中国科技论文统计源期刊　中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖  
医药导报
医药导报, 2020, 39(11): 1496-1501
doi: 10.3870/j.issn.1004-0781.2020.11.008
十一酸睾酮原位凝胶植入剂避孕效果及对雄性大鼠生殖系统的影响*
Hormonal Contraceptive Effect of Testosterone Undecanoate Loaded In Situ Forming Implants in Reproductive System of Adult Male Rats
张晓伟1,2,3,, 金瑛2,3, 易东旭2,3, 杨立群2,3, 张翀2,3, 刘丹华2,3, 孟胜男1,
1.中国医科大学药学院药剂教研室,沈阳 110122
2.辽宁省计划生育科学研究院,沈阳 110031
3.国家卫健委生殖健康与遗传医学重点实验室,沈阳 110031
ZHANG Xiaowei1,2,3,, JIN Ying2,3, YI Dongxu2,3, YANG Liqun2,3, ZHANG Chong2,3, LIU Danhua2,3, MENG Shengnan1,
1. Department of Pharmaceutics,School of Pharmacy,China Medical University,Shenyang 110122,China
2. Liaoning Research Institute of Family Planning,Shenyang 110031,China
3. Key Laboratory of Reproductive Health and Medical Genetics,National Health Commission,Shenyang 110031,China
通信作者 孟胜男(1966-),女,辽宁沈阳人,教授,博士,主要从事药物吸收和代谢特征的评价、药动学、药物新剂型研究。电话:024-31939448,E-mail:shnmeng@hotmail.com。

作者简介 张晓伟(1986-),女,内蒙古赤峰人,副研究员,博士,主要从事新型缓释给药系统的开发工作。ORCID:0000-0002-9372-7107,电话:024-86800665,E-mail:sally00125@163.com。
基金资助: “十三五”国家重点研发计划(2016YFC1000902)
中图分类号: R979.2;R965     文献标识码: A     文章编号: 1004-0781(2020)11-1496-06
摘要:

目的 制备十一酸睾酮原位凝胶植入剂(TU-ISFI),考察其在大鼠体内避孕效果及对雄性大鼠生殖系统的影响。方法 以聚己内酯丙交酯为凝胶骨架材料,N-甲基吡咯烷酮为有机溶剂,制备TU-ISFI。以市售十一酸睾酮注射液为阳性对照,大鼠皮下注射植入TU-ISFI,考察大鼠血浆药物浓度、精子计数、精子活动力、生殖能力和睾丸、附睾等生殖器官变化。结果 体内外药物释放结果表明,TU-ISFI 3个月内能够稳定释放,大鼠体内血药浓度平稳,无明显波谷现象。皮下植入1个月后,TU-ISFI各剂量组大鼠附睾精子计数和精子活动力均明显下降。给药3个月后,TU-ISFI大、中剂量组(600,300 mg)生殖配对,大鼠完全丧失生殖能力,TU-ISFI小剂量组(150 mg)部分大鼠保留繁殖能力,子代个数明显低于对照组。结论 TU-ISFI具有平稳药物缓控释能力,对雄性大鼠避孕效果优良,是一种具有广阔应用前景的激素补充制剂和男性避孕制剂。
关键词: 十一酸睾酮 ; 原位凝胶植入剂 ; 避孕 ; 精子发生 ; 药物缓释

Abstract:

Objective To prepare testosterone undecanoate-loaded injectable in situ forming implants (TU-ISFI),and to investigate the influence on reproductive system and contraceptive effect in adult male rats. Methods The TU-loaded ISFI was prepare with adult male SD rats were treated with vehicle,TU-ISFI or TU injection.Fertility test,serum testosterone concentration,epididymal sperm count, motility,morphology and histology of testis were detected. Results The in vitro drug release test showed TU-loaded ISFI increased serum testosterone levels in rats steadily without fluctuations in three months.One month after administration, epididymal sperm count,sperm motility and percent of normal spermatozoa were all decreased significantly in all experimental groups.After three months,the animals treated with 600 and 300 mg TU-ISFI were 100% infertility,and no implantation sites were produced in the mated females.However,part of males in 150 mg TU-ISFI group and TU injection group still hold fertility but implantation were also significantly lower than control value. Conclusion The present findings suggest that TU-ISFI at an appropriate dose has potential as a long-acting male contraceptive drug or hormone replacement supplement drug.
Key words: Testosterone undecanoate ; In situ forming implants ; Contraception ; Spermatogenesis ; Drug release

开放科学(资源服务)标识码(OSID)

男性激素避孕是一种非常有潜力的避孕手段,目前已经有大量临床试验证明了其安全性和有效性[1,2]。但是药物制剂释放速度不平稳导致体内激素水平急剧变化带来的不良反应,如情绪变化、痤疮、性功能障碍等,降低了人们对这种避孕方法的接受度,也成为男性激素避孕手段继续发展的瓶颈[3]。因此,对该类激素相关药物的剂型加以改善,降低激素相关不良反应发生率,不仅有助于男性激素避孕手段的继续发展,也有助于改进激素补充疗法等相关药物平台。植入剂是避孕领域最常见的药物缓释剂型,但传统植入剂制备工艺复杂,成本高昂,需要在局部麻醉下进行外科切口后埋植。如果植入剂为生物不可降解型物质,还需额外手术进行清除,使用极为不便,患者顺应性差[4,5]。

溶剂沉淀型原位凝胶植入剂(solvent-removal precipitation based in situ forming implant,SRP-ISFI)是将高分子聚合物与药物一同溶解或溶胀于可与水互溶的适宜有机溶剂中所得可注射制剂[6]。局部注射后,SRP-ISFI中有机溶剂与生理环境中的水相互交换,聚合物沉淀凝固形成半固体或固体药物缓释贮库。目前,SRP-ISFI已经有多种制剂被美国食品药品管理局(FDA)批准上市,包括Atridox®、Eligard®等[7,8,9]。SRP-ISFI克服了传统植入剂缺点,具有可用于病变部位局部给药、延长释药周期、降低给药剂量和药物不良反应、避免植入剂手术植入的痛苦、患者顺应性好、制备工艺相对简单等优点。

笔者之前采用聚己内酯丙交酯制备十一酸睾酮原位凝胶植入剂(testosterone ondecanoate-loaded injectable in situ forming implants,TU-ISFI),并对该制剂工艺和药物体外释放机制等进行初步考察,TU-ISFI可以在体外稳定释放药物长达3个月[10]。笔者在本实验观察该药在大鼠体内避孕效果及可逆性,现报道如下。

1 材料与方法
1.1 材料

十一酸睾酮(testosterone undecanoate,TU,纯度:98%,购自武汉远成药业有限责任公司);TU注射液(浙江仙居制药股份有限公司生产,批号:180601);TU-ISFI(本实验室自行制备[10])。聚己内酯丙交酯[poly (DL-lactide-ε-caprolactone),PLCA,购自山东岱刚生物技术有限公司,批号:20171110]。其他试剂均为分析纯。

8周龄Sprague-Dawley大鼠,雄性体质量200~220 g,雌性体质量180~200 g,由辽宁长生生物技术有限公司提供,实验动物生产许可证号:SCXK(辽) 2010-0001。本实验涉及的动物实验研究内容,严格按照中国医科大学实验伦理学相关政策文件规定要求执行。

1.2 TU-ISFI的制备

按20%浓度比例称取适量PLCA溶于N-甲基吡咯烷酮(N-methylpyrrolidone,NMP),37 ℃搅拌保存过夜,直至得到透明澄清PLCA溶液。将该溶液在65 ℃加热,除去其中所溶解气体。分批称取适量过筛孔内径0.148 mm筛(100目)TU药粉,分散在PLCA/NMP溶液,搅拌至完全溶解,使最终所得TU-ISFI载药量16%。

1.3 大鼠血药浓度测定

将雄性大鼠按体质量随机分为给药组和空白对照组,每组40只,给药组给予TU-ISFI,空白对照组给予不含药物的同基质同处方原位凝胶注射植入剂。将大鼠麻醉,以20-21号针头背部皮下注射。注射前后称重,精密确定给药剂量。分别于给药后适当时间点随机取大鼠5只,尾静脉取血约0.7 mL。取血后处死大鼠,取出剩余埋植剂,去除包裹组织,蒸馏水洗涤,冻干,甲醇复溶,浸泡,超声处理2 h,过滤,高效液相色谱(HPLC)法测定埋植剂中残余TU量(LA-30A,Shimadzu,日本)。血样经3500 r·min-1离心10 min(r=10 cm)得血浆,-20 ℃冷冻保存。电子发光法测定其中睾酮含量(cobas e 411,Roche,德国)。

1.4 药效学动物分组

将雄性大鼠随机分为TU-ISFI大、中、小剂量组和十一酸睾酮注射液组(阳性对照组)、空白对照组,每组30只。TU-ISFI大、中、小剂量组分别注射TU-ISFI 600,300,150 mg(相当于TU 3.0,1.5和0.75 mg·kg-1·d-1),空白对照组给予空白原位凝胶植入剂0.3 g,阳性对照组按1.5 mg·kg-1·d-1剂量按月给药,共注射3次。给药后1,3,4个月(因TU-ISFI可持续释放3个月,给药后4个月相当于停药1个月),每组取10只进行生育力实验。

1.5 生育力实验

交配生育实验:取各组雄性大鼠与12周龄雌性大鼠,按♂:♀=1:2合笼。合笼后每天10:00之前检测雌性大鼠阴道涂片,阴道涂片内出现精子或阴栓时,算一次交配行为。记录交配情况,将交配过的雌性大鼠编号取出,18 d后处死,记录子宫内存活胎仔及死胎数。检测交配行为共进行6 d,6 d后未发现交配行为的雌鼠,也在18 d后处死,观察怀孕情况。实验结束计算怀孕率、平均胎仔数、死胎率。

1.5.1 生殖系统发育 雄性大鼠配对结束后称重,脱臼处死,解剖,记录睾丸、附睾和精囊质量,计算生殖器相对质量。生殖器相对质量=器官质量/体质量×100。

1.5.2 睾丸组织细胞形态学 取新鲜分离的大鼠睾丸组织,Bouin’s固定液固定至少24 h。常规上行梯度乙醇脱水、石蜡包埋,切取厚度5 μm组织切片。常规苏木精-伊红(HE)染色,观察睾丸内细胞形态和精子发生状况。

1.5.3 精子计数和精子活动力测定 另取两侧附睾尾组织各约100 mg,剪碎置15 mL任氏液,37 ℃孵育10 min,使精子在培养液内分散均匀。取一滴精子悬液滴在血细胞计数板上,按照血细胞计数法测定精子密度,并分别计算活动精子数和不活动精子数,换算成精子活动力百分比和每个附睾中精子总数。

1.5.4 精子形态 取上述精子悬液30 μL滴在载玻片上,盖玻片与载玻片呈45度角迅速推膜,制成精液涂片,水平放置10 min,晾干。晾干后浸入95%乙醇与甲醇混合液中固定2~3 min,取出后再次晾干。常规HE染色,磷酸盐缓冲液冲洗调色,高倍显微镜下观察精子形态。

1.6 统计学方法

采用SPSS 19.0版软件对实验数据进行统计分析,计数资料采用卡方检验,计量资料采用单因素方差分析法和t检验,以P<0.05为差异有统计学意义。

2 结果
2.1 大鼠体内释放情况

TU-ISFI在血浆中的睾酮浓度-时间曲线见图1。植入后,给药组血浆睾酮浓度迅速超过空白对照组,7 d后给药组血浆睾酮水平开始急剧上升,28 d达到最大值,然后开始缓慢下降,90 d血浆睾酮浓度与空白对照组持平。实验结果提示TU-ISFI可在3个月内持续维持大鼠体内较高血浆睾酮浓度,3个月后大鼠体内睾酮水平回落至正常。植入剂残余药量测定结果表明,TU-ISFI在大鼠体内药物突释量较小,第7天共释放约14.7%药物,第28天共释放约47.3%,第63天累积释放量达到89.9%,第90天时基本全部释放。


图1 两组大鼠血浆睾酮浓度变化

Fig.1 Changes of serum testosterone levels in two groups of rats

2.2 交配生育实验结果

结果见表1。给药1个月后,TU-ISFI大、中、小剂量组和阳性对照组怀孕率和平均胎仔数均较空白对照组高,此时外源性睾酮已经开始抑制新的精子产生,但由于大鼠精子整个发生时程为48 d,睾酮主要在精子产生初期发生作用,因此1个月时还不能达到避孕效果。大鼠精子发生周期时程为12 d,整个精子发生时程为48 d,给药1个月,因为睾丸内睾酮水平下降,导致减数分裂期和精子形成期生精细胞大量丢失,但对已经成熟或者接近成熟的精子不起抑制作用,因此不能达到完全避孕效果。给药3个月后,TU-ISFI大、中剂量组可达到100%成功避孕;TU-ISFI小剂量组避孕成功率75%,怀孕胎仔数明显下降;阳性对照组避孕成功率90%,10只雄鼠中有1只雄鼠的两只配对雌鼠怀孕,未达到100%避孕效果。停药1个月后,TU-ISFI大、中、小剂量组繁殖能力开始恢复,阳性对照组繁殖能力仍受到抑制。

表1 大鼠交配生育实验的结果
Tab.1 Results of mating experiment in rats n=20
组别与时间 怀孕率/
%		 平均胎仔
数/个		 死胎率/
%
空白对照组
1个月 75.0 13.38 7.47
3个月 80.0 13.00 5.13
4个月 85.0 12.78 3.91
阳性对照组
1个月 95.0 13.95 4.53
3个月 10.0 10.00 5.00
4个月 0.0 0.00 0.00
TU-ISFI大剂量组
1个月 75.0 16.09 1.30
3个月 0.0 0.00 0.00
4个月 25.0 11.40 5.26
TU-ISFI中剂量组
1个月 90.0 14.8 4.05
3个月 0.0 0.00 0.00
4个月 40.0 15.63 8.80
TU-ISFI小剂量组
1个月 90.0 14.73 4.32
3个月 25.0 7.57 5.66
4个月 55.0 13.36 6.12

表1 大鼠交配生育实验的结果

Tab.1 Results of mating experiment in rats n=20

2.3 生殖系统发育分析

结果见图2。给药后1个月,与空白对照组比较,TU-ISFI大、中、小剂量组生殖器整体相对质量增加,睾丸质量减轻,精囊增大,附睾无明显变化;阳性对照组生殖系统整体质量下降,睾丸、附睾均缩小,精囊稍增大。给药后3个月,与空白对照组比较,其他各组生殖系统整体质量较低,主要由于睾丸和附睾萎缩,其中TU-ISFI大、中、小剂量组睾丸质量约为空白对照组的50%,阳性对照组睾丸质量为空白对照组的三分之一。停药后1个月,TU-ISFI大、中、小剂量组睾丸和附睾大小恢复较快,阳性对照组生殖系统恢复较慢。


图2 TU-ISFI对大鼠体质量和生殖系统发育的影响

Fig.2 Effect of TU-ISFI on body mass and reproductive system of rats

2.4 睾丸组织细胞形态学检测

结果见图3。给药后1个月,TU-ISFI各剂量组睾丸曲细精管内各级精母细胞、精子细胞、精子及间质细胞均清晰可辨,未见明显形态学变化;阳性对照组部分曲细精管内生殖细胞蜕变,坏死脱落。给药后3个月,TU-ISFI大剂量组和阳性对照组大部分曲细精管内生殖细胞明显减少,排列疏松,层次变薄,腔缘不整齐;精子、精子细胞及精母细胞部分蜕变,脱落;部分区域管腔皱缩,细胞稀少,腔内空虚,近基底膜仅见少许散在精原细胞、精母细胞或支持细胞,部分仅衬覆几个精原细胞,管腔内明显可见多个多核巨细胞。TU-ISFI中、小剂量组可见局部曲细精管内生殖细胞减少,排列疏松,层次变薄,细胞稀少,部分腔内空虚,近基底膜仅见少许散在的精原细胞,支持细胞或蜕化中的精母细胞亦见多核巨细胞。与TU-ISFI大剂量组比较,TU-ISFI中、小剂量组形态学变化及范围具有明显剂量依赖性。


图3 5组睾丸组织形态学变化(St.睾丸精子细胞;Sc.精母细胞;Sg.精原细胞;G.多核巨细胞;*.曲细精管空腔;×400)

Fig.3 Histological changes of testicular sections in five groups [St.spermatids;Sc.spermatocytes;Sg.spermatogenous cells;G.Multinucleated giant cell;*.empty space (crack) between spermatogenic cells;×400]


图4 5组精子形态变化(Sp.精子;WBC.白细胞;ab-SP.畸形精子;d-Sc.退变坏死的精母细胞;×400)

Fig.4 Morphological changes of sperms of five groups (Sp.sperm;WBC.leukocyte; ab-SP.abnormal sperm;d-Sc.degenerating spermatocytes;×400)

停药后1个月,阳性对照组大部分曲细精管仍皱缩,生殖细胞明显较少,排列疏松,层次变薄,细胞稀少,腔内空虚,近基底膜仅见少许精原细胞、精母细胞及支持细胞,小部分曲细精管内生精细胞清晰可见,仍见精子发生。TU-ISFI大、中、小剂量组可见部分区域曲细精管内生殖细胞减少,排列疏松,层次变薄。局部曲细精管内生殖细胞蜕变,坏死,脱落,腔内空虚,但大部分曲细精管内各级精母细胞、精子细胞及正常精子均清晰可辨,间质未见明显形态学变化,其形态学变化及范围具有明显剂量依赖性。

2.5 精子计数和精子活动力

结果见表2。给药后1个月,与空白对照组比较,其他各组精子数量明显下降,下降程度依次为:阳性对照组>TU-ISFI大剂量组>TU-ISFI中剂量组>TU-ISFI小剂量组,可能由于外源性睾酮作用,TU-ISFI大、中、小剂量组精子活力与空白对照组相比显著提高。给药3个月后,除空白对照组外,其他各组精子数均极少,TU-ISFI大、中剂量组精子活动力为0,TU-ISFI小剂量组和阳性对照组精子活动能力底下。停药1个月后,TU-ISFI大、中、小剂量组精子数有所恢复,精子活动率回升至20%以上,阳性对照组仍处于被抑制状态。

表2 5组不同时间附睾精子数和精子活动率
Tab.2 Epididymal sperm count and motility in five groups at different time points n=10
组别与时间 附睾精子数/
(个·g-1)		 精子活动力/
%
空白对照组
1个月 1975.8 37.67
3个月 1880.3 29.42
4个月 2014.6 40.76
阳性对照组
1个月 694.4 34.24
3个月 39.4 1.67
4个月 135.8 2.72
TU-ISFI大剂量组
1个月 991.6 52.39
3个月 110.7 0.00
4个月 643.8 21.19
TU-ISFI中剂量组
1个月 1206.5 45.63
3个月 97.5 0.00
4个月 731.2 21.91
TU-ISFI小剂量组
1个月 1520.1 49.03
3个月 355.8 8.03
4个月 1301.4 25.27

表2 5组不同时间附睾精子数和精子活动率

Tab.2 Epididymal sperm count and motility in five groups at different time points n=10

2.6 精子形态

给药1个月时,TU-ISFI中、小剂量组精子形态未见明显异常;TU-ISFI大剂量组可见个别异常形态精子,主要表现为尾部折叠、头部无钩等;阳性对照组可见大量异常形态精子,主要表现为无定形、胖头等。给药3个月,阳性对照组出现大量精母细胞,精子细胞及精子蜕变、坏死,大量精子出现无头、断尾等畸形表现;TU-ISFI大、中、小剂量组出现大量精母细胞、精子细胞及精子蜕变、坏死,精子形态学变化均与阳性对照组相近,程度略低。

停药1个月后,TU-ISFI大、中、小剂量组仍可见单个精母细胞及精子细胞蜕变、坏死,精子形态大部分完好,畸形率较低,形态学变化与给药1个月时相近;阳性对照组可见部分蜕变坏死精母细胞、精子细胞及精子,部分精子畸形,主要是无钩、胖头、断尾等。

3 讨论

我国曾开展过TU注射液用于男性激素避孕的临床多中心研究,该研究中,TU在男性避孕方面的有效性得到肯定,但在不良反应发生率以及安全性方面存有质疑。此外,部分受试者希望能够有更长效的TU制剂[11]。

本研究结果表明,给药1个月后,TU-ISFI各剂量组精子数有所下降,但精子活动力上升,因此母鼠妊娠率较空白对照组高。大鼠精子发生周期时程为12 d,整个精子发生时程为48 d,给药1个月时,因为睾丸内睾酮水平下降,导致减数分裂期和精子形成期生精细胞大量丢失,但对已经成熟或者接近成熟的部分精子起不到抑制作用,因此不能达到完全避孕效果。给药3个月后,各剂量组均达到抑制精子发生效果,在避孕效果上,TU-ISFI大、中剂量组优于阳性对照组,避孕率达到100%。实验发现,给予大鼠小剂量TU并不能对睾丸本身合成和分泌睾酮的功能实现完全干扰,仍有极少部分有活力精子产生,导致避孕失败。从停药1个月后恢复情况看,由于后期TU-ISFI释放药物量逐渐降低,避免了阳性对照组每个月一次给药带来的波谷现象,有利于停药后精子数目和精子活力恢复。

综上所述,TU-ISFI以300~600 mg剂量(即1.5~3.0 mg·kg-1·d-1剂量TU)对大鼠给药后可达到优于阳性对照组的避孕效果,停药后大鼠生殖能力可迅速恢复。后续研究中,笔者还将考察其安全性和不良反应发生情况,对其剂量进一步筛选。从目前研究来看,TU-ISFI具有平稳药物缓控释能力,对雄性大鼠避孕效果优良,作用更为温和并且可靠,是一种具有广阔应用前景的激素补充制剂和男性避孕制剂。

参考文献
[1] THIRUMALAI A,PAGE S T.Recent developments in male contraception[J].Drugs,2019,79(1): 11-20.
Unplanned pregnancies are an ongoing global burden, posing health and economic risks for women, children, and families. Advances in male contraception have been historically stymied by concerning failure rates, problematic side effects, and perceived market limitations. However, increased interest in reliable and reversible options for male contraception have resulted in resurgent efforts to introduce novel contraceptives for men. Hormonal male contraception relies on exogenous androgens and progestogens that suppress gonadotropin production, thereby suppressing testicular testosterone and sperm production. In many men, effective suppression of spermatogenesis can be achieved by androgen-progestin combination therapy. Small-scale contraceptive efficacy studies in couples have demonstrated effectiveness and reversibility with male hormonal methods, but side effects related to mood, sexual desire and cholesterol remain concerning. A number of novel androgens have reached clinical testing as potential contraceptive agents; many of these have both androgenic and progestogenic action in a single, modified steroid, thereby holding promise as single-agent contraceptives. Currently, these novel steroids hold promise as both a
DOI:10.1007/s40265-018-1038-8      PMID:30588563      URL    
[本文引用:1]
[2] LONG J E,LEE M S, BLITHE D L.Male contraceptive development: update on novel hormonal and nonhormonal methods[J].Clinical Chemistry,2019,65(1): 153-160.
BACKGROUND: Development of new methods of male contraception would address an unmet need for men to control their fertility and could increase contraceptive options for women. Pharmaceutical research and development for male contraception was active in the 1990s but has been virtually abandoned. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has supported a contraceptive development program since 1969 and supports the majority of hormonal male contraceptive development. Nonhormonal methods are also in development but are at earlier stages. CONTENT: Several hormonal male contraceptive agents have entered clinical trials. Single-agent products being evaluated include dimethandrolone undecanoate, 11beta-methyl-nortestosterone dodecyl carbonate, and 7alpha-methyl-19-nortestosterone. A contraceptive efficacy trial of Nestorone((R)) gel and testosterone gel in a single application will begin in 2018. Potential nonhormonal methods are at preclinical stages of development. Many nonhormonal male contraceptive targets that affect either sperm production or sperm function have been identified. Targeted pathways include the retinoic acid pathway, bromodomain and extraterminal proteins, and pathways for Sertoli cell-germ cell adhesion or sperm motility. Druggable targets include CatSper, the sperm Na+/K+-exchanger, TSSK, HIPK4, EPPIN, and ADAMs family proteins. Development of a procedure to reversibly block the vas deferens (initially developed in India in the 1980s) is undergoing early stage research in the US under the trade name Vasalgel. SUMMARY: NICHD has supported the development of reversible male contraceptive agents. Other organizations such as the World Health Organization and the Population Council are pursuing male contraceptive development, but industry involvement remains dormant.
DOI:10.1373/clinchem.2018.295089      PMID:30602479      URL    
[本文引用:1]
[3] BEHRE H M,ZITZMANN M,ANDERSON R A,et al.Efficacy and safety of an injectable combination hormonal contraceptive for men[J].J Clin Endocrinol Metab, 2016,101(12):4779-4788.
CONTEXT: The development of a safe and effective reversible method of male contraception is still an unmet need. OBJECTIVE: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. DESIGN: Prospective multicentre study. SETTING: Ten study centers. PARTICIPANTS: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems. INTERVENTION: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. MAIN OUTCOMES MEASURES: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. RESULTS: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. CONCLUSIONS: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.
DOI:10.1210/jc.2016-2141      PMID:27788052      URL    
[本文引用:1]
[4] DASH A K,CUDWORTH G C.Therapeutic applications of implantable drug delivery systems[J].J Pharmacol Tox Met,1998,40(1):1-12.
[本文引用:1]
[5] LEVY R J,LABHASETWAR V,STRICKBERGER S A,et al.Controlled release implant dosage forms for cardiac arrhythmias:review and perspectives[J].Drug Delivery,1996,3(3):137-142.
Cardiac implants using drug-polymer systems for the release of anti-arrhythmic agents directly to the myocardium have been successfully utilized in experimental studies for preventing and treating arrhythmias. This approach is hypothesized to be optimal since anti-arrhythmic agents are provided directly to the heart, and therefore the possibility of systemic side effects is reduced. Furthermore, anti-arrhythmic agents with poor oral bioavailability or with first-pass clearance characteristics following intravenous administration, such as the class III agent ibutilide, are optimally used by the direct cardiac route of administration. Cardiac controlled release implants have been demonstrated to be effective for optimizing the therapy of ventricular tachycardia, ventricular fibrillation, and atrial flutter. Monolithic matrices have been used for fixed rate release kinetics, and modulation of release has been possible through the use of iontophoretic drug delivery systems. Future implants will interface with forefront strategies in tissue engineering and molecular genetics to provide optimal therapy of the diseased arrhythmogenic myocardium.
DOI:10.3109/10717549609029442      PMID:26790908      URL    
[本文引用:1]
[6] KEMPE S,MDER K.In situ forming implants-an attractive formulation principle for parenteral depot formulations[J].J Controlled Release,2012,161(2):668-679.
DOI:10.1016/j.jconrel.2012.04.016      URL    
[本文引用:1]
[7] JOHNSON L R,STOLLER N H.Rationale for the use of Atridox therapy for managing periodontal patients[J].Compend Coutin Edul Dent,1999,20(4 Suppl):19.
[本文引用:1]
[8] ZEIDNER N S,MASSUNG R F,DOLAN M C,et al.A sustained-release formulation of doxycycline hyclate (Atridox) prevents simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi transmitted by tick bite[J].J Med Microbiol,2008,57(4):463-468.
[本文引用:1]
[9] BRAECKMAN J,MICHIELSEN D.Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard ® /Depo-Eligard ® ) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study[J].Archives Med SciAms,2014,3:477-483.
[本文引用:1]
[10] ZHANG X,ZHANG C,ZHANG W,et al.Feasibility of poly (ε-caprolactone-co-DL-lactide) as a biodegradable material for in situ forming implants: evaluation of drug release and in vivo degradation[J].Drug Dev Ind Pharm,2015,41(2):342.
[本文引用:2]
[11] 谷翊群,王兴海,徐铎,等.十一酸睾酮酯注射液避孕有效性的多中心Ⅱ期临床研究[J].生殖医学杂志,2003,12(2):67-73.
[本文引用:1]
资源
PDF (2396KB) | 摘要
PDF下载数    
RichHTML 浏览数    
摘要点击数    
分享
导出
EndNote | Ris | Bibtex
相关文章:
关键词（key words）
十一酸睾酮
原位凝胶植入剂
避孕
精子发生
药物缓释
Testosterone undecanoate
In situ forming implants
Contraception
Spermatogenesis
Drug release
作者
张晓伟
金瑛
易东旭
杨立群
张翀
刘丹华
孟胜男
ZHANG Xiaowei
JIN Ying
YI Dongxu
YANG Liqun
ZHANG Chong
LIU Danhua
MENG Shengnan