Aminopterin for the Treatment of Severe Recalcitrant Atopic Dermatitis

描述（由申请人提供）：特应性皮炎（AD）是一种瘙痒，炎症性皮肤病。这是人类和犬类致残的最常见原因之一。人类特应性皮炎的发病率正在稳步上升。治疗轻度人类疾病的主要方法是局部治疗。病情严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。其他系统性免疫抑制药物，包括甲氨蝶呤，正在研究中，但对这些患者有效、安全的治疗方法尚未确定。据估计，10%的狗患有阿尔茨海默病。每天用局部药物治疗一次或两次患有AD的狗是困难的，而且没有有效的治疗方法。此外，犬AD （CAD）是AD的最佳临床前模型。这促使研究人员对犬类的口服全身免疫抑制治疗进行研究，从而开发出一种对犬类和人类都有效的治疗方法。该项目的长期目标是开发氨蝶呤（AMT），一种与甲氨蝶呤（MTX）密切相关的抗叶酸药物，用于多种抗炎疾病，包括犬类和人类AD。对AMT的兴趣源于发现AMT比MTX引起更少的不良反应，同时明显更有效。对于炎症适应症，AMT可以每周低剂量一次。总之，这些数据表明AMT将提供比MTX更好的治疗选择，并且AMT将是一种重要的、安全的、具有成本效益的治疗中重度AD和其他炎症性疾病的新方法。为了开发用于治疗AD和其他炎症性疾病的AMT，进行了一项小型开放标签临床前试验，研究CAD的治疗。该试验证明AMT是安全有效的。这些结果为一项双盲、随机、安慰剂对照、剂量范围试验提供了基础，该试验旨在研究低剂量口服氨基蝶呤治疗CAD的安全性和有效性。本提案的具体目的是：(1)：评估口服AMT治疗犬特应性皮炎的安全性。(2)：建立口服AMT治疗犬特应性皮炎的量效关系。(3)：确定每周给药两次还是每周给药一次。将采用有效的措施评估疗效。该建议的完成将确定AMT治疗CAD的剂量和时间表。这些结果将为人类特应性皮炎的IND申请提供重要的临床前数据。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。证明氨基蝶呤是一种安全有效的治疗特应性皮炎的狗，将满足狗的未满足的需求，并将极大地推动开发一种治疗中度至重度特应性皮炎的新疗法。

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.