A device containing an immobilized chelator to remove aluminum from total parente

一种含有固定螯合剂的装置，用于去除总母体中的铝

• 批准号: 7801648
• 负责人: Robert Allen Yokel
• 金额: $ 54.7万
• 依托单位: ALKYMOS, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801648
• 关键词: Address; Adult; Advocacy; Aluminum; Alzheimer' s Disease; Animal Model; Award; Binding; Birth; Brain; Businesses; Calcium; Calcium Gluconate; Caliber; Caring; Chelating Agents; Child; Childhood; Cholestasis; Clinical; Cyclic GMP; Development; Devices; Encephalopathies; Endotoxins; European; Excision; Filtration; Goals; Guidelines; HDPE; Health Personnel; Hemodialysis; Housing; Human; IV Fluid; Infant; Infant formula; Injection of therapeutic agent; Intake; Intravenous; Intravenous Feeding; Kentucky; Kidney; Label; Lead; Ligand Binding; Liver; Marketing; Medical Device; Membrane; Metabolic Bone Diseases; Metals; Methods; Modeling; Neonatal; Neonatal Intensive Care Units; Oral; Particulate Matter; Patients; Pharmacopoeias; Pharmacy facility; Phase; Plant Resins; Plastics; Polymers; Positioning Attribute; Premature Infant; Preparation; Price; Process; Production; Property; Pyrogens; Recommendation; Renal function; Research; Research Institute; Residual state; Resolution; Respondent; Risk; Safety; Skeletal system; Small Business Technology Transfer Research; Sodium Chloride; Solutions; Solvents; Stage 5 renal failure; Staging; Sterility; Stress; Surveys; Testing; Total Parenteral Nutrition; Toxic effect; United States; Universities; Variant; Work; base; chemical binding; chemical release; computational chemistry; design; drinking water; feeding; fluid flow; gluconate; meetings; mental development; neonate; novel; phase 2 study; pre-clinical; pressure; prototype; public health relevance; safety study

DESCRIPTION (provided by applicant): A high percentage of the ~ 500,000 children born prematurely each year in the US require intravenous feeding after birth because they do not tolerate oral feeding. This is accomplished with a total parenteral nutrition (TPN) solution, which is prepared from component solutions: small and large volume parenterals (SVPs and LVPs). Aluminum (Al) is a common contaminant in some SVPs, particularly calcium gluconate solution. Excessive Al can produce toxicity to the skeletal system and brain, and perhaps the liver. The potential for Al toxicity is significantly greater in humans, such as premature infants, who have reduced renal function; because the kidneys excrete Al. Medical personnel who care for neonates have suggested for decades that the Al in these solutions needs to be greatly decreased to avoid Al-induced toxicity. The FDA implemented a labeling requirement for these component solutions that sets a maximum Al concentration in LVPs and requires a statement of the maximum Al concentration in SVPs at expiry. This merely documents estimated maximum Al concentration. It is not the actual Al concentration nor does this reduce the Al in SVPs. Based on prior work to develop new chemicals that bind Al (chelators), the long- term objective is to develop a flow-through filter device containing a chelator that is immobilized on small polymer beads to remove Al from solutions. Based on results obtained using computational chemistry, which predicted the strength of binding of novel immobilized chelators with Al, and results obtained before and during the Phase I award from novel chelators we have synthesized, it is proposed to advance the lead resin (a chelator immobilized on a resin bead), and develop prototype devices containing the lead resin, and test these devices for their efficacy to remove Al from calcium gluconate solution and their safety. We will then assess the safety and efficacy of the resultant optimized device in a pre-clinical proof- of-principle piglet model of the neonate, receiving TPN. The results will position this project to advance to Phase III, in which the resin and device will be manufactured under cGMP conditions and the device tested in a clinical proof-of-principle study in neonates receiving TPN in a neonatal intensive care unit. PUBLIC HEALTH RELEVANCE: The proposed work will advance the lead resin (immobilized chelator) and develop and test prototype devices to contain the resin, to create a medical device to remove a toxic contaminant, aluminum (Al), from intravenous solutions. This device will be tested in a pre- clinical proof-of-principle study in an animal model of the neonate receiving intravenous feeding. This will remove the potential for Al to produce toxicity to premature infants and other patients who are exposed to Al through intravenous fluids, solving a decades-old problem that has escaped resolution to date.

描述（由申请人提供）：美国每年过早出生的约500,000名儿童中有很高的比例需要在出生后静脉注射，因为他们不容忍口服喂养。这是通过总肠胃外营养（TPN）溶液来完成的，该溶液是根据组件解决方案制备的：小和大容量寄宿生物（SVPS和LVP）。铝（AL）是某些SVP的常见污染物，尤其是葡萄糖酸钙溶液。过度的Al会对骨骼系统和大脑以及肝脏产生毒性。在肾功能降低的早产婴儿中，人类的毒性潜力明显更大。因为肾脏排泄。关心新生儿的医务人员已经建议数十年来，这些解决方案中的AL需要大大减少，以避免AL诱导的毒性。 FDA针对这些组件解决方案实现了标签要求，该解决方案设置了LVP中的最大AL浓度，并且需要在有效期内对SVP中的最大AL浓度表示。这仅记录了估计的最大浓度。它不是实际的浓度，也不是SVP中的AL。基于先前开发结合Al（螯合剂）的新化学物质的工作，长期目标是开发一个含有螯合剂的流动滤清器设备，该设备固定在小聚合物珠上，以从溶液中去除Al。基于使用计算化学获得的结果，该结果预测了与Al的新型固定螯合剂结合的强度，并在我们合成的新型螯合剂中获得了第一阶段和期间获得的结果，它提议推进铅树脂（固定在树脂珠上的螯合剂），并从固定在树脂束上的固定液中，从而从这些量和测试铅型设备进行验证，并将其置于铅型铅嵌入量和效果，并将其固定效果供应，并将其固定在铅型材料上，并促进了他们的量化量，并将其固定效果供应量，并降低了铅型启发性的效果，并将其固定在铅树脂上，并将其固定在铅树脂上，并且 安全。然后，我们将评估新生儿原本仔猪模型的临床前证明中所得优化装置的安全性和功效，并接受TPN。结果将定位该项目将在CGMP条件下制造树脂和设备的第三阶段，并在新生儿重症监护病房接受TPN的新生儿进行临床原理研究中测试的设备。 公共卫生相关性：拟议的工作将推进铅树脂（固定的螯合剂），并开发和测试原型设备以包含树脂，以创建一种医疗装置，以从静脉内溶液中去除有毒污染物的铝（AL）。该设备将在接受静脉注射的新生儿模型中的临床前原则研究中进行测试。这将消除AL对过早婴儿和其他通过静脉内液体暴露于AL的患者产生毒性的潜力，从而解决了迄今已逃脱的数十年问题。