Aminopterin for the Treatment of Severe Recalcitrant Atopic Dermatitis

描述(申请人提供)：特应性皮炎(AD)是一种瘙痒，炎症性皮肤病。它是导致人类和犬类残疾的最常见原因之一。人类特应性皮炎的发病率正在稳步上升。对于较轻微的人类疾病，主要的治疗方法是局部治疗。病情较重的患者会出现慢性瘙痒和皮疹，通常需要全身免疫抑制治疗。全身皮质类固醇是有效的，但有不可接受的副作用。包括甲氨蝶呤在内的其他全身免疫抑制药物正在研究中，但对这些患者的有效、安全的治疗尚未确定。据估计，有10%的狗患有阿尔茨海默病。用局部药物治疗患有AD的狗每天一到两次是困难的，而且没有有效的治疗方法。此外，犬AD(CAD)是AD最好的临床前模型。这促使研究人员研究狗的口服全身免疫抑制治疗，以便开发出对狗和人类有效的治疗方法。该项目的长期目标是开发氨基喋呤(AMT)，一种与甲氨蝶呤(MTX)密切相关的抗叶酸药物，用于包括犬和人类AD在内的各种抗炎条件。对AMT的兴趣源于一项发现，AMT引起的不良反应比MTX少，同时明显更有效。对于炎症适应症，AMT可以每周一次以低剂量服用。总之，这些数据表明，AMT将提供比MTX更好的治疗选择，并且AMT将成为治疗中重度AD和其他炎症性疾病的一种重要的新的、安全的、成本效益高的治疗方法。为了寻求开发AMT用于治疗AD和其他炎症性疾病，进行了一项小型开放标签临床前试验，调查CAD的治疗。本试验证明，AMT是安全有效的。这些结果为研究小剂量口服氨基蝶呤治疗冠心病的安全性和有效性的双盲、随机、安慰剂对照、剂量范围试验提供了基础。本建议的具体目的是：(1)：评价口服AMT治疗犬特应性皮炎的安全性。(2)：建立犬特应性皮炎口服AMT的量效关系。(3)：确定首选的剂量是每周两次还是每周一次。疗效将通过有效的措施进行评估。这项提案的完成将确定AMT治疗冠心病的剂量和时间表。这些结果将为人类特应性皮炎IND的备案提供重要的临床前数据。公共卫生相关性特应性皮炎是人类残疾的主要原因，需要改进治疗方法。10%的狗也患有特应性皮炎，缺乏适当的治疗。证明氨蝶呤是一种安全有效的治疗犬特应性皮炎的方法将满足狗的需求，并将极大地推动中到重度特应性皮炎的新疗法的开发。

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is an itchy, inflammatory skin disease. It is one of the most common causes of human and canine disability. The incidence of human atopic dermatitis is steadily increasing. The mainstay of therapy for milder human disease is topical treatment. Patients with more severe disease suffer chronic itching and rash and often require systemic immunosuppressive therapy. Systemic corticosteroids are effective but have unacceptable side effects. Other systemic immunosuppressive medications, including methotrexate, are being investigated, but an effective, safe treatment for these patients has yet to be defined. It is estimated that 10% of dogs suffer from AD. Treating dogs with AD once or twice daily with topical medications is difficult and effective therapies are not available. Furthermore, canine AD (CAD) is the best pre- clinical model for AD. This has motivated investigators to investigate oral systemic immunosuppressive treatment for dogs so that an effective treatment for dogs and humans can be developed. The long term goal of this project is to develop aminopterin (AMT), an anti-folate drug closely related to methotrexate (MTX), for a variety of anti-inflammatory conditions, including canine and human AD. The interest in AMT stems from discoveries that AMT causes less adverse reactions than MTX, while being significantly more potent. For inflammatory indications AMT can be administered at low doses once weekly. Together these data argue that AMT will provide a better treatment option than MTX, and that AMT will be an important new, safe, cost-effective treatment for moderate to severe AD and other inflammatory diseases. In pursuit of developing AMT for the treatment of AD and other inflammatory diseases, a small open- label pre-clinical trial investigating the treatment of CAD was performed. This trial demonstrated that AMT was safe and effective. These results provide the foundation for a double-blind, randomized, placebo-controlled, dose-ranging trial investigating the safety and efficacy of low dose oral aminopterin for the treatment of CAD. The specific aims of this proposal are to: (1): Assess the safety of oral AMT in the treatment of canine atopic dermatitis. (2): Establish the dose-response relationship of oral AMT in canine atopic dermatitis. (3): Determine if twice weekly or once weekly dosing is preferred. The efficacy will be evaluated with validated measures. Completion of this proposal will define a dose and schedule for AMT treatment of CAD. These results will provide important pre-clinical data for the filing of an IND for human atopic dermatitis. PUBLIC HEALTH RELEVANCE Atopic dermatitis is a leading cause of human disability and improved therapies are needed. Ten percent of dogs also suffer atopic dermatitis and lack adequate therapy. Demonstrating that aminopterin is a safe and effective treatment of dogs with atopic dermatitis would serve an unmet need of dogs, and will greatly advance the development of a new treatment for people with moderate to severe atopic dermatitis.