KIDNEY STONE INHIBITORS

描述（由申请人提供）：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年用于诊断尿石症的索赔估计为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等人，1996年）。结石损伤肾脏，引起感染和梗阻，许多患者遭受结石通过疼痛、尿路感染和出血（Chow埃塔尔，2004).治疗后结石的复发通常通过饮食和/或口服药物来控制，这些药物可以降低尿中钙的浓度，例如噻嗪类和/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仅改变结石形成的速率。我们提出的材料设计用于通过多位点吸附抑制以极低剂量直接抑制晶体形成。预期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强效抑制剂用于结石预防管理和感染控制。 我们提出的创新是在单个有效抑制剂分子中结合了一些关键特征-不溶性结石形成钙化合物的吸附抑制和由于其亲水性而可能减少蛋白质吸附。预计拟议化合物的毒理学特性有利于人类使用。威斯康星州医学院的肾脏病学家Jeff Wesson博士是该领域的知名权威，他将担任体外试验的顾问，该试验将在IET和布法罗大学、SUNY化学工程系进行。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，作为抑制剂的浓度和类型的函数。将使用可接受的肾上皮细胞系评价体外毒性。肾结石的医学预防是在节省成本的基础上合理的，除了其在降低发病率和外科手术、梗阻和感染的风险方面对患者的益处之外（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).