KIDNEY STONE INHIBITORS

描述（申请人提供）：尿石症是一个世界性的问题。在美国，尿石症的终生患病率男性为13%，女性为7% (NIDDK)， 2000年尿石症的诊断费用估计为21亿美元，比1994年增加了50% （Pearle, 2005）。高达50%的患者可能在5年内复发。（Asplin et al., 1996）。结石损伤肾脏，引起感染和梗阻，许多患者出现结石通过疼痛、尿路感染和出血（Chow etal.,2004）。治疗后结石的复发通常通过饮食和/或口服药物来控制，这些药物可降低尿钙浓度，如噻嗪类药物和/或柠檬酸钾。目前这些药物的剂量非常高，可能导致严重的副作用、胃肠道病变、恶心和其他并发症，导致依从性差。这种小的抑制剂分子在高剂量下只会改变结石形成的速度。我们提出的材料设计用于通过多位点吸附抑制在极低剂量下直接抑制晶体形成。预计所提出的化合物在分子水平上具有穿透屏障并达到肾小球浓度的能力。迫切需要这种有效的有效抑制剂来预防、管理和控制结石感染。我们提出的创新是在一个单一的有效抑制剂分子中结合了一些关键特征-吸附抑制不溶性结石形成的钙化合物和由于其亲水性而减少蛋白质吸附的潜力。所提出的化合物的毒理学性质预计有利于人类使用。jeff Wesson医学博士，威斯康辛医学院肾病专家，该领域的知名权威，将担任IET和布法罗大学化学工程系体外测试的顾问。我们希望建立我们的抑制剂化合物对CaOx成核、生长动力学、聚集、形态和组成的显著抑制作用，作为抑制剂浓度和类型的函数。体外毒性将使用公认的肾上皮细胞系进行评估。医疗预防肾结石除了在降低发病率和外科手术、梗阻和感染的风险方面对患者有益外，还可以在节省成本的基础上得到证明（Parks等人，1996年）。

DESCRIPTION (provided by applicant): Urolithiasis is a worldwide problem. The lifetime prevalence of urolithiasis is 13% for men and 7% for women in the U.S (NIDDK) and an estimated $2.1 billion was spent in claims for diagnosis for urolithiasis in 2000 which was 50% more than 1994 (Pearle, 2005). Up to 50% of patients may have recurrence within 5 years. (Asplin et al., 1996). Stones injure kidneys, cause infection and obstruction and many patients suffer from pain of stone passage, urinary infection and bleeding (Chow etal.,2004).The recurrence of stones after treatment is normally controlled by diet and/or oral medications that reduce urinary concentrations of calcium such as thiazides and/or potassium citrate. Current dosages for these medications are very high and could cause serious side effects, gastrointestinal lesions, nausea and other complications resulting in poor compliance. Such small inhibitor molecules in high doses alter only the rate of stone formation. Our proposed materials are designed for the direct inhibition of crystal formation at extremely low doses via multisite adsorptive inhibition. The proposed compounds are anticipated to have the ability at the molecular level to penetrate the barriers and achieve glomerular concentrations. There is a dire need for such effective potent inhibitors for stone prevention management and infection control. The innovation that we present is the incorporation of some key features in a single potent inhibitor molecule -adsorptive inhibition of insoluble stone forming calcium compounds and potential reduction of protein adsorption due to their hydrophilic properties. The toxicological properties of the proposed compounds are anticipated to be favorable for human use. Dr.Jeff Wesson M.D, Nephrologist, at the medical College of Wisconsin, a well known authority in this area of will serve as an advisor for in vitro testing that will be conducted at IET and University of Buffalo, SUNY chemical engineering dept. We hope to establish the significant inhibitory effect of our inhibitor compounds on CaOx nucleation, growth kinetics, aggregation, morphology and composition as a function of concentration and type of the inhibitors. In vitro toxicity will be evaluated using accepted kidney epithelial cell lines. Medical prevention of Nephrolithiasis is justified on a cost saving basis quite apart from its benefits to patients in tems of reduced morbidity and risk from surgical procedures, obstruction, and infection (Parks et al., 1996).