Malaria and the safety of iron interventions: absorption and NTBI

描述(申请人提供)：这项研究将确定恶性疟原虫急性感染对育龄妇女从铁补充剂和其他铁制剂中铁的吸收、药代动力学和代谢的影响。我们的项目将结合在成功治疗急性无并发症恶性疟疾期间和之后铁吸收的测量、血浆非转铁蛋白结合铁(NTBI)出现的药代动力学特征以及铁调节激素、海普西丁和其他铁代谢蛋白的测量。我们将研究Pemba补铁试验中使用的补铁剂，以及可以最大限度地减少或避免血浆非转铁蛋白结合铁形成的替代铁干预措施。我们的研究将设在东南亚，那里现在有近10亿人接触到疟疾，世界上25%的疟疾临床发作发生在那里。该项目将利用泰国曼谷Mahidol大学的资源和专业知识的独特汇聚：(I)营养研究所，该研究所最近与瑞士Z Cirich的瑞士联邦理工学院(ETH)人类营养实验室的研究人员合作，完成了一系列稳定的铁吸收同位素研究；(Ii)曼谷热带疾病医院热带医学院，这是世界著名的疟疾研究机构，与美国纽约哥伦比亚大学的研究人员建立了长达十年的疟疾研究联盟。 这项研究有三个具体目标： (1)研究口服补铁或其他铁干预后非转铁蛋白结合铁在体循环中出现的药代动力学特征； (2)研究急性无并发症恶性疟疾对铁吸收的影响。 补充剂和其他铁干预措施，使用红细胞掺入稳定的铁同位素； (3)反复观察急性无并发症恶性疟疾对铁代谢的影响 测定血清海普西丁、转铁蛋白受体、铁蛋白、结合珠蛋白和前白蛋白浓度。 (Th-1)和抗(Th-2)炎性细胞因子、红细胞锌原卟啉和全血 用网织红细胞绝对计数和网织红细胞血红蛋白含量(CHR)进行计数。 由于确保母亲铁充足的公共卫生重要性，我们的研究重点是育龄妇女，但结果应该广泛适用于婴儿和儿童。 公共卫生相关性：这些关于恶性疟原虫对铁吸收和代谢的影响的研究将加深我们对铁与疟疾和其他感染之间相互作用的基本理解。检查传统铁补充剂产生的血浆铁的变化可以导致开发新的干预措施，最大限度地增加铁的吸收，并将与血浆非转铁蛋白结合铁(NTBI)相关的风险降至最低。我们的研究结果有助于提高疟疾流行地区预防和治疗缺铁症的安全性。

DESCRIPTION (provided by applicant): 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.