Prevention of Kidney Stone Crystal Retention

预防肾结石晶体滞留

• 批准号: 7196098
• 负责人: JACK G KLEINMAN
• 金额: $ 24.83万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196098
• 关键词: Accident and Emergency department; Acids; Animals; Autopsy; Biological Assay; Biotin; Calcium Oxalate; Calcium Oxalate Monohydrate; Calculi; Carbohydrates; Cells; Clinical; Contracts; Crystal Formation; Cultured Cells; Deposition; Detection; Dose; Duct (organ) structure; Effectiveness; Ethylene Glycols; Fluorescent Dyes; Goals; Human; Implant; In Vitro; Inorganic Sulfates; Intervention; Intestines; Kidney; Kidney Calculi; Label; Laboratories; Lithotripsy; Measures; Medical; Morbidity - disease rate; Nephrolithiasis; Oligosaccharides; Operative Surgical Procedures; Oral; Oral Administration; Pentosan Sulfuric Polyester; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Phase; Polymers; Preclinical Testing; Prevention; Procedures; Proteins; Rate; Rattus; Recurrence; Renal function; Resources; Route; Screening procedure; Serine; Site; Testing; Therapeutic Agents; Time; Toxic effect; Treatment Protocols; United States Food and Drug Administration; Unspecified or Sulfate Ion Sulfates; Urine; Visit; Work; acrylic acid; day; dosage; ethylene glycol; experience; feeding; functional group; in vivo; inhibitor/antagonist; osmotic minipump; polyanion; prevent

DESCRIPTION (provided by applicant): Kidney stones are a significant medical problem, causing morbidity and entailing expenses due to emergency room visits, medications, and lithotripsy or other procedures. The long-term goal of this work is to produce an inhibitor of crystal deposition that would be suitable for testing in humans. The overall hypothesis of this work is that inhibitors of crystal attachment will be effective therapeutic agents in clinical nephrolithiasis. Specific objective are as follows: 1. To test molecules for the ability to inhibit calcium oxalate monohydrate (COM) crystal attachment to inner medullary collecting duct (IMCD) cells or to one another. We will test the anionic homopolymers poly(aspartic), poly(glutamic), and poly(acrylic) acids to determine the most effective inhibitors of COM crystal attachment to IMCD cells and to each other, using in vitro cell culture and aggregation assays, respectively. In addition, we will determine whether polymers with other anionic functional sites, poly(serine), the sulfated carbohydrates enoxiparin and pentosan, some sialie acid-containing oligosaccharides, and phosphorylated proteins and peptide homopolymers, have similar ef- fects on crystal attachment. 2. To test inhibitors of crystal attachment to cultured cells for their ability to ameliorate crystal deposition in ex- perimental animals. Polyanions and small to intermediate MW polymers containing other functional groups that may interfere with crys- tal attachment will be tested for their ability to inhibit calcium oxalate crystal deposition in rats treated with ethylene glycol and NH4C1 when administered using implanted osmotic minipumps. We will also determine the delivery to urine of effective inhibitors of calcium oxalate crystal retention by labeling compounds with fluorescent dyes or with biotin to permit detection. Renal function will also be measured in these animals to look for early renal toxicity. 3. To determine which of the inhibitors are effective when given orally. Inhibitors that are effective at preventing calcium oxalate crystal retention when administered using the implanted minipumps will be tested for their ability to inhibit crystal retention when given orally. Dosage regimens, feeding strategies, systemic medications, or accompany- ing agents will be employed as necessary to deliver adequate amounts of inhibitors via the oral route. 4. To determine whether the effective inhibitors have significant short and intermediate-term general and renal toxicity. Several inhibitors that are effective with oral dosing will be administered to rats at 5-10 times their effective doses for up to 180 days. Animals will be observed for general well being, and those that become sick or reach the end of the study period will have a complete battery of laboratory tests drawn. All ill animals and a selection of animals that appear healthy at the end of the study period will have necropsies performed. At the conclusion of this project, we expect to have three agents suitable for more comprehensive animal toxicity studies, presumably performed by a commercial laboratory with experience in satisfying FDA requirements. Should any of them be suitably free of toxicity, Phase I testing in human would be contemplated, presumably by a licensee.

描述（由申请人提供）：肾结石是一个严重的医疗问题，会导致发病，并因急诊室就诊、药物治疗、碎石术或其他手术而产生费用。这项工作的长期目标是生产一种适合人体测试的晶体沉积抑制剂。这项工作的总体假设是晶体附着抑制剂将成为临床肾结石的有效治疗剂。具体目标如下： 1.测试分子抑制一水草酸钙(COM)晶体附着于内髓集合管(IMCD)细胞或彼此附着的能力。我们将分别使用体外细胞培养和聚集测定来测试阴离子均聚物聚天冬氨酸、聚谷氨酸和聚丙烯酸，以确定 COM 晶体与 IMCD 细胞以及彼此之间附着的最有效抑制剂。此外，我们将确定具有其他阴离子功能位点的聚合物，聚（丝氨酸），硫酸化碳水化合物依诺肝素和戊聚糖，一些含唾液酸的寡糖，以及磷酸化蛋白质和肽均聚物，对晶体附着是否具有类似的影响。 2. 测试晶体附着于培养细胞的抑制剂改善实验动物晶体沉积的能力。当使用植入式渗透微型泵给药时，将测试聚阴离子和含有其他可能干扰晶体附着的官能团的小到中等分子量聚合物抑制草酸钙晶体沉积的能力，这些大鼠接受乙二醇和NH4C1处理。我们还将通过用荧光染料或生物素标记化合物以允许检测来确定草酸钙晶体保留的有效抑制剂向尿液的输送。还将测量这些动物的肾功能，以寻找早期肾毒性。 3. 确定哪些抑制剂口服时有效。当使用植入的微型泵给药时，可有效防止草酸钙晶体保留的抑制剂将被测试其在口服给药时抑制晶体保留的能力。将根据需要采用剂量方案、喂养策略、全身药物或伴随药物，以通过口服途径输送足够量的抑制剂。 4.确定有效抑制剂是否具有显着的短期和中期全身毒性和肾毒性。几种口服有效的抑制剂将以有效剂量的 5-10 倍给予大鼠，持续长达 180 天。将观察动物的总体健康状况，并对那些生病或达到研究期结束的动物进行全套实验室测试。所有患病动物和研究期结束时表现健康的精选动物将进行尸检。在该项目结束时，我们期望拥有三种适合更全面的动物毒性研究的药物，这些研究可能由具有满足 FDA 要求经验的商业实验室进行。如果它们中的任何一个适当地无毒性，则将考虑进行第一阶段的人体测试，大概是由被许可人进行的。