Topical Cyclosporin A for Dermatitis and Psoriasis

描述：(字面意思)皮肤的外层，即皮肤的保护层 角质层，用于排除环孢素A(CsA)等治疗药物。 初步实验已经明确地证明，短聚合物 精氨酸穿过小鼠和人皮肤的角质层进入 表皮和真皮组织。相似的渗透到皮肤的所有层 当精氨酸的短聚合物与环孢素A偶联时观察到 非结合形式不能穿透皮肤。这些共轭化合物达到了 炎症皮肤真皮内T细胞浸润。相关共轭函数使用 可释放的连接物提供具有治疗活性的环孢素A结合物，因此 为有系统毒性的药物的集中输送提供一种手段 治疗银屑病和皮炎的同时缓解全身性问题 毒性。 这项提议的目标是选择一种主要的环孢素A-转运体结合物 进一步发展。这将需要综合和评估一系列 包括一组具有以下范围的转运体的GSA-转运体结合物 组织穿透能力。将对标记的子集进行组织评估 渗透性和相应的可释放亚组将通过以下方法在体外进行评估 检测其抑制活化T细胞分泌IL-2的能力 活体使用接触性皮炎的动物模型。 建议的商业应用： 目前治疗皮炎和牛皮癣的局部疗法都存在根本性问题。口服时，免疫抑制剂可以有效，通过皮损内注射，环孢素A显著减少或清除牛皮癣皮损。CsA目前不用于治疗皮炎，由于全身毒性，仅用于严重的牛皮癣病例。拟议的结合物有望为特应性/接触性皮炎和牛皮癣提供第一批高效的局部治疗，这些药物加在一起将使美国患者总数达到2000万人。

DESCRIPTION: (Verbatim) The protective outer layer of the skin, the stratum corneum, serves to exclude therapeutic drugs like cyclosporin A (CsA). Preliminary experiments have unambiguously established that short polymers of arginine cross the stratum corneum of murine and human skin to enter the epidermal and dermal tissue. Similar penetration into all layers of the skin was observed when short polymers of arginine were conjugated to CsA, which in unconjugated form fails to penetrate skin. These conjugates reached infiltrating T cells in the dermis of inflamed skin. Related conjugates using a releasable linker provided therapeutically active CsA conjugates, thus providing a means of focally delivering systemically toxic drugs for the treatment of psoriasis and dermatitis while alleviating the problem of systemic toxicity. The goal of this proposal is to select a lead CsA -transporter conjugate for further development. This will entail the synthesis and evaluation of a series of GsA-transporter conjugates comprising a set of transporters with a range of tissue penetrating ability. A labeled subset will be assessed for tissue penetration and a corresponding releasable subset will be evaluated in vitro by assaying their ability to inhibit secretion of Il-2 by activated T cells and in vivo using an animal model of contact dermatitis. PROPOSED COMMERCIAL APPLICATION: Current topical therapies for dermatitis and psoriasis all have fundamental problems. When administered orally, immunosuppressants can be effective, and by, intralesional injection, CsA dramatically reduces or clears psoriatic lesions. CsA is not currently used to treat dermatitis and is used only in severe cases of psoriasis because of systemic toxicity. The proposed conjugates are expected to provide the first highly efficacious topical treatments for atopic/contact dermatitis and psoriasis, which together total >20 million US patients.