• chelating drugs
• chelation in medicine
• deferiprone
• ferric iron tri-maltol
• iron deficiency
• iron overload
• natural chelators

• Humans
• Iron Overload/drug therapy
• Iron Overload/metabolism
• Iron Chelating Agents/therapeutic use
• Iron Chelating Agents/pharmacology
• Anemia, Iron-Deficiency/drug therapy
• Anemia, Iron-Deficiency/metabolism
• Iron/metabolism
• Animals
• Deferiprone/therapeutic use
• Deferiprone/pharmacology

• atrial fibrillation
• cardiac arrhythmia
• hemochromatosis
• iron accumulation

• Fenton reaction
• carcinogenesis
• diagnostic techniques
• ferroptosis
• free radicals
• hemochromatosis
• iron overload
• iron toxicity
• mechanisms
• thalassemia

• Humans
• Medicine
• Iron
• Iron Overload
• Hemochromatosis
• Alzheimer Disease

• accrufer
• deferiprone
• drug design, development and use
• feraccru
• ferric maltol
• iron deficiency anemia
• iron metabolism
• iron overload
• iron toxicity
• iron-maltol
• orphan diseases
• orphan drugs
• thalassemia

• Humans
• Iron/therapeutic use
• Deferiprone
• Iron Chelating Agents/therapeutic use
• Iron Overload/drug therapy
• Drug Design
• Pyridones/therapeutic use

• cancer
• chelators
• chelator–metal complexes
• deferiprone
• drug combinations
• drug design
• drug targeting
• ferroptosis
• free radicals
• iron
• multi-target drugs

• Osteoporosis
• deferoxamine
• magnesium
• regeneration
• β-tricalcium phosphate

• Rats
• Animals
• Magnesium/therapeutic use
• Magnesium/pharmacology
• Deferoxamine/pharmacology
• Deferoxamine/therapeutic use
• Vascular Endothelial Growth Factor A/genetics
• Rats, Sprague-Dawley
• Calcium Phosphates/therapeutic use
• Calcium Phosphates/pharmacology
• Bone Regeneration
• Osteogenesis
• Cell Differentiation

• drugs in iron diseases
• iron chelation
• metal metabolism
• metal related diseases
• metal toxicity
• treatment

• Chelation Therapy
• Disease/classification
• Disease/etiology
• Drug Therapy/trends
• Humans
• Iron/metabolism
• Iron Chelating Agents/therapeutic use
• Iron Deficiencies/drug therapy
• Iron Overload/drug therapy
• Metals/metabolism
• Therapeutics/methods
• Therapeutics/trends

• Biocompatible
• Iron(II) detection
• Nontoxic
• Reduced Fluoresceinamine
• Specific

• Cadmium Compounds
• Ferrous Compounds
• Fluorescent Dyes
• Iron
• Quantum Dots/toxicity
• Spectrometry, Fluorescence
• Tellurium

• Aligned nanofibers
• Angiogenesis
• Deferoxamine
• Macrophage polarization
• Nerve regeneration
• P(MMD-co-LA)

The trimaltol iron complex (International Non-proprietary Name: ferric maltol) was originally designed, synthesised, and screened in vitro and in vivo in 1980–1981 by Kontoghiorghes G.J. following his discovery of the novel alpha-ketohydroxyheteroaromatic (KHP) class of iron chelators (1978–1981), which were intended for clinical use, including the treatment of iron deficiency anaemia (IDA). Iron deficiency anaemia is a global health problem affecting about one-third of the world’s population. Many (and different) ferrous and ferric iron complex formulations are widely available and sold worldwide over the counter for the treatment of IDA. Almost all such complexes suffer from instability in the acidic environment of the stomach and competition from other dietary molecules or drugs. Natural and synthetic lipophilic KHP chelators, including maltol, have been shown in in vitro and in vivo studies to form stable iron complexes, to transfer iron across cell membranes, and to increase iron absorption in animals. Trimaltol iron, sold as Feraccru or Accrufer, was recently approved for clinical use in IDA patients in many countries, including the USA and in EU countries, and was shown to be effective and safe, with a better therapeutic index in comparison to other iron formulations. Similar properties of increased iron absorption were also shown by lipophilic iron complexes of 8-hydroxyquinoline, tropolone, 2-hydroxy-4-methoxypyridine-1-oxide, and related analogues. The interactions of the KHP iron complexes with natural chelators, drugs, metal ions, proteins, and other molecules appear to affect the pharmacological and metabolic effects of both iron and the KHP chelators. A new era in the treatment of IDA and other possible clinical applications, such as theranostic and anticancer formulations and metal radiotracers in diagnostic medicine, are envisaged from the introduction of maltol, KHP, and similar lipophilic chelators.

• Accrufer
• Feraccru
• alpha-ketohydroxyheteroaromatic chelators
• clinical applications
• ferric maltol
• iron deficiency
• iron deficiency anaemia
• lipophilic chelators
• maltol
• pharmacology

• Anemia, Iron-Deficiency/drug therapy
• Animals
• Biological Availability
• Ferric Compounds/chemistry
• Ferric Compounds/pharmacology
• Ferric Compounds/therapeutic use
• Humans
• In Vitro Techniques
• Iron/therapeutic use
• Iron Chelating Agents/chemistry
• Iron Chelating Agents/pharmacology
• Iron Chelating Agents/therapeutic use
• Pyrones/chemistry
• Pyrones/pharmacology
• Pyrones/therapeutic use

• Catechol
• Fenton reaction
• Ferritin
• Hydroxyl radical
• Iron chelation
• Natural product

Ascorbic acid (AscH₂) is one of the most important vitamins found in the human diet, with many biological functions including antioxidant, chelating, and coenzyme activities. Ascorbic acid is also widely used in medical practice especially for increasing iron absorption and as an adjuvant therapeutic in iron chelation therapy, but its mode of action and implications in iron metabolism and toxicity are not yet clear. In this study, we used UV–Vis spectrophotometry, NMR spectroscopy, and EPR spin trapping spectroscopy to investigate the antioxidant/pro-oxidant effects of ascorbic acid in reactions involving iron and the iron chelator deferiprone (L1). The experiments were carried out in a weak acidic (pH from 3 to 5) and neutral (pH 7.4) medium. Ascorbic acid exhibits predominantly pro-oxidant activity by reducing Fe³⁺ to Fe²⁺, followed by the formation of dehydroascorbic acid. As a result, ascorbic acid accelerates the redox cycle Fe³⁺ ↔ Fe²⁺ in the Fenton reaction, which leads to a significant increase in the yield of toxic hydroxyl radicals. The analysis of the experimental data suggests that despite a much lower stability constant of the iron–ascorbate complex compared to the FeL1₃ complex, ascorbic acid at high concentrations is able to substitute L1 in the FeL1₃ chelate complex resulting in the formation of mixed L1₂AscFe complex. This mixed chelate complex is redox stable at neutral pH = 7.4, but decomposes at pH = 4–5 during several minutes at sub-millimolar concentrations of ascorbic acid. The proposed mechanisms play a significant role in understanding the mechanism of action, pharmacological, therapeutic, and toxic effects of the interaction of ascorbic acid, iron, and L1.

• EPR spin trapping
• Fenton reaction
• TMIO spin trap
• ascorbic acid
• ascorbyl radical
• deferiprone
• hydroxyl radical
• iron chelation
• iron toxicity
• vitamin C

Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978–1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells’ count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.

• Chelation therapy
• Deferiprone
• Deferoxamine
• Iron detoxification
• Iron overload
• Thalassaemia

• Controversies
• Deferasirox
• Deferiprone
• Deferoxamine
• Iron chelation therapy
• Iron diseases
• Iron metabolism
• Medical journals

• chelation therapy
• deferasirox
• deferiprone
• deferoxamine
• efficacy
• iron absorption
• iron overload
• safety
• thalassemia intermedia

• iron
• copper
• male fertility
• spermatozoa
• oxidative stress
• ros

• Copper/metabolism
• Fertility/physiology
• Germ Cells/metabolism
• Gonads/metabolism
• Humans
• Iron/metabolism
• Male
• Reproductive Techniques, Assisted
• Spermatogenesis
• Trace Elements/metabolism
• Zinc/metabolism

Thalassaemia major (TM) and Friedreich’s ataxia (FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients. Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.

• Thalassaemia
• Friedreich ataxia
• Prenatal diagnosis
• Survival
• Chelation therapy
• Deferiprone
• Deferoxamine
• Cyprus

Macrophages play a very important role in host defense and in iron homeostasis by engulfing senescent red blood cells and recycling iron. Hepcidin is the master iron regulating hormone that limits dietary iron absorption from the gut and limits iron egress from macrophages. Upon infection macrophages retain iron to limit its bioavailability which limits bacterial growth. Recently, a short chain butyrate dehydrogenase type 2 (BDH2) protein was reported to contain an iron responsive element and to mediate cellular iron trafficking by catalyzing the synthesis of the mammalian siderophore that binds labile iron; therefore, BDH2 plays a crucial role in intracellular iron homeostasis. However, BDH2 expression and regulation in macrophages have not yet been described. Here we show that LPS-induced inflammation combined with ER stress led to massive BDH2 downregulation, increased the expression of ER stress markers, upregulated hepcidin expression, downregulated ferroportin expression, caused iron retention in macrophages, and dysregulated cytokine release from macrophages. We also show that ER stress combined with inflammation synergistically upregulated the expression of the iron carrier protein NGAL and the stress-inducible heme degrading enzyme heme oxygenase-1 (HO-1) leading to iron liberation. This is the first report to show that inflammation and ER stress downregulate the expression of BDH2 in human THP-1 macrophages.

According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The criteria for drug development, price levels and use needs to be readdressed to improve drug safety and minimise costs. New global health policies based on cheaper drugs can help the treatment of many categories of orphan and rare diseases and millions of orphan patients in developing and developed countries.

• World health issues
• Global diseases
• Orphan drugs
• Orphan diseases
• Rare diseases
• Orphan patients
• Thalassaemia
• Deferiprone
• Deferasirox
• Deferoxamine
• Iron overload

• Benzoates/poisoning
• Deferasirox
• Drug-Related Side Effects and Adverse Reactions/mortality
• Ethics, Medical
• Ethics, Research
• Humans
• Iron Overload/drug therapy
• Iron Overload/mortality
• Triazoles/poisoning

• Absorption
• Chelation Therapy
• Hemochromatosis/drug therapy
• Humans
• Iron Chelating Agents/metabolism
• Iron Chelating Agents/therapeutic use
• Iron, Dietary/metabolism
• Iron, Dietary/therapeutic use
• beta-Thalassemia/drug therapy