Development of a Hormonal Male Contraceptive With Health Benefits: Safety, Effic

开发具有健康益处的激素男性避孕药：安全、有效

• 批准号: 8549282
• 负责人: NARENDER KUMAR
• 金额: $ 23.96万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8549282
• 关键词: Acetates; Aftercare; Androgens; Animal Model; Animals; Atrophic; Binding; Blood Pressure; Bone Growth; Bone Regeneration; Cell physiology; Clinical Trials; Combined Modality Therapy; Contraceptive Agents; Contraceptive methods; Couples; Depo Provera; Development; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Estrogens; Etonogestrel; Female Contraceptive Agents; Funding; Gel; Generations; Goals; Gonadotropins; Health Benefit; Hormonal; Implant; In Vitro; Injectable; Injection of therapeutic agent; Instruction; Investigational New Drug Application; Levonorgestrel; M cell; Maintenance; Male Contraceptions; Male Contraceptive Agents; Medroxyprogesterone; Medroxyprogesterone 17-Acetate; Methods; Modeling; Myelin; Nandrolone; Natural regeneration; Neurons; Orchiectomy; Pamphlets; Pharmaceutical Preparations; Production; Progestins; Prostate; Pump; Randomized; Rattus; Recovery; Regimen; Regulation; Research; Research Personnel; Research Project Grants; Resistance; Safety; Schedule; Serum; Sex Behavior; Sex Hormone-Binding Globulin; Silastic; Spermatogenesis; Surveys; Synthetic Progestogens; Testis; Testosterone; Transactivation; Treatment Protocols; Update; Vaccinated; Woman; aged; arm; base; bone; bone mass; contraceptive efficacy; design; in vivo; leydig interstitial cell; male; men; muscle form; protective effect; remyelination; safety study; sperm cell; stem; unintended pregnancy; young adult

PROJECT SUMMARY (See instructions): The proprietary androgen, 7a-methyl-19-nortestosterone (MENT¿) in combination with DMPA progestin is being investigated for male contraception. MENT is 10 fold more effective than testosterone (T) in suppressing gonadotropins and maintaining muscle mass. Therefore, it is possible to deliver a dose of MENT via silastic implants that will be effective in suppressing gonadotropins and spermatogenesis. In addition, MENT will have potential health benefits on prostate, bone and muscle mass and myelin regeneration based on the results of in vitro and animal studies. For example, (1) MENT is resistant to 5a-reduction, therefore, it is less stimulatory on the prostate at a comparable replacement dose; (2) MENT is aromatized to a potent estrogen, thereby, maintains sexual behavior in animals and men; (3) MENT does not bind to sex hormone binding globulin (SHBG) and has similar pharmacokinetics as T; and (4) MENT was recently shown to increase remyelination of neuronal cells (M. Schumacher, unpublished). Hence the long-term use of MENT in men is expected to be superior to T with added health benefits. First generation exogenous treatment regimens using testosterone injection, gel or biodegradable pellet or MENT acetate (MENT Ac) silastic implant showed limited efficacy in male contraceptive clinical trials. Second generation regimens using androgen in combination with a progestin such as levonorgestrel, etonogestrel or DMPA showed higher efficacy in suppressing spermatogenesis. In this research project, we will use a regimen of three MENT Ac implants (releasing ~ 1500 pg/day of MENT Ac) in combination with either a single DMPA injection at the start or multiple injections at 3 month intervals. MENT Ac implants will be manufactured, and the clinical trial will commence during the next funding cycle (pending approval). In addition, pharmacological and mechanistic studies will be conducted to determine the safety and health benefits of MENT and DMPA use. MENT Ac is an acetylated derivative of MENT and is used in implant manufacturing for optimal release rates. MENT and MENT Ac are used interchangeably since MENT Ac released from implants is rapidly hydrolyzed to the active MENT. Depo Provera (DMPA, Pfizer) injectable is an approved female contraceptive and is being investigated for male contraception. Depo provera releases an active progestin, medroxyprogesterone acetate (MPA). MPA will be used in animal and in vitro studies.

项目摘要（参见说明）： 正在研究专有雄激素 7a-甲基-19-去甲睾酮 (MENT¿) 与 DMPA 孕激素的组合，在抑制促性腺激素和肌肉质量方面，MENT 的效果比睾酮 (T) 高 10 倍。可以通过硅橡胶植入物输送一定剂量的 MENT，这将有效抑制促性腺激素和精子发生。 根据体外和动物研究的结果，MENT 对前列腺、骨骼和肌肉质量以及髓磷脂再生具有潜在的健康益处，例如，(1) MENT 对 5a 还原具有抵抗力，因此对前列腺的刺激较小。在相当的替代剂量下，MENT 被芳香化为有效的雌激素，从而维持动物和男性的性行为；(3) MENT 不与性激素结合； 结合球蛋白 (SHBG) 且具有与 T 类似的药代动力学；(4) MENT 最近被证明可以增加神经元细胞的髓鞘再生（M. Schumacher，未发表），因此预计 MENT 在男性中的长期使用优于男性。 T 具有额外的健康益处。 使用睾酮注射剂、凝胶或可生物降解颗粒或 MENT 醋酸酯 (MENT Ac) 硅橡胶植入物在男性避孕临床试验中显示出有限的功效，使用雄激素与孕激素（如左炔诺孕酮、依托孕烯或 DMPA）联合使用的第二代方案在抑制精子发生方面显示出更高的功效。在本研究项目中，我们将使用三个 MENT Ac 植入物（释放约 1500 皮克/天的 MENT Ac）与将生产一开始注射一次 DMPA 或每隔 3 个月注射多次的 MENT Ac 植入物，并将在下一个资助周期开始临床试验（待批准）。确定 MENT 和 DMPA 使用的安全性和健康益处 MENT Ac 是 MENT 的乙酰化衍生物，用于植入物制造以获得最佳释放率 MENT 和 MENT Ac 可以互换使用，因为 MENT Ac 是从植入物中释放的。 Depo Provera（DMPA，辉瑞）注射剂是一种经批准的女性避孕药，正在研究用于男性避孕。Depo Provera 快速释放活性孕激素醋酸甲羟孕酮 (MPA)，将用于动物和体外研究。