Assessment of the Effect of the Oral Iron Chelator Deferiprone on Asymptomatic Plasmodium Falciparum Parasitemia in Humans

While the parenteral iron-chelating agent desferrioxamine B has anti- malarial activity in humans, the usefulness of an orally active chelator for this indication has not been investigated previously in vivo. We conducted a prospective, double-blind, placebo-controlled, cross-over trial of deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered daily for three or four days in divided doses of 75 or 100 mg/kg of body weight, dosages that are effective for treating iron overload. No reduction in asexual intra-erythrocytic parasites was observed during or after deferiprone treatment. The mean peak plasma concentration of deferiprone (108.9 ± 24.9 μmol/L) achieved was within the range demonstrated to inhibit the growth of P. falciparum in vitro, but the systemic exposure as determined by the 24-hr plasma concentration-time curve would not be predicted inhibit growth in vivo. No evidence of deferiprone- associated hematological toxicity was noted in this short-term study of these subjects, all of whom had clinical evidence of normal body iron stores. Because of the risk of neutropenia and other adverse effects with higher doses or prolonged use of the chelator, additional trials of deferiprone as a sole anti-malarial agent would not seem to be justified. In contrast, further efforts are needed to develop other orally active iron-chelating agents specifically for their antimalarial action

How early can myocardial iron overload occur in Beta thalassemia major?

BACKGROUND: Myocardial siderosis is the most common cause of death in patients with beta thalassemia major(TM). This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Chinese population with beta TM. METHODS AND RESULTS: We analyzed T2* cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in 201 beta TM patients. The median age was 9 years old. Patients received an average of 13 units of blood per year. The median SF level was 4536 ng/ml and 165 patients (82.1%) had SF>2500 ng/ml. Myocardial iron overload was detected in 68 patients (33.8%) and severe myocardial iron overload was detected in 26 patients (12.6%). Twenty-two patients ≤10 years old had myocardial iron overload, three of whom were only 6 years old. No myocardial iron overload was detected under the age of 6 years. Median LVEF was 64% (measured by CMR in 175 patients). Five of 6 patients with a LVEF<56% and 8 of 10 patients with cardiac disease had myocardial iron overload. CONCLUSIONS: The TM patients under follow-up at this regional centre in China patients are younger than other reported cohorts, more poorly-chelated, and have a high burden of iron overload. Myocardial siderosis occurred in patients younger than previously reported, and was strongly associated with impaired LVEF and cardiac disease. For such poorly-chelated TM patients, our data shows that the first assessment of cardiac T2* should be performed as early as 6 years old

Conclusions and recommendations of a who expert consultation meeting on iron supplementation for infants and young children in malaria endemic areas [Conclusions et recommandations à l\u27issue de la consultation de l\u27oms sur la lutte contre la carence martiale chez le nourrisson et le jeune enfant dans les pays d\u27endémie palustre]

This article presents the results of an expert consultation meeting aimed at evaluating the safety and public health implications of administering supplemental iron to infants and young children in malaria-endemic areas. Participants at this meeting that took place in Lyon, France on June 12-14, 2006 reached consensus on several important issues related to iron supplementation for infants and young children in malaria-endemic areas. The conclusions in this report apply specifically to regions where malaria is endemic

An international survey of patients with thalassemia major and their views about sustaining life-long desferrioxamine use

BACKGROUND: Management of thalassemia major requires patients to have life-long access to a treatment regimen of regular blood transfusions coupled with iron chelation therapy. The objective of this study was to investigate patients' reasons for missing iron chelation therapy with desferrioxamine, and the support to sustain life-long adherence to treatment. METHODS: From October 1999 to May 2000 a survey of patients with thalassemia major was conducted in ten countries: Cyprus, Egypt, Greece, Hong Kong, India, Iran, Italy, Jordan, Taiwan, and the United States. RESULTS: 1,888 questionnaires (65%) were returned. Most patients (1,573) used desferrioxamine, and 79% administered a dose at least 4 days a week. Inaccessibility of the drug was a common reason for missing a dose in India (51%), and in Iran (25%), whereas, in any other country, it was a reason for less than 17% of patients. Overall, 58% reported reasons for missing a dose related to their beliefs or feelings about the medication, and 42% drug-related side effects. CONCLUSION: Many patients miss doses of desferrioxamine and an opportunity remains to develop interventions that provide more support to sustain use of desferrioxamine

Beta-thalassemia

Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload

Genome-Wide Identification of Molecular Pathways and Biomarkers in Response to Arsenic Exposure in Zebrafish Liver

10.1371/journal.pone.0068737PLoS ONE87-POLN

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Prenatal Iron Deficiency and Replete Iron Status Are Associated with Adverse Birth Outcomes, but Associations Differ in Ghana and Malawi

Background Previous literature suggests a U-shaped relation between hemoglobin concentration and adverse birth outcomes. There is less evidence on associations between iron status and birth outcomes. Objective Our objective was to determine the associations of maternal hemoglobin concentration and iron status with birth outcomes. Methods We conducted a secondary data analysis of data from 2 cohorts of pregnant women receiving iron-containing nutritional supplements (20–60 mg ferrous sulfate) in Ghana (n = 1137) and Malawi (n = 1243). Hemoglobin concentration and 2 markers of iron status [zinc protoporphyrin and soluble transferrin receptor (sTfR)] were measured at ≤20 weeks and 36 weeks of gestation. We used linear and Poisson regression models and birth outcomes included preterm birth (PTB), newborn stunting, low birth weight (LBW), and small-for-gestational-age. Results Prevalence of iron deficiency (sTfR \u3e6.0 mg/L) at enrollment was 9% in Ghana and 20% in Malawi. In early pregnancy, iron deficiency was associated with PTB (9% compared with 17%, adjusted RR: 1.63; 95% CI: 1.14, 2.33) and stunting (15% compared with 23%, adjusted RR: 1.44; 95% CI: 1.09, 1.94) in Malawi but not Ghana, and was not associated with LBW in either country; replete iron status (sTfR \u3c10th \u3epercentile) was associated with stunting (9% compared with 15%, adjusted RR: 1.71; 95% CI: 1.06, 2.77) in Ghana, but not PTB or LBW, and was not associated with any birth outcomes in Malawi. In late pregnancy, iron deficiency was not related to birth outcomes in either country and iron-replete status was associated with higher risk of LBW (8% compared with 16%, adjusted RR: 1.90; 95% CI: 1.17, 3.09) and stunting (6% compared with 13%, adjusted RR: 2.14; 95% CI: 1.21, 3.77) in Ghana, but was not associated with birth outcomes in Malawi. Conclusions The associations of low or replete iron status with birth outcomes are population specific. Research to replicate and extend these findings would be beneficial. These trials were registered at clinicaltrials.gov as NCT00970866 (Ghana) and NCT01239693 (Malawi)