ANDROGEN IMPLANT

雄激素植入物

• 批准号: 6436449
• 负责人: KALYAN SUDARAM
• 金额: $ 7.41万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436449
• 关键词: Macaca fascicularis; androgen analog; behavioral /social science research tag; clinical research; contraceptives; cooperative study; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; hormone regulation /control mechanism; human subject; laboratory mouse; laboratory rat; male; pharmacokinetics; reproductive system pharmacology; sex behavior; slow release drug; spermatogenesis; spermatogenesis inhibitor; testosterone

The need for effective and reversible methods of fertility control for men, such as those available to women, is widely recognized. Suppression of spermatogenesis by blocking gonadotropin secretion using an implant that delivers an LHRH analog represents one promising approach. However, the loss of gonadotropins results in diminished testosterone synthesis and release, requiring the long-term concomitant administration of an androgen. The aim of this project is to develop a convenient method of androgen supplementation via an implant. For this purpose we plan to utilize 7alpha-methyl-19-nortestosterone (MENT) a synthetic androgen that is considerably more potent than testosterone. We estimate the daily dose of MENT to be 300-500 mug/day, delivered subdermally via controlled release formulation. We plan to manufacture subdermal implants that would deliver this dose of MENT for up to one year. In addition to its greater potency relative to testosterone, MENT has an advantage over testosterone and its esters which are widely used as androgen supplements. The biological potency of testosterone is amplified 3 to 5 fold in the prostate, seminal vesicles, and sexual skin by its conversion to dihydrotestosterone (DHT). Although the physiological requirement for DHT in the adult male has not be established, it is suspected to be an important factor in the development of prostatic hyperplasia and prostate cancer. MENT does not undergo 5alpha-reduction in the prostate; therefore, its action is not amplified in this organ. Hence, MENT can be used at doses that can adequately maintain muscle mass, potency, and libido without overstimulating the prostate. In the studies proposed here, we will initially determine the biological and toxicological actions of MENT in animals and then conduct Phase 1 and 2 clinical trials in men. We will study the pharmacologic profile of MENT to determine whether, apart from its androgenic actions, MENT has residual estrogenic, progestogenic, or corticosteroid-like actions. In addition, we will study the distribution and disposition of MENT in rats. Provided that no adverse effects are seen in animal studies, pharmacokinetic studies to determine the metabolic clearance rate and bioavailability of MENT in men following intravenous and subdermal injection will be performed. In addition, MENT and testosterone will be compared for their anti- gonadotropic actions in men. One of our aims is to develop and manufacture MENT implants that would deliver a pre-determined dose in a sustained fashion for at least one year and conduct Phase 2 studies. Chronic toxicity studies will be done in rabbits and monkeys to determine the long- term safety of MENT so that the MENT implant method of androgen supplementation can proceed to large-scale clinical trials. Development of a MENT implant would not only be an important component of a male contraceptive, but such a contraceptive could be viewed as health promoting with respect to the development of prostatic disease.

需要对男性生育能力控制的有效和可逆方法， 例如女性可用的人，被广泛认可。 抑制 通过使用植入物阻断促性腺激素分泌的精子发生 提供LHRH模拟代表一种有前途的方法。 但是， 促性腺激素的丧失导致睾丸激素的合成减少和 释放，需要长期伴随雄激素给药。 该项目的目的是开发一种方便的雄激素方法 通过植入物补充。 为此，我们计划利用 7alpha-methyl-19-19-北植物（MENT）一种合成雄激素 比睾丸激素更有效。 我们估计每日剂量 每天是300-500杯，通过受控释放透露运送 配方。 我们计划制造可提供的下植入物 这种剂量长达一年。 除了更大的效力 相对于睾丸激素，MENT比睾丸激素具有优势 广泛用作雄激素补充剂的酯。 生物学 睾丸激素的效力在前列腺中的3至5倍放大 囊泡和性皮肤通过转化为二氢睾丸激素（DHT）。 尽管成年男性的DHT的生理要求不是 已建立，怀疑是发展的重要因素 前列腺增生和前列腺癌。 不经历 5降低前列腺；因此，它的行动不会放大 这个器官。 因此，可以以足够维护的剂量使用。 肌肉质量，效力和性欲，而没有过度刺激前列腺。 在 在这里提出的研究，我们最初将确定生物学和 MENT在动物中的毒理学作用，然后进行第1阶段和第2阶段 男性的临床试验。 我们将研究MENT的药理特征 确定除了其雄激素作用外，是否有残留 雌激素，孕激发或类皮质类固醇样作用。 另外，我们 将研究大鼠的分布和处置。 提供了 在动物研究中未见不良影响，药代动力学研究 确定男性的代谢清除率和生物利用度 将进行静脉注射和下部注射后。 在 补充，将比较睾丸激素的抗 男性的促性腺激素作用。 我们的目标之一是开发和制造 植入物将在持续的 时尚至少一年，并进行第二阶段研究。 慢性的 毒性研究将在兔子和猴子中进行，以确定长期 术语的术语安全，使雄激素的植入方法 补充可以进行大规模的临床试验。 发展 植入物不仅是男性的重要组成部分 避孕药，但是这种避孕药可以被视为健康促进 关于前列腺疾病的发展。