Inhibition of Intestinal Na/Phosphate Cotransporter in Renal Failure and Hyperten

描述（由申请人提供）：50万美国人处于慢性肾脏疾病（CKD）的晚期，另外4000万人由于肥胖、糖尿病和高血压而处于发展CKD的风险中，肾脏疾病是现代流行病。血清磷（Pi）水平被认为是CKD中导致疾病进展速度和患者预后不良的关键问题。在后期，当残余肾功能不能跟上血清Pi时，高磷酸盐血症变得明显。目前的治疗在降低CKD晚期70%患者的血清Pi方面无效，并且不能防止肾功能的持续丧失。需要围绕防止异常Pi处理设计的新CKD治疗。本建议的重点是通过抑制肠道蛋白质来减少膳食磷的吸收，肠道蛋白质负责50%至70%的Pi吸收。2 '-fluorophosphoretin（2FP）是一种小的天然产物衍生物，没有已知的肠道副作用或心血管毒性。长期目标是为CKD人群带来2FP的药丸形式。本提案的目的是检查2FP在大鼠和豚鼠中的毒性和药代动力学。 具体目标是：1.确定2FP 2的遗传、哺乳动物细胞、心脏和肝脏毒性。测定2FP在大鼠和豚鼠中的无明显不良作用水平（NOAEL）。 3检测血、尿中2FP代谢产物，并测定2FP及其代谢产物在各器官的分布。 具体目标1的完成将通过完成IND所需的初步毒性研究来加速药物开发。首先，人体研究需要在动物种属中进行NOAEL研究，以确定人体的初始剂量。具体目标3将确认2FP代谢和器官分布。预期这些研究将验证ab二氧化硅结果，表明2FP具有有限的肠渗透性，2FP被根皮素代谢，并且2FP具有短的血液半衰期。除了验证2FP的安全性外，这些研究将为完整IND数据包所需的进一步动物研究提供指导。 公共卫生相关性：慢性肾脏疾病（CKD）是一种主要的医疗保健负担，占医疗保险支出的近8%。有效的治疗将减缓疾病进展，减少医疗保险支出，并将逆转70%未受当前治疗影响的CKD患者的肾功能丧失。

DESCRIPTION (provided by applicant): With 500,000 Americans in the final stage of chronic kidney disease (CKD) and another 40 million at risk for developing CKD due to obesity, diabetes and hypertension renal disease is a modem epidemic. Serum phosphorus (Pi) levels are thought to be the crux of the problem In CKD contributing to the rate of disease progression and poor patient outcomes. In the later stages When residual kidney function cannot keep pace with serum Pi, hyperphosphatemia becomes overt. Current treatments are ineffective at reducing serum Pi for 70% of pat tents in the later stages of CKD and cannot prevent the continued loss of renal function. New CKD treatments designed around preventing abnormal Pi handling are needed. Decreasing dietary phosphorus absorption by inhibiting the intestinal protein responsible for 50% to 70% of Pi absorption is the focus of this proposal. The Inhibitor, 2'-fluorophosphophloretin (2FP) is a small natural product derivative with no known intestinal side effects or cardiovascular toxicities. The long term goal is to bring a pill form of 2FP to the CKD population. The goal of this proposal is to examine the toxicity and pharmacokinetics of 2FP in rats and guinea pigs. The specific aims are: 1. Determine genetic, mammalian cell, cardiac, and liver toxicity of 2FP 2. Determine the no observed adverse effect level (NOAEL) of 2FP in rats and guinea pigs. 3 Examine blood and urine metabolites of 2FP and determine organ distributions of 2FP and its metabolites. Completion of specific aim 1 will accelerate drug development by completing preliminary toxicity studies required for the IND. First in human studies require NOAEL studies in a animal species to establish initial doses in humans. Specific aim 3 will confirm 2FP metabolism and organ distribution. These studies are expected to verify ab silica results indicating that 2FP has limited intestinal permeability, that 2FP is metabolized o phloretin, and that 2FP has a blood short half-life. In addition 10 verifying the safety of 2FP these studies will provide guidance for further animal studies required for the complete IND packet. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) is a major healthcare burden accounting for nearly 8% of Medicare spending. An effective therapy will slow disease progression, reduce Medicare Spending, and Will reverse the loss of renal function for the 70% of CKD patients unaffected by current therapies.