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Grant Abstract

Grant Number: 1U01HD061233-01
PI Name: BRITTENHAM, GARY M
Project Title: MALERIA AND THE SAFETY OF IRON INTERVENTIONS: ABSORPTION AND NTBI

Abstract: This research will determine the effects of acute infection with Plasmodium falciparum on the absorption, pharmacokinetics and metabolism of iron from iron supplements and other Iron preparations in women of childbearing age. Our project will combine measurements of iron absorption during and after successful treatment of acute uncomplicated falciparum malaria with characterization of the pharmacokinetics of the appearance of plasma non-transferrin-bound Iron (NTBI) and measurements of the iron regulatory hormone, hepcidin, and other proteins of iron metabolism. We will examine iron supplements like those used in the Pemba supplementation trial as well as alternative iron interventions that could minimize or avoid the formation of plasma non-transferrin-bound iron. Our research will be based in Southeast Asia, where nearly one billion people are now exposed to malaria and 25% of the world's clinical attacks of malaria occur. This project will take advantage of a unique convergence of resources and expertise at Mahidol University in Bangkok, Thailand: (i) the Institute of Nutrition, which has recently completed a series of stable isotope studies of iron absorption in collaboration with investigators from the Laboratory for Human Nutrition, Swiss Federal Institute of Technology (ETH), Z Cirich, Switzerland, and (ii) the Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, a world-renowned malaria research facility with an established, decade-long alliance in studies of malaria with researchers at Columbia University, New York, N.Y., U.S.A. This research has three specific aims: (1) to characterize the pharmacokinetics of the appearance of non-transferrin bound iron in the systemic circulation after oral administration of an iron supplement or other iron intervention; (2) to determine the effect of acute uncomplicated falciparum malaria on absorption of iron from iron supplements and other iron interventions, using erythrocyte incorporation of stable isotopes of iron; (3) to assess the effects of acute uncomplicated falciparum malaria on Iron metabolism by repeated measurements of serum hepcidin, transferrin receptor, ferritin, haptoglobin, and concentrations of pro- (Th-1) and anti- (Th-2) inflammatory cytokines, erythrocyte zinc protoporphyrin, and the complete blood count with absolute reticulocyte count and reticulocyte hemoglobin content (CHr). Because of the public health importance of assuring iron sufficiency in mothers, our studies are focused on women of childbearing age but the results should be broadly applicable to infants and children. PUBLIC HEALTH RELEVANCE: These studies of the effects of P. falciparum on iron absorption and metabolism will further our basic understanding of interactions of iron with malaria and other infections. Examining changes in plasma iron produced by conventional iron supplements could lead to development of new interventions tp maximize iron absorption and minimize risks associated with plasma non-transferrin-bound iron (NTBI). Our results could help improve the safety of prevention and treatment of iron deficiency in malaria-endemic regions.

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