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European Journal of Haematology May 2023Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow... (Review)
Review
Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow erythroid hyperplasia, or a chronic transfusional regimen. In normal conditions, intracellular and systemic mechanisms contribute to maintaining iron balance. When this complex homeostatic mechanism fails, an iron overload could be present. Detecting an iron overload is not easy. The gold standard remains the liver biopsy, even if it is invasive and dangerous. Identifying iron using noninvasive techniques allowed a better understanding of the rate of iron overload in different organs, with a low risk for the patient. Estimating serum ferritin (mg/L) is the easiest and, consequently, the most employed diagnostic tool for assessing body iron stores, even if it could be a not specific method. The most common hematological causes of iron overload are myelodysplastic syndromes, sickle cell disease, and thalassemia. In all of these conditions, three drugs have been approved for the treatment of iron overload: deferiprone, deferoxamine, and deferasirox. These chelators have been demonstrated to help lower tissue iron levels and prevent iron overload complications, improving event-free survival (EFS). Nowadays, the decision to start chelation and which chelator to choose remains the joint decision of the clinician and patient.
Topics: Humans; Chelation Therapy; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Pyridones; Benzoates; Triazoles; Iron Overload; Iron
PubMed: 36708354
DOI: 10.1111/ejh.13935 -
Nutrients Jan 2023Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type... (Review)
Review
Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.
Topics: Humans; Ferroptosis; Cardiovascular Diseases; Myocardial Reperfusion Injury; Deferoxamine; Lipid Peroxidation; Iron; Hypertension
PubMed: 36771298
DOI: 10.3390/nu15030591 -
Journal of Controlled Release :... Jul 2018According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In... (Review)
Review
According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found which could present sufficient experimental findings to support its clinical safety profile. It also underlines the fact that majority of work related to the nose-to-brain delivery of anti-AD drugs is limited only up to preclinical studies. In this review article, we have discussed the latest works on various novel formulations loaded with various anti-Alzheimer agents. These agents include galantamine, deferoxamine, tacrine, tarenflurbil, rivastigmine, risperidone, curcumin, quercetin, piperine, insulin, etc. and various peptides towards the development of a promising IN drug delivery system for the treatment of AD. Through this review article, we want to drag the attention of the researchers working in this field towards the challenges and hurdles of practical applicability IN delivery of anti-AD drugs. Moreover, the attention towards the clinical studies will ease the approval process for the administration of anti-Alzheimer drugs via IN route.
Topics: Administration, Intranasal; Alzheimer Disease; Animals; Biological Availability; Blood-Brain Barrier; Brain; Deferoxamine; Donepezil; Drug Carriers; Drug Liberation; Galantamine; Humans; Mucociliary Clearance; Nanoparticles; Nasal Mucosa; Nose; Olfactory Bulb; Risperidone; Tissue Distribution
PubMed: 29772289
DOI: 10.1016/j.jconrel.2018.05.011 -
IUBMB Life Nov 2022Growing evidence indicates that iron overload is an independent risk factor for osteoporosis. However, the mechanisms are not fully understood. The purpose of our study...
Growing evidence indicates that iron overload is an independent risk factor for osteoporosis. However, the mechanisms are not fully understood. The purpose of our study was to determine whether iron overload could lead to ferroptosis in osteoblasts and to explore whether ferroptosis of osteoblasts is involved in iron overload-induced osteoporosis in vitro and in vivo. Ferric ammonium citrate was used to mimic iron overload conditions, while deferoxamine and ferrostatin-1 were used to inhibit ferroptosis of MC3T3-E1 cells in vitro. The ferroptosis, osteogenic differentiation and mineralization of MC3T3-E1 cells were assessed in vitro. A mouse iron overload model was established using iron dextran. Immunohistochemical analysis was performed to determine ferroptosis of osteoblasts in vivo. Enzyme-linked immunosorbent assays and calcein-alizarin red S labelling were used to assess new bone formation. Dual x-ray absorptiometry, micro-computed tomography and histopathological analysis were conducted to evaluate osteoporosis. The results showed that iron overload reduced cell viability, superoxide dismutase and glutathione levels, increased reactive oxygen species generation, lipid peroxidation, malondialdehyde levels and ferroptosis-related protein expression, and induced ultrastructural changes in mitochondria. Iron overload could also inhibit osteogenic differentiation and mineralization in vitro. Inhibiting ferroptosis reversed the changes described above. Iron overload inhibited osteogenesis, promoted the ferroptosis of osteoblasts and induced osteoporosis in vivo, which could also be improved by deferoxamine and ferrostatin-1. These results demonstrate that ferroptosis of osteoblasts plays a crucial role in iron overload-induced osteoporosis. Maintaining iron homeostasis and targeting ferroptosis of osteoblasts might be potential measures of treating or preventing iron overload-induced osteoporosis.
Topics: Mice; Animals; Osteogenesis; Ferroptosis; Deferoxamine; Reactive Oxygen Species; Dextrans; X-Ray Microtomography; Osteoblasts; Iron Overload; Osteoporosis; Iron; Glutathione; Superoxide Dismutase; Malondialdehyde
PubMed: 35638167
DOI: 10.1002/iub.2656 -
Annals of the New York Academy of... Nov 2023Combination chelation therapies are considered in transfusion-dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or... (Review)
Review
Combination chelation therapies are considered in transfusion-dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or intensification of iron chelation therapy is required for the rapid reduction of excess iron to avoid permanent organ damage. Combination chelation may provide a more flexible approach for individualizing chelation therapy, thereby improving tolerability, adherence, and quality of life. In principle, iron chelators can be combined with an infinite number of dosing regimens; these involve simultaneous or sequential exposure to the chelators on the same day or alternating the drugs on different days. Clinical studies have established the safety and efficacy of chelation combinations. However, real-life data with combination therapies indicate the significance of compliance for a meaningful reduction in iron overload compared to monotherapies.
Topics: Humans; Chelation Therapy; Deferasirox; Deferoxamine; Deferiprone; Quality of Life; Benzoates; Triazoles; Pyridones; Iron Chelating Agents; Iron Overload; Iron; Drug Therapy, Combination
PubMed: 37594980
DOI: 10.1111/nyas.15052 -
Ethiopian Journal of Health Sciences Jul 2023Arsenic trioxide is an activist agent in the treatment of acute promyelocytic leukemia (APL), which acts alone, but has an adverse effect on patients. Moreover,...
BACKGROUND
Arsenic trioxide is an activist agent in the treatment of acute promyelocytic leukemia (APL), which acts alone, but has an adverse effect on patients. Moreover, deferoxamine has antiproliferative activity and induces leukopenia. In order to enhance antileukemic effectiveness and to reduce the dosage of arsenic trioxide, the combination effect of it with deferoxamine (DFO) was evaluated on the APL cell line (NB4).
METHODS
In this experimental study, to investigate the cytotoxic effects of ATO/DFO in acute promyelocytic leukemia, the NB4 cell line (provided by Pasteur Institute of Iran) was treated with different doses and then at 24, 48, and 72 hrs intervals, the percentage of survival, cell count, metabolic activity and apoptosis induction were investigated respectively. Also, hTERT gene expression was analyzed by the RT-PCR method.
RESULTS
We found that DFO alone and in combination with ATO has cytotoxic and antiproliferative effects, and reduces viability and cell metabolic activity in the NB4 cell line in a dose and time-dependent manner. In addition, this combination causes an increase in apoptosis, up-regulation of Caspase-3, and down-regulation of hTERT genes in cells.
CONCLUSION
Combined ATO/ DFO treatment cooperatively decreased the mRNA levels of the hTERT and increased the mRNA levels of Caspase-3 in a time-dependent manner compared to DFO alone.
Topics: Arsenic Trioxide; Humans; Arsenicals; Leukemia, Promyelocytic, Acute; Deferoxamine; Cell Survival; Cell Line, Tumor; Apoptosis; Telomerase; Oxides; Antineoplastic Agents; Cell Proliferation
PubMed: 38784214
DOI: 10.4314/ejhs.v33i4.17 -
Current Pharmaceutical Biotechnology 2022Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in... (Review)
Review
Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in some organs including the liver, glands, brain, heart, gastrointestinal tract and lung. Iron chelation therapy could be considered an effective approach for removing excess iron. Deferoxamine, deferiprone and deferasirox are three common iron chelators in clinical practice but cause several side effects. In this context, the use of curcumin, a dietary phytochemical derived from turmeric, as a natural and safe antioxidant with iron-chelating activity may be a useful strategy for the management of iron overload. This review focuses on the deleterious effect of iron accumulation in different organs of the body as well as the therapeutic potential of curcumin against iron-induced toxicity.
Topics: Curcumin; Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Iron Overload; Pyridones
PubMed: 34521323
DOI: 10.2174/1389201022666210914122846 -
Molecules (Basel, Switzerland) Apr 2024Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of... (Review)
Review
Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies.
Topics: Deferoxamine; Humans; Animals; Neovascularization, Physiologic; Regeneration; Wound Healing; Neovascularization, Pathologic; Angiogenesis
PubMed: 38731540
DOI: 10.3390/molecules29092050 -
Molecular Pharmaceutics Jun 2023Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor...
Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor progression and poor prognosis in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and breast cancer. The expression of Gal-3BP by a variety of neoplasms makes it an enticing target for both diagnostics and therapeutics, including immuno-positron emission tomography (immunoPET) probes and antibody-drug conjugates (ADCs). Herein, we report the development, characterization, and evaluation of a pair of Gal-3BP-targeting radioimmunoconjugates for Zr-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its corresponding ADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine (DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing 1-2 DFO/monoclonal antibody. Both DFO-modified immunoconjugates retained their affinity for Gal-3BP in enzyme-linked immunosorbent assay experiments. The chelator-bearing antibodies were radiolabeled with zirconium-89 ( ≈ 3.3 d) to produce radioimmunoconjugates ─ [Zr]Zr-DFO-1959 and [Zr]Zr-DFO-1959-sss/DM4 ─ with high specific activity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intact after 168 h in human serum at 37 °C). In mice bearing subcutaneous Gal-3BP-secreting A375-MA1 xenografts, [Zr]Zr-DFO-1959 clearly delineated tumor tissue, reaching a maximum tumoral activity concentration (54.8 ± 15.8%ID/g) and tumor-to-background contrast (tumor-to-blood = 8.0 ± 4.6) at 120 h post-injection. The administration of [Zr]Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressing melanoma patient-derived xenografts produced similarly promising results. [Zr]Zr-DFO-1959 and [Zr]Zr-DFO-1959-sss/DM4 exhibited nearly identical pharmacokinetic profiles in the mice bearing A375-MA1 tumors, though the latter produced higher uptake in the spleen and kidneys. Both [Zr]Zr-DFO-1959 and [Zr]Zr-DFO-1959-sss/DM4 effectively visualized Gal-3BP-secreting tumors in murine models of melanoma. These results suggest that both probes could play a role in the clinical imaging of Gal-3BP-expressing malignancies, particularly as companion theranostics for the identification of patients likely to respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.
Topics: Animals; Humans; Mice; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Deferoxamine; Galectin 3; Immunoconjugates; Lung Neoplasms; Melanoma; Positron-Emission Tomography; Zirconium
PubMed: 37191353
DOI: 10.1021/acs.molpharmaceut.3c00241 -
Journal of Trace Elements in Medicine... 2015The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The... (Review)
Review
The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review.
Topics: Administration, Oral; Antidotes; Benzoates; Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Heavy Metal Poisoning; Humans; Penicillamine; Poisoning; Pyridones; Succimer; Triazoles; Trientine; Unithiol
PubMed: 25457281
DOI: 10.1016/j.jtemb.2014.10.001