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

描述(申请人提供)：有50万美国人处于慢性肾脏病(CKD)的最后阶段，另有4000万人因肥胖、糖尿病和高血压而有患CKD的风险。肾脏疾病是一种现代流行病。血清磷(PI)水平被认为是慢性肾脏病问题的症结所在，导致疾病进展速度和患者预后不良。在残留肾功能不能与血清PI同步的晚期，高磷血症变得明显。目前的治疗方法不能有效降低CKD后期70%的PAT患者的血清PI，也不能阻止肾功能的持续丧失。需要围绕防止异常PI处理而设计的新的CKD治疗方法。通过抑制负责磷吸收的50%到70%的肠道蛋白来减少日粮磷的吸收是这项建议的重点。该抑制剂2‘-氟磷脂(2Fp)是一种小的天然产物衍生物，没有已知的肠道副作用和心血管毒性。长期目标是将2Fp的药片形式带到CKD人群中。本提案的目的是研究2Fp在大鼠和豚鼠体内的毒性和药代动力学。其具体目的是：1.测定2Fp的遗传毒性、哺乳动物细胞毒性、心脏毒性和肝脏毒性。测定2Fp对大鼠和豚鼠的未观察到的不良反应水平(NOAEL)。3检测血、尿2Fp代谢物，测定2Fp及其代谢物的器官分布。完成特定目标1将通过完成IND所需的初步毒性研究来加速药物开发。首先，在人体研究中，需要在动物物种中进行NOAEL研究，以确定人类的初始剂量。具体目标3将确定2Fp的代谢和器官分布。这些研究有望证实白炭黑结果表明，2Fp具有有限的肠道通透性，2Fp代谢为根皮素，2Fp的血液半衰期较短。此外，验证2Fp的安全性，这些研究将为完整IND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)是一项主要的医疗负担，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患者的肾功能损失。

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.