BUCILLAMINE AND RADIOCONTRAST - INDUCED NEPHROPATHY

描述（由申请方提供）：拟在动物模型中检测布西拉明（一种强效抗氧化剂和免疫调节剂）给药预防放射造影剂诱导肾病的潜在疗效。将在与临床放射造影剂诱导的肾脏疾病恶化相关的两个单独的大鼠模型中研究布西拉明的静脉内和经口给药。一个是通过夹闭肾蒂的短暂缺血引起的急性肾小管坏死的模型，另一个是用一氧化氮抑制剂预处理后的放射性造影剂诱导的肾坏死的模型。在动物模型中，布西拉明可有效减轻氧化或再灌注应激引起的心脏、肝脏或肺损伤。造影剂引起的肾损伤与这些情况有相当大的相似性，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，布西拉明已被证明在正常人中静脉给药是安全的，并且在国外市场上已成功用于类风湿性关节炎的口服治疗。Keystone Biomedical拥有使用布西拉明治疗氧化和再灌注损伤的专利保护。 在肾功能异常患者的临床诊断检查中，经常需要使用放射性造影剂，但这与肾损害恶化的风险相关。迫切需要一种治疗方法来降低放射性造影剂暴露导致肾脏疾病恶化的风险。成功的治疗将在美国和国外获得非常大的市场。如果拟议的研究成功，申请人将申请II期研究的资金，以确认这种治疗在人类中的原理证据，并评估最佳剂量。随后，将寻求III期研究的商业资金，旨在获得足够的疗效验证，以通过食品和药物管理局获得上市批准。

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.