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Critical Reviews in Analytical Chemistry 2020Acute iron poisoning and chronic iron overload consequences in significant morbidity and mortality worldwide. Treatment of acute iron poisoning and chronic iron overload... (Review)
Review
Acute iron poisoning and chronic iron overload consequences in significant morbidity and mortality worldwide. Treatment of acute iron poisoning and chronic iron overload can be challenging and care providers are often tackled with management dilemmas. Iron chelating agents are commonly prescribed for patients with iron deficiency anemia. In this review article, different analytical techniques are reported used for qualitative and quantitative analysis of iron chelating agents like, deferiprone, deferoxamine, and deferasirox. Efforts are taken to collect all related articles published till October 2018. This review discusses all analytical methods, its advantages and disadvantages as well as its applications. This article will help you to know about basic analytical techniques as well as advanced hyphenated techniques practiced for determination of iron chelating agents in different matrices. The techniques discussed in this review follow the ICH guidelines for method validation.
Topics: Humans; Iron Chelating Agents
PubMed: 31140834
DOI: 10.1080/10408347.2019.1620095 -
Profiles of Drug Substances,... 2024Deferasirox is an iron-chelating drug developed by Novartis company for treatment of diseases accompanied by chronic iron overload; such as β-thalassemia or sickle cell...
Deferasirox is an iron-chelating drug developed by Novartis company for treatment of diseases accompanied by chronic iron overload; such as β-thalassemia or sickle cell diseases. Owing to its advantages such as high affinity, specificity and wide therapeutic window, it is considered as first line treatment. The current chapter describes the physicochemical characteristics, mode of action, pharmacokinetics, therapeutic applications and synthetic methods for deferasirox. Moreover, it includes Fourier transform infrared spectrometry (FTIR) and nuclear magnetic resonance spectroscopy (NMR) analysis for its functional groups. In addition, the selected analytical methods are summarized to aid the analysts in their routine analysis of deferasirox.
Topics: Humans; Deferasirox; Benzoates; Triazoles; Iron Chelating Agents; Iron Overload; Iron
PubMed: 38423705
DOI: 10.1016/bs.podrm.2023.11.001 -
Pharmacological Research Sep 2022Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in... (Review)
Review
Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in health and disease. Indeed, iron is associated with both physiological (e.g., immune cell biology and function and hematopoiesis) and pathological (e.g., inflammatory and infectious diseases, ferroptosis and ferritinophagy) processes, yet few studies have addressed the potential functional link between iron, the aforementioned processes and extramedullary hematopoiesis, despite the obvious benefits that this could bring to clinical practice. Further investigation in this direction will shape the future development of individualized treatments for iron-linked diseases and chronic inflammatory disorders, including extramedullary hematopoiesis, metabolic syndrome, cardiovascular diseases and cancer.
Topics: Ferroptosis; Hematopoiesis, Extramedullary; Homeostasis; Humans; Iron; Iron Metabolism Disorders
PubMed: 35933006
DOI: 10.1016/j.phrs.2022.106386 -
Frontiers in Bioscience (Landmark... Jan 2020The trace element iron plays important roles in biological systems. Vital functions of both host organisms and pathogens require iron. During infection, the innate... (Review)
Review
The trace element iron plays important roles in biological systems. Vital functions of both host organisms and pathogens require iron. During infection, the innate immune system reduces iron availability for invading organisms. Pathogens acquire iron through different mechanisms, primarily through the secretion of high-affinity iron chelating compounds known as siderophores. Bacterial siderophores have been used clinically for iron chelation, however synthetic iron chelators are superior for treating infection because - in contrast to siderophore-bound iron - bacteria are not able to utilize iron bound to those molecules. Additionally, utilizing siderophores-dependent iron uptake in a "trojan horse" manner represents a potential option to carry antibiotics into bacterial cells. Recently, synthetic iron chelators have been shown to enhance antibiotic effectiveness and overcome antibiotic resistance. This has implications for the treatment of infections through combination therapy of iron chelators and antibiotics.
Topics: Animals; Bacteria; Bacterial Infections; Biological Transport; Deferasirox; Drug Resistance, Bacterial; Humans; Iron; Iron Chelating Agents; Siderophores
PubMed: 31585910
DOI: 10.2741/4827 -
Antioxidants (Basel, Switzerland) Apr 2022Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital...
Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital role in various physiological processes within the human body, its accumulation contributes to cellular aging in several species. In its free form, iron can initiate the formation of free radicals at a cellular level and contribute to systemic disorders. This is most evident in high iron conditions such as hereditary hemochromatosis, when accumulation of iron contributes to the development of arthritis, cirrhosis, or cardiomyopathy. A growing body of research has further identified iron's contributory effects in neurodegenerative diseases, ocular disorders, cancer, diabetes, endocrine dysfunction, and cardiovascular diseases. Reducing iron levels by repeated phlebotomy, iron chelation, and dietary restriction are the common therapeutic considerations to prevent iron toxicity. Chelators such as deferoxamine, deferiprone, and deferasirox have become the standard of care in managing iron overload conditions with other potential applications in cancer and cardiotoxicity. In certain animal models, drugs with iron chelating ability have been found to promote health and even extend lifespan. As we further explore the role of iron in the aging process, iron chelators will likely play an increasingly important role in our health.
PubMed: 35624729
DOI: 10.3390/antiox11050865 -
Transplantation and Cellular Therapy May 2021Many patients with hematologic malignancies receive RBC transfusion support, which often causes systemic and tissue iron toxicity. Because of their compromised bone... (Review)
Review
Many patients with hematologic malignancies receive RBC transfusion support, which often causes systemic and tissue iron toxicity. Because of their compromised bone marrow function, hematopoietic stem cell transplant (HSCT) recipients are especially vulnerable to excess iron levels. Iron toxicity may compromise transplant engraftment and eventually promote relapse by mediating oxidative and genotoxic stress in hematopoietic stem cells (HSCs) and further impairing the already dysfunctional bone marrow microenvironment in HSCT recipients. Iron toxicity is thought to be primarily mediated by its ability to induce reactive oxygen species and trigger inflammation. Elevated iron levels in the bone marrow can decrease the number of HSCs and progenitor cells, as well as their clonogenic potential, alter mesenchymal stem cell differentiation, and inhibit the expression of chemokines and adhesion molecules involved in hematopoiesis. In vivo, in vitro, and clinical studies support the concept that iron chelation therapy may limit iron toxicity in the bone marrow and promote hematologic improvement and engraftment in HSCT recipients. This review will provide an overview of the current knowledge of the detrimental impact of iron toxicity in the setting of HSCT in patients with hematologic malignancies and the use of iron restriction approaches to improve transplant outcome.
Topics: Chelation Therapy; Hematopoietic Stem Cell Transplantation; Humans; Iron; Iron Overload; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 33969823
DOI: 10.1016/j.jtct.2020.11.007 -
Biomolecules Feb 2022The accumulation of iron may contribute to Alzheimer's disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients....
The accumulation of iron may contribute to Alzheimer's disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients. However, desferrioxamine requires injection, which is inconvenient and may hinder compliance. We therefore tested an oral iron chelator, desferasirox (Exjade), in transgenic animal models. Tg2576 mice overexpress the mutant human APP protein and produce the Aβ peptide. JNPL3 mice (Tau/Tau) overexpress the mutant human tau protein. Crossing these produced APP/Tau mice, overexpressing both APP and tau. Treating the three models with 1.6 mg deferasirox thrice weekly from age 8 to 14 months did not affect memory as measured by contextual fear conditioning or motor function as measured by rotarod, but tended to decrease hyperphosphorylated tau as measured by AT8 immunohistochemistry and immunoblotting. Deferasirox might act by decreasing iron, which aggregates tau, or directly binding tau to inhibit aggregation.
Topics: Alzheimer Disease; Animals; Deferasirox; Deferoxamine; Disease Models, Animal; Humans; Iron; Iron Chelating Agents; Mice; Mice, Transgenic; Tauopathies; tau Proteins
PubMed: 35327557
DOI: 10.3390/biom12030365 -
Cells Jun 2020Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The... (Review)
Review
Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The diversity of the activity and function of iron and its associated pathologies is based on bond formation with adjacent ligands and the overall structure of the iron complex in proteins or with other biomolecules. The control of the metabolic pathways of iron absorption, utilization, recycling and excretion by iron-containing proteins ensures normal biologic and physiological activity. Abnormalities in iron-containing proteins, iron metabolic pathways and also other associated processes can lead to an array of diseases. These include iron deficiency, which affects more than a quarter of the world's population; hemoglobinopathies, which are the most common of the genetic disorders and idiopathic hemochromatosis. Iron is the most common catalyst of free radical production and oxidative stress which are implicated in tissue damage in most pathologic conditions, cancer initiation and progression, neurodegeneration and many other diseases. The interaction of iron and iron-containing proteins with dietary and xenobiotic molecules, including drugs, may affect iron metabolic and disease processes. Deferiprone, deferoxamine, deferasirox and other chelating drugs can offer therapeutic solutions for most diseases associated with iron metabolism including iron overload and deficiency, neurodegeneration and cancer, the detoxification of xenobiotic metals and most diseases associated with free radical pathology.
Topics: Animals; Humans; Iron; Iron Overload; Medicine; Metals; Oxidative Stress; Triazoles
PubMed: 32545424
DOI: 10.3390/cells9061456 -
Journal of Biochemistry Jul 2023Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes...
Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression and is expected to contribute to future ferroptosis research.
Topics: Animals; Humans; Mice; Fibroblasts; Ferroptosis; Phospholipid Hydroperoxide Glutathione Peroxidase; Iron; Glutathione; Basic-Leucine Zipper Transcription Factors
PubMed: 37094356
DOI: 10.1093/jb/mvad036 -
Medicines (Basel, Switzerland) Jul 2021Regulatory policies on drugs have a major impact on patient safety and survival. Some pharmaceutical companies employ all possible methods to achieve maximum sales in... (Review)
Review
Differences between the European Union and United States of America in Drug Regulatory Affairs Affect Global Patient Safety Standards and Public Health Awareness: The Case of Deferasirox and Other Iron Chelating Drugs.
Regulatory policies on drugs have a major impact on patient safety and survival. Some pharmaceutical companies employ all possible methods to achieve maximum sales in relation to the monopoly of their patented drugs, leading sometimes to irregularities and illegal activities. Misinformation on the orphan drug deferasirox has reached the stage of criminal investigations and fines exceeding USD 100 million. Additional lawsuits of USD 3.5 billion for damages and civil fines were also filed by the FBI of the USA involving deferasirox and mycophenolic acid, which were later settled with an additional fine of USD 390 million. Furthermore, a USD 345 million fine was also settled for bribes and other illegal overseas operations including an EU country. However, no similar fines for illegal practises or regulatory control violations have been issued in the EU. Misconceptions and a lack of clear guidelines for the use of deferasirox in comparison to deferiprone and deferoxamine appear to reduce the effective treatment prospects and to increase the toxicity risks for thalassaemia and other iron loaded patients. Similar issues have been raised for the activities of other pharmaceutical companies promoting the use of new patented versus generic drugs. Treatments for different categories of patients using new patented drugs are mostly market driven with no clear safeguards or guidelines for risk/benefit assessment indications or for individualised effective and safe optimum therapies. There is a need for the establishment of an international organisation, which can monitor and assess the risk/benefit assessment and marketing of drugs in the EU and globally for the benefit of patients. The pivotal role of the regulatory drug authorities and the prescribing physicians for identifying individualised optimum therapies is essential for improving the survival and safety of millions of patients worldwide.
PubMed: 34357152
DOI: 10.3390/medicines8070036