The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency.

The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases.

Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across the main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports the contribution of iron in disease pathologies, but the delineation of its pathogenic role is yet challenged by the complex involvement of iron in multiple neurotoxicity mechanisms and evidence supporting a reciprocal influence between accumulation of iron and protein pathology. Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Pharmacogenomics of Drugs Used in ß-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications.

In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of ß-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases.

Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure.

The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.

Efficacy of the iron-chelating agent, deferiprone, in patients with Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: Several studies have reported iron accumulation in the basal ganglia to be associated with the development of Parkinson's Disease (PD). Recently, a few trials have examined the efficacy of using the iron-chelating agent Deferiprone (DFP) for patients with PD. We conducted this meta-analysis to summarize and synthesize evidence from published randomized controlled trials about the efficacy of DFP for PD patients. METHODS: A comprehensive literature search of four electronic databases was performed, spanning until February 2023. Relevant RCTs were selected, and their data were extracted and analyzed using the RevMan software. The primary outcome was the change in the Unified Parkinson's Disease Rating Scale (UPDRS-III). RESULTS: Three RCTs with 431 patients were included in this analysis. DFP did not significantly improve UPDRS-III score compared to placebo (Standardized mean difference -0.06, 95% CI [-0.69, 0.58], low certainty evidence). However, it significantly reduced iron accumulation in the substantia nigra, putamen, and caudate as measured by T2*-weighted MRI (with high certainty evidence). CONCLUSION: Current evidence does not support the use of DFP in PD patients. Future disease-modification trials with better population selection, adjustment for concomitant medications, and long-term follow up are recommended.

Deferasirox: A comprehensive drug profile.

Deferasirox is an iron-chelating drug developed by Novartis company for treatment of diseases accompanied by chronic iron overload; such as ß-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.

The impact of chelation compliance in health outcome and health related quality of life in thalassaemia patients: a systematic review.

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.

Two risk factors for hypozincemia in diabetic ß-thalassemia patients: Hepatitis C and deferasirox.

BACKGROUND AND AIM: Hypozincemia is a prevalent adverse consequence in diabetes mellitus (DM) and ß-Thalassemia patients. We aimed to evaluate the level of serum zinc in ß-thalassemia patients with DM and a risk assessment for hypozincemia. METHODS: The study population included transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) with overt DM (fasting plasma glucose (FPG) ≥126 mg/dL, and/or 2-h plasma glucose≥200 mg/dL). Serum zinc concentration was measured by the colorimetric method, and the values below 70 µg/dL were defined as hypozincemia. Myocardial and liver T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) were valued by a free contrast MRI. The demographic, clinical, paraclinical, and laboratory data were also recorded. The data belonged to the period from December 2018 until December 2020. RESULTS: Of 64 diabetic ß-thalassemia patients, 41 cases had zinc data in their medical files (aged 38 ± 9 years, 48.8% female). 78.05% of patients (n = 32) were TDT, and 21.95% were NTDT (n = 9). The mean ± standard deviation of zinc level was 110.2 ± 127.6 µg/dL. The prevalence of hypozincemia was 9.76%, 95% confidence interval [CI] 0.27 to 19.24 (four cases). After controlling age, the odds of hypozincemia for using deferasirox (DFX) was 8.77, 95% CI 0.60 to 127.1. In ß-thalassemia patients, the age-adjusted risk of hypozincemia was calculated at 15.85, 95% CI 0.47 to 529.3 for hepatitis C. The adjusted risk of hypozincemia based on age for antacid use was 6.34, 95% CI 0.39 to 102.7. CONCLUSION: In light of this study, as well as hepatitis C, using DFX and antacids is associated with a high risk of hypozincemia amid diabetic ß-thalassemia cases. However, upward bias should be taken into consideration.

Health-related quality of life with standard and curative therapies in thalassemia: A narrative literature review.

Health-related quality of life (HRQOL) is a patient-reported outcome that assesses the impact of a disease or illness on different domains of a patient's life. Different general and disease-specific measures can be used to evaluate HRQOL. This article aimed to summarize the evidence for HRQOL among patients with transfusion-dependent (TDT) and non-transfusion-dependent thalassemia (NTDT). We included HRQOL data related to standard therapy with blood transfusions, iron chelation, and/or luspatercept in TDT and NTDT, as well as curative therapies for TDT, including hematopoietic stem cell transplant (HSCT) and gene therapy. Patients with thalassemia had worse HRQOL scores compared to the general population, and chronic pain was seen to increase in frequency and severity over time with age. NTDT patients reported worse physical health and functioning, mental health, general health, and vitality than TDT patients. However, TDT patients reported worse pain, change in health, and social support than NTDT. Most therapies improved overall HRQOL among thalassemia patients. Deferasirox, an oral iron chelator, was associated with more HRQOL benefits compared to deferoxamine, an intravenous iron chelator. Luspatercept showed clinically meaningful improvement in physical functioning among TDT and NTDT. Furthermore, HSCT and gene therapy were associated with better physical, emotional, and mental domains scores.

Chelation of Mitochondrial Iron as an Antiparasitic Strategy.

Iron, as an essential micronutrient, plays a crucial role in host-pathogen interactions. In order to limit the growth of the pathogen, a common strategy of innate immunity includes withdrawing available iron to interfere with the cellular processes of the microorganism. Against that, unicellular parasites have developed powerful strategies to scavenge iron, despite the effort of the host. Iron-sequestering compounds, such as the approved and potent chelator deferoxamine (DFO), are considered a viable option for therapeutic intervention. Since iron is heavily utilized in the mitochondrion, targeting iron chelators in this organelle could constitute an effective therapeutic strategy. This work presents mitochondrially targeted DFO, mitoDFO, as a candidate against a range of unicellular parasites with promising in vitro efficiency. Intracellular Leishmania infection can be cleared by this compound, and experimentation with Trypanosoma brucei 427 elucidates its possible mode of action. The compound not only affects iron homeostasis but also alters the physiochemical properties of the inner mitochondrial membrane, resulting in a loss of function. Furthermore, investigating the virulence factors of pathogenic yeasts confirms that mitoDFO is a viable candidate for therapeutic intervention against a wide spectrum of microbe-associated diseases.

Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.

BACKGROUND: In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months. MATERIALS AND METHODS: We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique. RESULTS: At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups. DISCUSSION: In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.

An Iron-chelating Agent Improved the Cardiac Function in a Patient with Severe Heart Failure Due to Hereditary Hemochromatosis.

A 24-year-old man was admitted to our hospital because of severe heart failure. Although he was treated with diuretics and positive inotropic agents, his heart failure progressed. An endomyocardial biopsy revealed iron deposition in his myocytes. Finally, he was diagnosed with hereditary hemochromatosis. After starting administration of an iron-chelating agent in addition to conventional treatment for heart failure, his condition improved. We should consider hemochromatosis in heart failure patients with severe right ventricular dysfunction in addition to left ventricular dysfunction.

Effects on hearing after long-term use of iron chelators in beta-thalassemia: Over twenty years of longitudinal follow-up.

OBJECTIVE: The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. METHODS: We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. RESULTS: A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. CONCLUSION: This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.

Management of transfusion-dependent ß-thalassemia (TDT): Expert insights and practical overview from the Middle East.

ß-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent ß-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.

Can iron chelators ameliorate viral infections?

The redox reactivity of iron is a double-edged sword for cell functions, being either essential or harmful depending on metal concentration and location. Deregulation of iron homeostasis is associated with several clinical conditions, including viral infections. Clinical studies as well as in silico, in vitro and in vivo models show direct effects of several viruses on iron levels. There is support for the strategy of iron chelation as an alternative therapy to inhibit infection and/or viral replication, on the rationale that iron is required for the synthesis of some viral proteins and genes. In addition, abnormal iron levels can affect signaling immune response. However, other studies report different effects of viral infections on iron homeostasis, depending on the class and genotype of the virus, therefore making it difficult to predict whether iron chelation would have any benefit. This review brings general aspects of the relationship between iron homeostasis and the nonspecific immune response to viral infections, along with its relevance to the progress or inhibition of the inflammatory process, in order to elucidate situations in which the use of iron chelators could be efficient as antivirals.

Vanillin serves as a potential substitute for chemical chelator desferal in iron-overloaded mice.

PURPOSE: Iron toxicity occurs under iron-overloaded settings, such as a high iron diet and blood transfusion, and damages important organs. Vanillin has been proven to have potential iron chelation capability. Given the negative effects of commonly used iron chelators like deferoxamine (DFO), we sought to examine the iron chelation potency of vanillin and evaluate its potential effect in the treatment of iron overload-related disorders. METHODS: 42 male NMRI mice were prepared for this purpose, and except for the negative control group, iron overload conditions were generated in them by injecting iron. Then normal saline (as a control), vanillin, and DFO (n = 7) were subsequently given to iron-overloaded mice. In the following, the activity of antioxidant enzymes catalase and superoxide dismutase were measured in the blood serum, brain, kidney, spleen, lung, and liver tissues of mice. Furthermore, the level of lipid peroxidation was determined by measuring the amount of malondialdehyde. Also, Perl's and H&E staining were used to examine the physiopathology changes of tissues. FINDINGS: Vanillin, a natural antioxidant compound, outperformed deferoxamine, a chemical iron chelator. Along with a decrease in iron content, the activity of catalase and superoxide dismutase enhanced in the iron-overloaded groups that were treated with vanillin. The level of lipid peroxidation was also declined in the iron-overloaded mice receiving vanillin. CONCLUSION: Vanillin can be used as a suitable substitute for chemical chelators with fewer side effects and equivalent efficiency. We encourage the use of this compound as a natural iron chelator following performing additional safety and efficacy studies.

Adherence to Iron Chelation Therapy Among Children with Beta Thalassemia Major: A Multicenter Cross-Sectional Study.

BACKGROUND: Adherence to iron chelation therapy (ICT) remains an issue among thalassemia patients. This study aimed to determine the prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia and the factors associated with it. METHODS: This was a cross-sectional study conducted between November 2019 and November 2021 at seven tertiary hospitals in Malaysia. Participants registered with Malaysian Thalassemia Registry were recruited by convenience sampling. Adherence was measured via pill count and self-reported adherence. Knowledge about thalassemia and ICT was measured using a questionnaire from Modul Thalassemia by Ministry of Health of Malaysia. A decision tree was used to identify predictors of non-adherence. RESULTS: A total of 135 patients were recruited. The prevalence of non-adherence to ICT in those who took subcutaneous ± oral medications was 47.5% (95% CI: 31.5%, 63.9%) and the prevalence of non-adherence to ICT in those who took oral medications only was 21.1% (95% CI: 13.4%, 30.6%). The median knowledge score was 67.5% (IQR 15%). A decision tree has identified two factors associated with non-adherence. They were ICT's route of administration and knowledge score. Out of 100 patients who were on oral medications only, 79 were expected to adhere. Out of 100 patients who were on subcutaneous ± oral medications and scored less than 56.25% in knowledge questionnaire, 86 were expected to non-adhere. Based on the logistic regression, the odds of non-adherence in patients who took oral medications only was 71% lower than the odds of non-adherence in patients who took subcutaneous ± oral medications (OR = 0.29; 95% CI = 0.13, 0.65; p = .002). CONCLUSION: The prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia was 20/95 (21.1%) in those who took oral medications only and the prevalence of non-adherence was 19/40 (47.5%) in those who took subcutaneous ± oral medications. The factors associated with non-adherence were ICT's route of administration and knowledge score.

Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds.

Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc- system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis' involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.