BUCILLAMINE AND RADIOCONTRAST - INDUCED NEPHROPATHY

描述(由申请人提供)：建议在动物模型中测试给予布比拉明的潜在疗效，布比拉明是一种有效的抗氧化剂和免疫调节剂，用于预防放射造影剂诱导的肾病。静脉和口服布比拉明将在两种不同的大鼠模型上进行研究，这些模型与临床放射造影剂导致的肾脏疾病恶化有关。一种是夹闭肾蒂造成的短暂性缺血所致的急性肾小管坏死模型，另一种是用一氧化氮合酶抑制剂预处理后放射性造影剂诱导的肾坏死模型。在动物模型中，布比拉明在减少氧化或再灌流应激引起的心脏、肝脏或肺损伤方面是有效的。造影剂引起的肾脏损伤与这些环境有很大的相似之处，因为它似乎也与短暂性缺血和氧化应激有关。在I期研究中，Bucillamine已被证明在静脉给药的正常人中是安全的，并已在国外市场上成功地成为治疗类风湿性关节炎的口服药物。Keystone Biomedical对布比拉明在氧化和再灌注损伤中的使用具有专利保护。 在肾脏异常的患者中，使用放射造影剂进行临床诊断试验经常是必要的，但与加重肾脏损害的风险有关。迫切需要一种治疗方法，以降低由于放射造影剂暴露而恶化的肾脏疾病的风险。成功的治疗将在美国和国外赢得非常大的市场。如果建议的研究成功，申请者将申请第二阶段研究的资金，以确认这种治疗在人体上的原则证据，并评估最佳剂量。随后，将为第三阶段研究寻求商业资金，这些研究旨在通过食品和药物管理局获得足够的疗效核查，以获得市场批准。

DESCRIPTION (provided by applicant): It is proposed to test in animal models the potential efficacy of administration of bucillamine a potent antioxidant and immunomodulating agent for prevention of radiocontrast-induced nephropathy. Both intravenous and oral administration of bucillamine will be investigated in two separate rat models relevant to clinical radiocontrast-induced worsening of renal disease. One is a model of acute tubular necrosis due to transient ischemia by clamping the renal pedicals and the other is a model of radio contrast-induced renal necrosis following pretreatment with a nitric oxide inhibitor. Bucillamine has been effective in reducing cardiac, liver or lung injury due to oxidative or reperfusion stress in animal models. Renal injury due to contrast agents has considerable similarity to these settings in that it also appears to be related to transient ischemia and oxidative stress. Bucillamine has been demonstrated to be safe in normal humans with intravenous administration in Phase I studies and has been a successful oral treatment for rheumatoid arthritis in foreign markets. Keystone Biomedical has patent protection for use of bucillamine in oxidative and reperfusion injury. Use of radiocontrast agents for clinical diagnostic tests in patients with renal abnormalities is frequently necessary but is associated with a risk of worsening the renal impairment. There is an urgent need for a treatment to reduce the risk of worsening renal disease due to radiocontrast exposure. A successful treatment would garner a very large market in the U.S. and abroad. If the proposed studies are successful the applicant will apply for funds for Phase II studies to confirm proof of principle of this treatment in humans and to assess optimal dosing. Subsequently commercial funding for Phase III studies aimed at gaining sufficient verification of efficacy to acquire markeing approval through the Food and Drug Administration will be sought.