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European Journal of Haematology Sep 2018Effective iron chelation therapy is an important part of treatment in patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes (MDS).... (Review)
Review
Effective iron chelation therapy is an important part of treatment in patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion-dependent thalassaemia or lower-risk MDS showed better adherence to the deferasirox film-coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion-dependent thalassaemia and lower-risk MDS.
Topics: Blood Transfusion; Chelation Therapy; Deferasirox; Disease Management; Humans; Iron Chelating Agents; Iron Overload; Liver Function Tests; Medication Adherence; Myelodysplastic Syndromes; Thalassemia; Treatment Outcome
PubMed: 29904950
DOI: 10.1111/ejh.13111 -
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 -
Frontiers in Pharmacology 2023Deferasirox is an iron-chelating agent prescribed to patients with iron overload. Due to the interindividual variability of deferasirox responses reported in various...
Deferasirox is an iron-chelating agent prescribed to patients with iron overload. Due to the interindividual variability of deferasirox responses reported in various populations, this study aims to determine the genetic polymorphisms that influence drug responses. A systematic search was performed from inception to March 2022 on electronic databases. All studies investigating genetic associations of deferasirox in humans were included, and the outcomes of interest included pharmacokinetics, efficacy, and adverse drug reactions. Fixed- and random-effects model meta-analyses using the ratio of means (ROM) were performed. Seven studies involving 367 participants were included in a meta-analysis. The results showed that subjects carrying the A allele (AG/AA) of rs2273697 had a 1.23-fold increase in deferasirox C (ROM = 1.23; 95% confidence interval [CI]:1.06-1.43; = 0.007) and a lower Vd (ROM = 0.48; 95% CI: 0.36-0.63; < 0.00001), compared to those with GG. A significant attenuated area under the curve of deferasirox was observed in the subjects with rs3806596 AG/GG by 1.28-fold (ROM = 0.78; 95% CI: 0.60-0.99; = 0.04). In addition, two SNPs of were also associated with the decreased C: rs2248359 CC (ROM = 0.50; 95% CI: 0.29-0.87; = 0.01) and rs2585428 GG (ROM = 0.47; 95% CI: 0.35-0.63; < 0.00001). Only rs2248359 CC was associated with decreased C (ROM = 0.26; 95% CI: 0.08-0.93; = 0.04), while rs2585428 GG was associated with a shorter half-life (ROM = 0.44; 95% CI: 0.23-0.83; = 0.01). This research summarizes the current evidence supporting the influence of variations in genes involved with drug transporters, drug-metabolizing enzymes, and vitamin D metabolism on deferasirox responses.
PubMed: 37261288
DOI: 10.3389/fphar.2023.1069854 -
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 -
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 -
Pediatric Nephrology (Berlin, Germany) Jul 2022
PubMed: 35084566
DOI: 10.1007/s00467-021-05415-y -
Hematology/oncology Clinics of North... Apr 2023Conventional therapy for severe thalassemia includes regular red cell transfusions and iron chelation therapy to prevent and treat complications of iron overload. Iron... (Review)
Review
Conventional therapy for severe thalassemia includes regular red cell transfusions and iron chelation therapy to prevent and treat complications of iron overload. Iron chelation is very effective when appropriately used, but inadequate iron chelation therapy continues to contribute to preventable morbidity and mortality in transfusion-dependent thalassemia. Factors that contribute to suboptimal iron chelation include poor adherence, variable pharmacokinetics, chelator adverse effects, and difficulties with precise monitoring of response. The regular assessment of adherence, adverse effects, and iron burden with appropriate treatment adjustments is necessary to optimize patient outcomes.
Topics: Humans; beta-Thalassemia; Iron Chelating Agents; Deferiprone; Deferoxamine; Pyridones; Iron Overload; Thalassemia; Iron
PubMed: 36907610
DOI: 10.1016/j.hoc.2022.12.013 -
Journal of the American Heart... Jan 2024Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial...
BACKGROUND
Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury.
METHODS AND RESULTS
The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R.
CONCLUSIONS
Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.
Topics: Mice; Animals; Cyclosporine; Myocardial Reperfusion Injury; Deferasirox; Ferroptosis; Ventricular Remodeling; Myocytes, Cardiac; Myocardial Infarction; Reperfusion Injury; Iron; Hypoxia; Iron Overload; Myocardial Ischemia
PubMed: 38158218
DOI: 10.1161/JAHA.123.031219 -
Blood Reviews Nov 2018Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone... (Review)
Review
Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment.
Topics: Anemia, Aplastic; Animals; Bone Marrow; Bone Marrow Cells; Cellular Microenvironment; Disease Susceptibility; Hematopoietic Stem Cells; Humans; Iron; Iron Chelating Agents; Iron Overload; Myelodysplastic Syndromes; Primary Myelofibrosis
PubMed: 29699840
DOI: 10.1016/j.blre.2018.04.004 -
Frontiers in Bioscience (Elite Edition) Jul 2022Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of... (Review)
Review
Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.
Topics: Benzoates; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Pyridones; Risk Assessment; Thalassemia; Triazoles
PubMed: 36137990
DOI: 10.31083/j.fbe1403018