Reduction of Toxicity in the Premature Neonate Associated with Aluminum as a Contaminant

  • Yokel, Robert (PI)

Grants and Contracts Details


A high percentage of the -60,000 children born prematurely each year in the US require intravenous feeding after birth because they do not tolerate oral feeding. The intravenous feeding solution, known as total parenteral nutrition (TPN) solution, is prepared for each neonate according to his or her needs, from component solutions. Some of these component solutions contain aluminum (AI). The human does not require AI. Excessive Al can produce toxicity to the skeletal system (metabolic bone disease), brain (an encephalopathy and impaired mental development in the young human) and bone marrow (producing an anemia). Al is commonly present in the component solutions used to make TPN solutions, as a contaminant. It is often particularly high in calcium and phosphorus solutions, which are commonly added to neonatal TPN solutions. Medical personnel who take care of neonates have been suggesting for years that the Al concentration ofthese solutions needs to be greatly decreased to reduce the potential for Al -induced toxicity to neonates. The FDA passed a labeling requirement that will require that the large volume parenterals used to prepare TPN solutions contain less than 25 /lg AliI and that small volume parenterals state the Al concentration. An association of manufacturers ofthese solutions told the FDA that it may be difficult to meet this requirement. We propose to develop a method that will remove essentially all of the Al from these solutions. The method involves the chemical bonding of chelators to small polymer beads. Chelators are chemicals that bond with a metal to form complexes incorporating the metal. By linking the chelator to a polymer bead, the formation of an AI-chelator complex on the surface of the bead will remove the Al from the bulk solution. One merely filters the beads from the solution to produce an AI-free product. This is similar to the familiar process of water softening, which uses a different type of resin (a cation exchange resin) to remove metal ions from tap water. Cation exchange resins bind metal with relatively low affinity and poor selectively. To treat TPN solutions, a resin must be designed that has the affinity and selectivity required to remove the toxic AI(III) ion from solutions containing high concentrations of other metal ions such as Ca(II). Chelators can be designed to selectively remove AI. Hydroxamates will be investigated as the Al chelator because this chemical group has been proven to very effectively bind AI. The number and arrangement ofthe hydroxamate groups will be varied to adjust the strength with which the chelator binds AI. The objective is to bind Al strongly enough to remove it from TPN solutions, yet not bind Al so strongly that the resin cannot be regenerated and reused. In addition, the organic chemical linker used to connect the chelator to the polymer bead will be varied to optimize the speed at which the chelator can bind the AI. We will initially prove the concept that hydroxamates linked to beads will rapidly remove essentially all Al from aqueous solutions. We will assess the ability of these new beads to remove Al from calcium gluconate and sodium phosphate solutions, which are the small volume parenteral component solutions that contribute the greatest amount of Al to TPN solutions. When we have produced a resin that removes Al from TPN component solutions, we wi~l submit to the Thrasher Research Foundation a second proposal to clinically evaluate the benefit ofremovmg essentially all Al from TPN solutions given to neonatal patients. Al-free solutions prepared using the resin we develop will be compared to the current therapy that mcludes mtravenous admInistratIOn of TPN solutions containing Al as a contaminant.
Effective start/end date9/1/032/28/06


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