Iron deficiency beyond erythropoiesis: should we be concerned?

Objective: To consider the key implications of iron deficiency for biochemical and physiological functions beyond erythropoiesis.

Methods: PubMed was searched for relevant journal articles published up to August 2017.

Results: Anemia is the most well-recognized consequence of persisting iron deficiency, but various other unfavorable consequences can develop either before or concurrently with anemia. Mitochondrial function can be profoundly disturbed since iron is a cofactor for heme-containing enzymes and non-heme iron-containing enzymes in the mitochondrial electron transport chain. Biosynthesis of heme and iron-sulfur clusters in the mitochondria is inhibited, disrupting synthesis of compounds such as hemoglobin, myoglobin, cytochromes and nitric oxide synthase. The physiological consequences include fatigue, lethargy, and dyspnea; conversely, iron repletion in iron-deficient individuals has been shown to improve exercise capacity. The myocardium, with its high energy demands, is particularly at risk from the effects of iron deficiency. Randomized trials have found striking improvements in disease severity in anemic but also non-anemic chronic heart failure patients with iron deficiency after iron therapy. In vitro and pre-clinical studies have demonstrated that iron is required by numerous enzymes involved in DNA replication and repair, and for normal cell cycle regulation. Iron is also critical for immune cell growth, proliferation, and differentiation, and for specific cell-mediated effector pathways. Observational studies have shown that iron-deficient individuals have defective immune function, particularly T-cell immunity, but more evidence is required. Pre-clinical models have demonstrated abnormal myelogenesis, brain cell metabolism, neurotransmission, and hippocampal formation in iron-deficient neonates and young animals. In humans, iron deficiency anemia is associated with poorer cognitive and motor skills. However, the impact of iron deficiency without anemia is less clear.

Conclusion: The widespread cellular and physiological effects of iron deficiency highlight the need for early detection and treatment of iron deficiency, both to ameliorate these non-erythropoietic effects, and to avoid progression to iron deficiency anemia.     

Betel Nut Chewing in Iron Age Vietnam? Detection of Areca catechu Alkaloids in Dental Enamel

The betel quid is one of the most commonly consumed psychoactive substances in the world. By archaeological evidence like the occurrence of areca nuts in archaeological sites, the typical overall reddish-brown staining on prehistoric human teeth or specific artifacts linked with the habit, it is assumed that this tradition reaches back to prehistoric times. Since this kind of evidence is indirect, it is frequently doubted. The present study provides the earliest direct analytical indication of betel nut chewing in human history. A typical stained tooth from an Iron Age skeleton (site Gò Ô Chùa in Southern Vietnam, 400–100 BC) was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-high-resolution mass spectrometry (LC-HR-ToF-MS) and the alkaloid arecoline which is specific for Areca catechu L. (Arecaceae) was detected.     

Iron oxide-based multifunctional nanoparticulate systems for biomedical applications: a patent review (2008 – present)

Introduction: Iron oxide nanoparticles (IO NPs) exhibit remarkable properties, including inherent magnetism, biocompatibility, high surface to volume ratio, and versatility of engineering, making them ideal candidates for a variety of clinical applications.

Areas covered: The review provides an in-depth discussion on recent patents and developments related to IO NPs in Biomedicine from the last 7 years. It covers innovations in the chemical synthesis, surface coating and functionalization, and biomedical applications, including MRI and multimodal imaging, molecular imaging, cell labeling, drug delivery, hyperthermia, hyperphosphatemia, and antibacterial activity. A brief outline of the important properties of IO NPs is also presented.

Expert opinion: The main focus of current research is the development of new approaches to generate high-quality IO NPs with optimal properties in terms of particle geometry, crystal structure, surface functionalities, stability, and magnetization. Among chemical synthesis methods, thermal decomposition and hydrothermal synthetics processes allow fine control of the particle properties. Plenty of coating materials have been successfully used as shells for these NPs to provide colloidal stability, even enabling the formulation of nanotheranostics for simultaneous disease diagnosis and therapy. However, long-term toxicity and pharmacokinetic studies are necessary before magnetic nanosystems can be approved for clinical use.     

Iron supplementation in the non-dialysis chronic kidney disease (ND-CKD) patient: oral or intravenous?

Abstract

Background:

The management of iron-deficiency anaemia in patients with non-dialysis chronic kidney disease (ND-CKD) remains controversial, particularly regarding the use of oral versus intravenous iron supplementation.     

Iron oxide nanoparticle agglomeration influences dose rates and modulates oxidative stress-mediated dose–response profiles in vitro

Spontaneous agglomeration of engineered nanoparticles (ENPs) is a common problem in cell culture media which can confound interpretation of in vitro nanotoxicity studies. The authors created stable agglomerates of iron oxide nanoparticles (IONPs) in conventional culture medium, which varied in hydrodynamic size (276 nm–1.5 μm) but were composed of identical primary particles with similar surface potentials and protein coatings. Studies using C10 lung epithelial cells show that the dose rate effects of agglomeration can be substantial, varying by over an order of magnitude difference in cellular dose in some cases. Quantification by magnetic particle detection showed that small agglomerates of carboxylated IONPs induced greater cytotoxicity and redox-regulated gene expression when compared with large agglomerates on an equivalent total cellular IONP mass dose basis, whereas agglomerates of amine-modified IONPs failed to induce cytotoxicity or redox-regulated gene expression despite delivery of similar cellular doses. Dosimetry modelling and experimental measurements reveal that on a delivered surface area basis, large and small agglomerates of carboxylated IONPs have similar inherent potency for the generation of ROS, induction of stress-related genes and eventual cytotoxicity. The results suggest that reactive moieties on the agglomerate surface are more efficient in catalysing cellular ROS production than molecules buried within the agglomerate core. Because of the dynamic, size and density-dependent nature of ENP delivery to cells in vitro, the biological consequences of agglomeration are not discernible from static measures of exposure concentration (μg/ml) alone, highlighting the central importance of integrated physical characterisation and quantitative dosimetry for in vitro studies. The combined experimental and computational approach provides a quantitative framework for evaluating relationships between the biocompatibility of nanoparticles and their physical and chemical characteristics.     

Superparamagnetic Iron Oxide–Loaded Lipid Nanocarriers Incorporated in Thermosensitive In Situ Gel for Magnetic Brain Targeting of Clonazepam

The objective of the study was to target clonazepam to the brain through the intranasal olfactory mucosa using nanolipid carriers loaded with superparamagnetic iron oxide nanoparticles (SPIONs) to allow nanocarrier guidance and retention with an external magnetic field. For improved delivery, the nanolipid carriers were incorporated in a thermosensitive mucoadhesive in situ gel. Different nanolipid carriers including solid lipid nanoparticles and nanostructured lipid carriers (NLC) were prepared and characterized with respect to particle size, zeta potential, entrapment efficiency, and in vitro release. The NLC composed of 3 solid lipids (Compritol^® 888, stearic acid, and glyceryl monostearate) and 2 liquid oils (oleic acid and glyceryl monooleate) showed the most satisfactory characteristics and was loaded with SPION (NLC/SPION). Both formulae (NLC and NLC/SPION) were incorporated in an optimized thermosensitive mucoadhesive in situ system composed of 15% pluronic 127 and 0.75% sodium alginate and evaluated for the anticonvulsant action in chemically induced convulsive Swiss Albino mice. The treatment of animals with NLC/SPION significantly prolonged the onset times for convulsion and considerably protected the animals from death. One can thus hope for the emergence of a new intranasal treatment of epilepsy with consequent decrease in peripheral side effects of clonazepam.     

Comparison of Pharmacokinetics and Urinary Iron Excretion of Two Single Doses of Deferiprone in β-Thalassemia/Hemoglobin E Patients

Dose-related pharmacokinetics and urinary iron excretion (UIE) of an orally active iron chelator, deferiprone (L1), was investigated in 12 severe β-thalassemia/hemoglobin E patients. The patients received two single doses of 25 and 50 mg/kg with a 2-week washout period. Deferiprone was rapidly absorbed and reached maximum concentration (C(max)) within 1 h after administration. Pharmacokinetic parameters including C(max) and area under concentration time curve from time zero to infinity (AUC(0-∞)) as well as urinary excretion of non-conjugated and glucuronide-conjugated deferiprone (L1 and L1-G) increased proportionally with the dose of deferiprone. A constant ratio of AUC(0-∞) of L1-G to L1 and a percentage of urinary excretion of L1-G indicated that increasing the dosage does not influence deferiprone biotransformation. Longer terminal elimination half-lifeand higher volume of distribution of L1 were observed with the high dose and correlated with deferiprone-chelated iron in serum. Unexpectedly, UIE did not show a linear relationship with the increased dose of deferiprone. The correlation between UIE and creatinine clearance suggested the possibility of L1-iron complex redistribution in patients with renal impairment treated with high-dose deferiprone.     

Iron sucrose – characteristics,efficacy and regulatory aspects of an established treatment of iron deficiency and iron-deficiency anemia in a broad range of therapeutic areas

Introduction: Iron is a key element in the transport and utilization of oxygen and a variety of metabolic pathways. Iron deficiency is a major cause of anemia and can be associated with fatigue, impaired physical function and reduced quality of life. Administration of oral or intravenous (i.v.) iron is the recommended treatment for iron-deficiency anemia (IDA) in different therapeutic areas.

Areas covered: This article provides an overview of studies that evaluated i.v. iron sucrose for anemia and iron status management, either alone or in combination with erythropoiesis-stimulating agents, across various diseases and conditions.

Expert opinion: Iron sucrose is an established, effective and well-tolerated treatment of IDA in patients with acute or chronic conditions such as chronic kidney disease, inflammatory bowel disease, pregnancy (second and third trimester), postpartum period, heavy menstrual bleeding and cancer who need rapid iron supply and in whom oral iron preparations are ineffective or not tolerated. Available data on patient blood management warrant further studies on preoperative iron treatment. First experience with iron sucrose follow-on products raises questions about their therapeutic equivalence without comparative clinical data in newly diagnosed patients or patients on existing chronic treatment.