Inhibitors of 5alpha-reductase for acne therapy

本应用解决了对痤疮选择性无毒的需要。在寻常痤疮和雄激素性脱发（男性型秃顶）中发现了过度的5 - α还原酶活性。目前对这些疾病的治疗产生了许多副作用，这两种疾病都起源于皮脂腺单位。我们已经开发了一种选择性的，有效的，局部应用的5 - α还原酶抑制剂来改变毛囊皮脂腺单位的病理过程。例如，为了实现这一目标，我们之前已经开发了一种选择性局部脂质体毛囊靶向技术，用于基因和其他大小分子。目前的应用将集中在我们最近观察到的5- α -还原酶抑制剂N， N-二乙基-4-甲基-3-氧-4-aza-5 - α -雄烷-17 - β -羧酰胺（4-MA）结合到脂体中选择性诱导细胞凋亡并抑制双氢睾酮（DHT）依赖性的鼠侧器官皮脂腺的生长。在选择性方面，当局部应用非脂质体4-MA时，选择性功效丧失，导致靶向对侧腺体受到影响。在安全性方面，与对照组相比，脂质体4-MA对前列腺重量、T/DHT比或体重增加没有显著影响，这表明局部应用脂质体4-MA的安全性和有效性。我们在此建议开发外用4-MAS脂质体作为抗痤疮剂。本试验的具体目的如下：1)优化外用4-MA脂质体选择性诱导雄性仓鼠皮脂腺细胞凋亡的效果；2)测定外用4- MA脂质体对SCID小鼠头皮毛囊和仓鼠皮脂腺的药代动力学；5)通过检测治疗动物DHT/T血液比值的变化，确定脂质体-4- ma有效剂量的安全性。在II期，为了使4-MA脂质体作为抗痤疮治疗药物进入临床，将在更大的动物身上进行选择性疗效和安全性研究。拟议的商业应用：4-MA脂质体将被开发为局部选择性靶向治疗痤疮，它们应该是一个非常大的市场。

This application addresses the need for selective non-toxic for acne. Excessive 5alpha-reductase activity is found in acne vulgaris as well as androgenic alopecia (male pattern baldness). Numerous side effects occur from current treatments of these diseases both of which originate in the pilosebaceous unit. We have developed a selective, effective, topically applied 5alpha-reductase inhibitor to modify pathological processes in the pilosebaceous unit. For example, toward this goal, we have previously developed a selective topical liposome hair follicle targeting technology fo r genes and other large and small molecules. The present application will focus on our recent observation that the 5-alpha- reductase inhibitor N, N-diethyl-4-methyl-3-oxo-4-aza-5alpha- androstane-17beta-carboxamide (4-MA) incorporated into liposomes selectively induces apoptosis and inhibits growth of the dihydrotestosterone (DHT)-dependent hamster flank organ sebaceous gland. With regard to selectivity, when non-liposomal 4-MA was topically applied, the selective efficacy was lost resulting in the on- targeted contralateral gland being affected. With regards to safety, liposome 4-MA did not significantly affect prostate weight, T/DHT ratios or body weight gain compared to controls indicating safety as well as efficacy of topical application of liposome 4-MA. We proposed here to develop topical liposomal 4-MAS as an anti-acne agent. The Specific Aims of this application are as follows: 1) Optimize efficacy of topical liposomal 4-MA to selectively induce apoptosis of sebaceous glands of male hamsters; 2) Determine pharmacokinetics of topical liposomal 4- MA to hair follicles of human scalp grafted into SCID mice and in the hamster sebaceous gland; 5) Determine safety of effective doses of liposomal-4-MA by detection of changes in DHT/T blood ratios in treated animals. In Phase II, selective efficacy and safety studies will be conducted on larger animals in order to enable liposomal 4-MA to enter the clinic as an anti-acne therapeutic. PROPOSED COMMERCIAL APPLICATIONS: Liposomal 4-MA will be developed as a topical selectively targeted therapeutic for acne for which they should be a very market.