Inhibitors of 5alpha-reductase for acne therapy

本申请解决了选择性无毒痤疮的需要。过度的5 α-还原酶活性在寻常痤疮以及雄激素性脱发（男性型脱发）中发现。许多副作用发生在这些疾病的当前治疗中，这两种疾病都起源于毛囊皮脂腺单位。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，以修改毛囊皮脂腺单位的病理过程。 例如，为了实现这一目标，我们先前已经开发了针对基因和其他大小分子的选择性局部脂质体毛囊靶向技术。本申请将集中于我们最近的观察，即掺入脂质体中的5-α-还原酶抑制剂N，N-二乙基-4-甲基-3-氧代-4-氮杂-5 α-雄甾烷-17 β-甲酰胺（4-MA）选择性地诱导细胞凋亡并抑制二氢睾酮（DHT）依赖性仓鼠胁腹器官皮脂腺的生长。关于选择性，当局部施用非脂质体4-MA时，选择性功效丧失，导致靶向对侧腺体受到影响。关于安全性，与对照相比，脂质体4-MA未显著影响前列腺重量、T/DHT比率或体重增加，表明脂质体4-MA局部应用的安全性和有效性。我们建议在这里开发局部脂质体4-MAS作为抗痤疮剂。本申请的具体目的如下：1）优化局部脂质体4-MA选择性诱导雄性仓鼠皮脂腺细胞凋亡的功效; 2）测定局部脂质体4- MA对移植到SCID小鼠中的人头皮毛囊和仓鼠皮脂腺中的药代动力学; 5）通过检测治疗动物中DHT/T血液比率的变化来确定有效剂量的脂质体-4-MA的安全性。在II期，将在较大动物中进行选择性疗效和安全性研究，以使脂质体4-MA能够作为抗痤疮治疗剂进入临床。拟议的商业应用：脂质体4-MA将被开发为一种局部选择性靶向治疗痤疮，他们应该是一个非常市场。

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.