing glucose tolerance and increasing insulin production. Lipid metabolism is also affected. 5% of those who use levonorgestrel discontinue it because of side effects, including headache, mastodynia, and acne; 19.1% of DMPA users did so, especially for weight gain and menstrual cycle abnormalities. Both methods have a higher frequency of menstrual abnormalities than normal. 27.7% of levonorgestrel users experienced prolonged bleeding, while 17% experienced spotting during the first 6 months. However, normal menses usually returned within a year, and only 7.9% discontinued use because of cycle abnormalities. In 1 study, less than 10% of DMPA users experienced normal cycles, and in another study 35% experienced amenorrhea (500/700 discontinued use). Amenorrhea replaced irregular bleeding with continued use, occurring in 68% of users by 2 years. There is also some concern about DMPA and breast cancer and bone loss. Based on 1 case-control study of 110 women with breast cancer who had taken DMPA, the relative risk is highest for those between ages 25 and 34 who use DMPA longer than 6 years. A WHO study concluded that the relative risk of developing breast cancer, because of DMPA, is inversely related to duration of use. A Phase IV study on DMPA and bone mineral density has been undertaken.     

Current developments in hormonal contraception]

The development of hormonal oral contraceptives (OCs) hitherto has been characterized by the endeavor to reduce associated health risks as much as possible without reducing the contraceptive efficacy of menstrual cycle control. This has led to a gradual reduction of the estrogen dose in the OCs as well as to the development of ever more effective gestagens for ovulation inhibition and satisfactory menstrual cycle control. Combination preparations were developed with 30-35 mcg of ethinyl estradiol (EE) and high gestagen doses that guaranteed ovulation inhibition (30 mcg of gestodene, 60 mcg of norgestimate). A three-phase preparation with gestodene, which contains 30 mcg of EE and only 50 mcg of gestodene in the first week, massively suppresses the follicle maturation, more forcefully than an equivalent three-phase OC with levonorgestrel (LNG). In Germany since March 1992, there has been on the market an OC containing 20 mcg of EE and 1 mg of norethindrone acetate, with an effectiveness equal to that of higher-dose OCs. However, with this preparation the rate of spotting was still over 20% in the 12th menstrual cycle of use, hence it has not been accepted. In the coming years it is expected that further combination OCs with 20 mcg of EE and appropriate gestagen components will be introduced. In order to avoid the heavy burden on liver metabolism, various types depot gestagens such as implants (Norplant) or the vaginal ring (180 mcg of estradiol and 290 mcg of LNG) were developed as highly effective alternatives to OCs, however, their menstruation control is not satisfactory. Another implant, Capronor, releases 30-50 mcg of LNG over a period of 12-18 months. Parenterally applied highly effective contraceptive steroids (medroxyprogesterone acetate and norethindrone enanthate injected every 2-3 months) also seem to be able to alter hormone-dependent serum parameters in similar ways as OCs.     

Experience of Finnish women with Norplant insertions and removals

Objective Norplant® and Norplant-2® have been available for use by Finnish women since 1984 and 1986, respectively. The objective of this study was to explore Norplant users' experiences of insertions, removals and medical treatments.
Design A questionnaire was sent to women who had received Norplant® or Norplant-2® implants one to two years earlier ( n = 262) in normal clinical settings; the response rate was 79%.
Results At insertion, problems were experienced by 9% and at least some pain by 23% of women. During the first year 20% of all users (14% of Norplant® and 33% of Norplant-2® users) had their implants removed. Problems were experienced at removal by 33% of women and pain was experienced by 40%; nevertheless most users were satisfied with the device. Findings were similar for the two types of Norplant. Forty-two percent of the women had received minipills containing levonorgestrel before Norplant insertions in an attempt to assess Norplant's suitability, and 8% had received drugs for adverse effects caused by Norplant.
Conclusions Studies including perspectives of Norplant users and the whole lifespan of Norplant (including removal) should be conducted in all clinical settings where Norplant is provided.     

Long-term follow-up of women treated with contraceptive implants of levonorgestrel Norplant

This report describe the long-term follow-up of 376 women who received Norplant implants in the period october 1974 through may 1979. One-hundred-and-ten subjects received replacement implants after variable lengths of use of the first set. The average levonorgestrel plasma levels declined steadily through eight years of use of Norplant capsules (r = -937). Values were 0.35 ng/ml, 0.29 ng/ml and 0.22 ng/ml at treatment years 1, 5 and 8, respectively. Levonorgestrel plasma levels after replacement with a second set of implants were similar to those observed after the first insertion, either when placed in the same site as the first set or in a different area. The levonorgestrel half-life after implant removal was 42 +/- 16 h (X +/- S.E.) and only trace amounts are detected after 96 h. Nineteen pregnancies occurred during 18,530 woman-months of use of the first set of implants, eleven of them during years 6 through 8 of treatment. The Pearl Index for the first years of Norplant implants use was 0.63. No pregnancy has occurred in 5.020 woman-months observed during treatment with a second set of capsules. Fifty-six women (14.9%) out of 376 acceptors of the first implant and 12 (10.9%) out of 110 acceptors of the replacement implants were terminated for other medical reasons, mainly side effects commonly associated with hormonal contraception. Removals for bleeding problems occurred in 5.6% and 3.6% of the acceptors of the first and second implant, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Norplant皮下埋植避孕法使用七年临床观察

目的 评价单纯孕激素避孕埋植剂Ｎｏｒｐｌａｎｔ在我国妇女和的效果及副反应。方法 １９８４年始在１２个中心及其分中心接受使用Ｎｏｒｐｌａｎｔ避孕的妇女共有１０７１８名,采用前瞻性方法进行５年观察;其中部分妇女继续使用至７年,对使用７年的临床效果观察。结果 在第５年时的年妊娠率为０．６３／１００妇女。共有７５５４名妇女使用满５年,３６２２名妇女使用满６年,２４３３名妇女使用满７年。第６、７年的年妊娠率     

Prevalence of enlarged ovarian follicles among users of levonorgestrel subdermal contraceptive implants (Norplant)

OBJECTIVE: The aim of this study was to determine the prevalence of enlarged follicles, as detected by a single clinical or ultrasonographic examination, among users of levonorgestrel subdermal contraceptive implants (Norplant implants). STUDY DESIGN: This was a cross-sectional study of 103 users of Norplant implants and 50 users of the TCu380A intrauterine contraceptive device, all of whom received reproductive health services from PROFAMILIA, Santo Domingo, Dominican Republic. Bimanual pelvic examination and vaginal ultrasonography were performed. Enlarged follicles (>25 mm) were followed up weekly. The chi(2) test was applied to these data. RESULTS: Enlarged follicles were detected by ultrasonography in 17. 5% of Norplant implants users and 4% of TCu380A intrauterine contraceptive device users, respectively (P <.04). There was no difference according to duration of use. The longest time to involution of the follicles was 4 weeks. Forty percent of the enlarged follicles detected by ultrasonography were also detected by bimanual pelvic examination. CONCLUSION: Enlarged follicles are a frequent finding among women who use Norplant implants, but they are less frequent than described in previous studies, which were based on serial ultrasonographic scans in selected groups of users. Physicians and users should be aware of the transient nature of these enlarged follicles, which do not require intervention.     

Rates and outcomes of planned pregnancy after use of Norplant capsules, Norplant II rods, or levonorgestrel-releasing or copper TCu 380Ag intrauterine contraceptive devices.

OBJECTIVES: The objectives were to measure rates of planned pregnancy and factors affecting these rates after use of very-long-acting contraceptive methods (Norplant or Norplant II implants, a levonorgestrel-releasing intrauterine contraceptive device, or the copper T (model TCu 380Ag) intrauterine contraceptive device. STUDY DESIGN: The design was a concurrent, multicenter prospective study of 372 women who stopped contraception for planned pregnancy. Analysis was by life-table, log-rank, and standard chi 2 methods. RESULTS: Pregnancy rates 12 and 24 months after cessation of contraceptive use were 82 and 89 per 100, respectively. Age at removal and family planning intentions at initiation of contraception were both significantly correlated with pregnancy rates (p less than 0.05), but former contraceptive regimen and duration of contraceptive use were not. Pregnancy outcomes did not deviate from normal limits and did not differ by contraceptive formerly used. CONCLUSION: Contraceptive implants releasing 30 micrograms/day of levonorgestrel or intrauterine contraceptive devices releasing 20 micrograms/day of levonorgestrel or having copper surface areas of 380 mm2 are associated with normal fertility after use for women seeking pregnancy at termination. Durations of use do not affect pregnancy rates.     

长期使用Norplant皮下埋植剂妇女血清左炔诺孕酮水平的测定

目的（１）测定ｏｒｐｌａｎｔ皮下埋植剂（１－１１年）的妇女血清左诺孕酮水平,预测其可能使用的最长有效期限;（２）观察长期（５年）用药后血清ＬＮＧ水平与受试者体重间相关性。方法 应用放射地测定血清中ＬＮＧ水平。结果 使用Ｎｏｒｐｌａｎｔ１、３、５年后,血清ＬＮＧ均值分别为１２７３．５μｍｏｌ／Ｌ、９２４．０ｐｍｏｌ／Ｌ和７３９．６ｐｍｏｌ／Ｌ。第５－７年血清ＬＮＧ均呈线性降低,第７－１０年,血清ＬＮ     

Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants

OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.