Novel Phosphate Binder: Effects on Hyperphosphatemia, Vascular Calcification & Bo

新型磷酸盐结合剂：对高磷血症、血管钙化的影响

• 批准号: 7912320
• 负责人: KEITH A HRUSKA
• 金额: $ 19.45万
• 依托单位: BIOLINK LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912320
• 关键词: Adverse effects; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Binding; Blood; Bone Diseases; Bone remodeling; Calcium; Calcium Carbonate; Carbonates; Cardiovascular Diseases; Cessation of life; Chronic Kidney Failure; Clinical; Combined Modality Therapy; Constipation; Cost Savings; Data; Development; Diabetes Mellitus; Dialysis patients; Dialysis procedure; Dietary Phosphorus; Disease; Disease Progression; Eating; Effectiveness; End stage renal failure; Europe; Failure; Functional disorder; Gastrointestinal tract structure; General Population; Government; Halitosis; Healthcare Systems; Hypertension; Hypoalbuminemia; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Ingestion; Injury; Insurance; International; Intestines; Ions; Kidney; Kidney Diseases; Kidney Failure; Label; Lanthanum; Magnesium; Malnutrition; Medicine; Monitor; Nutrient; Outcome; Oxidative Stress; Patients; Phase; Phosphorus; Physiological; Plant Resins; Platelet Factor 4; Play; Prevalence; Public Health; Quality of life; Race; Renal function; Reporting; Research; Risk; Risk Factors; Role; Running; Safety; Salts; Secondary Hyperparathyroidism; Skeleton; Small Business Technology Transfer Research; Sodium Chloride; Staging; Stomach; Stratification; Study Section; Succinates; Taste Perception; Time; Transplantation; United States; Vascular calcification; Vitamins; absorption; aging population; base; body system; bone; calcium acetate; compare effectiveness; compliance behavior; cost; cytokine; improved; in vivo; inorganic phosphate; lanthanum carbonate; lipoate; meetings; mortality; mouse model; novel; patient population; pill; prevent; public health relevance; sevelamer; sex; standard of care; uptake

DESCRIPTION (provided by applicant): In patients with chronic kidney disease (CKD), phosphate retention may contribute to progression of renal failure and is a major factor in the development of secondary hyperparathyroidism and vascular calcification. Progression of injury is causally associated with risk of mortality that is estimated 10 to 30 times higher for CKD patients undergoing dialysis than the general population. In fact, death is a more common outcome than dialysis or transplantation in patients with CKD. Phosphate binders are clinical mainstays in reducing dietary phosphate absorption and preventing hyperphosphatemia in the roughly 370,000 end-stage renal disease (ESRD) patients in the United States. While medicines exist that bind phosphorus effectively, all current forms of phosphate binder therapy are associated with very poor patient compliance due to a host of problems, including side effects that run the gamut of poor taste, halitosis, gastric bloating, constipation, the number of pills, and cost. Thus, there is great need for a better phosphate binder, defined as one which is both effective and taken by patients with high compliance. Preliminary studies indicate that a novel phosphate binder comprising combinations of calcium succinate and magnesium R-(+)-1-lipoate binds phosphate effectively at reasonable cost. The proposed Phase I STTR research will use a translational animal model to verify these preliminary results and determine whether this combination of salts concomitantly decreases the rate and progression of vascular calcification, attenuates adynamic bone disorder, and reduces inflammation and oxidative stress. In addition, activity will be compared to that of sevelamer carbonate, a standard of care for treatment of hyperphosphatemia in CKD patients in the U.S. End-stage renal disease (ESRD), already a major public health problem in the US, is increasing in incidence and prevalence. Today, treatment of hyperphosphatemia with phosphate binders costs patients, taxpayers, insurance companies, and the government over $1.2 billion a year. That cost would increase 2-3 times if all ESRD patients used non-calcium containing Pi binders. If successful, the proposed STTR Phase I research will confirm the usefulness of this approach for significantly enhanced treatment of the hyperphosphatemia and bone dysfunction of Stage 5 CKD. The approach has the potential to delay use of non-calcium containing Pi binders by extending the time of useful calcium-based phosphate binder therapy, thereby enabling a cost savings estimated at over $1 billion a year. PUBLIC HEALTH RELEVANCE: Kidney failure, already a major public health problem in the US, is becoming more common. People with kidney disease use phosphate binders to decrease phosphate intake from the food they eat. This prevents high blood phosphate levels. Current phosphate binders have side effects that make them poorly tolerated by the patients who use them, thus reducing their effectiveness. The proposed STTR Phase I research critically evaluates the usefulness of a new phosphate binder having the potential to correct high blood phosphate levels, improve the patient's quality of life, and yield significant cost savings to the patient, the health care system, and American taxpayers.

描述（由申请方提供）：在慢性肾脏疾病（CKD）患者中，磷酸盐潴留可能导致肾衰竭进展，并且是继发性甲状旁腺功能亢进和血管钙化发生的主要因素。损伤进展与死亡风险存在因果关系，估计接受透析的CKD患者的死亡风险比一般人群高10至30倍。事实上，在CKD患者中，死亡是比透析或移植更常见的结局。 磷酸盐结合剂是美国约370，000例终末期肾病（ESRD）患者减少膳食磷酸盐吸收和预防高磷酸盐血症的临床支柱。虽然存在有效结合磷的药物，但由于一系列问题，所有现有形式的磷酸盐结合剂疗法都与非常差的患者依从性相关，包括不良味觉、口臭、胃胀气、便秘、药丸数量和成本等副作用。因此，非常需要一种更好的磷结合剂，定义为既有效又能被高依从性患者服用的磷结合剂。 初步研究表明，包含琥珀酸钙和R-（+）-1-硫辛酸镁的组合的新型磷酸盐结合剂以合理的成本有效地结合磷酸盐。拟议的I期STTR研究将使用转化动物模型来验证这些初步结果，并确定这种盐的组合是否同时降低血管钙化的速率和进展，减轻粘连性骨疾病，并减少炎症和氧化应激。此外，将比较碳酸司维拉姆的活性，碳酸司维拉姆是美国CKD患者高磷血症的治疗标准。终末期肾病（ESRD）已经是美国的一个主要公共卫生问题，其发病率和患病率正在增加。今天，用磷酸盐结合剂治疗高磷血症每年花费患者，纳税人，保险公司和政府超过12亿美元。如果所有ESRD患者都使用不含钙的Pi结合剂，则该成本将增加2-3倍。如果成功，拟议的STTR I期研究将证实这种方法在显著增强5期CKD高磷血症和骨功能障碍治疗方面的有效性。该方法有可能通过延长有用的基于钙的磷酸盐结合剂治疗的时间来延迟不含钙的Pi结合剂的使用，从而每年节省估计超过10亿美元的成本。 公共卫生相关性：肾衰竭，在美国已经是一个主要的公共卫生问题，正在变得越来越普遍。患有肾脏疾病的人使用磷酸盐结合剂来减少他们从食物中摄入的磷酸盐。这可以防止高血磷水平。目前的磷结合剂具有副作用，使使用它们的患者耐受性差，从而降低了它们的有效性。拟议的STTR I期研究批判性地评估了一种新的磷酸盐结合剂的有用性，这种结合剂有可能纠正高血磷水平，改善患者的生活质量，并为患者，医疗保健系统和美国纳税人节省大量成本。