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Health and Quality of Life Outcomes Feb 2024Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically... (Review)
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.
Topics: Humans; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Quality of Life; Pyridones; Benzoates; Triazoles; Thalassemia; Chelation Therapy; Ferritins; Outcome Assessment, Health Care
PubMed: 38302961
DOI: 10.1186/s12955-023-02221-y -
Ecotoxicology and Environmental Safety Mar 2024Deferiprone, generally, is considered an important chelating agent for Fe overload. From a literature data analysis, a lack of information on the interaction of this...
Deferiprone, generally, is considered an important chelating agent for Fe overload. From a literature data analysis, a lack of information on the interaction of this molecule toward a series of metal cations emerged, inducing to fill out the topic. The complexing ability of deferiprone toward Ca, Mg, Cd and Pb was studied by potentiometry and H NMR spectroscopy, in KCl aqueous solutions at different ionic strength values (0.1 ≤ I/mol dm ≤ 1.0) and T = 298.15 K. The same speciation model featured by the ML, ML, ML and ML(OH) (M = metal and L = deferiprone or DFP) species was obtained for Cd and Pb; the formation constants calculated at infinite dilution are: logβ = 7.23±0.02, 12.47±0.03, 16.70±0.04, and -2.53±0.04, respectively for Cd and 9.91±0.01, 15.99±0.02, 19.93±0.05 and 0.99±0.02 for Pb. Only two species, namely ML and ML, were determined for Ca and Mg, whose formation constants at infinite dilution are respectively: 3.72±0.01 and 6.50±0.02, for the first one, 5.31±0.01 and 9.58±0.01, for the second. The ligand sequestering ability and affinity toward M were evaluated by determining the pL and pM parameters at different pHs and ionic strengths. The results suggest that deferiprone has the best complexing and sequestering ability toward Pb, followed by Cd, Mg and Ca, respectively. H NMR studies confirmed the DFP affinity for Cd and Pb, and in combination with DFT calculations showed that metal cations are bound to the hydroxo-oxo moiety of the pyridinone ring. The data reported in this study provide information on the possible employment of a small molecule like deferiprone, as a chelating and sequestering agent for Pb accumulation or overload from environmental and biological matrices.
Topics: Deferiprone; Cadmium; Lead; Cations; Models, Theoretical; Chelating Agents
PubMed: 38295733
DOI: 10.1016/j.ecoenv.2024.116027 -
MedComm Feb 2024The use of radiolabeled cells for positron emission tomography (PET) imaging tracking has been a promising approach for monitoring cell-based therapies. However, the...
The use of radiolabeled cells for positron emission tomography (PET) imaging tracking has been a promising approach for monitoring cell-based therapies. However, the presence of free radionuclides released from dead cells during tracking can interfere with the signal from living cells, leading to inaccurate results. In this study, the effectiveness of the iron chelators deferoxamine (DFO) and deferiprone in removing free radionuclides Zr and Ga, respectively, was demonstrated in vivo utilizing PET imaging. The use of DFO during PET imaging tracking of Zr-labeled mesenchymal stem cells (MSCs) significantly reduced uptake in bone while preserving uptake in major organs, resulting in more accurate and reliable tracking. Furthermore, the clearance of free Zr in vivo resulted in a significant reduction in radiation dose from Zr-labeled MSCs. Additionally, the avoidance of free radionuclide accumulation in bone allowed for more precise observation of the homing process and persistence during bone marrow transplantation. The efficacy and safety of this solution suggest this finding has potential for widespread use in imaging tracking studies involving various cells. Moreover, since this method employed iron chelator drugs in clinical use, which makes it is a good prospect for clinical translation.
PubMed: 38292327
DOI: 10.1002/mco2.473 -
ELife Dec 2023Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly...
Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether the treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin levels decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones and and increased ferritin stores in late-stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS.
Topics: Humans; Mice; Animals; Erythropoiesis; Deferiprone; Anemia; Iron Overload; Iron; Mice, Transgenic; Ferritins; Iron Chelating Agents
PubMed: 38153418
DOI: 10.7554/eLife.83103 -
International Journal of Molecular... Nov 2023The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols... (Review)
Review
The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.
Topics: Humans; Deferiprone; Deferoxamine; Pyridones; Iron Chelating Agents; Iron Overload; Chelation Therapy; Iron; beta-Thalassemia; Drug Therapy, Combination
PubMed: 38069073
DOI: 10.3390/ijms242316749 -
Cureus Nov 2023Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an... (Review)
Review
Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an optimal chelating regimen. Deferasirox (DFX) and deferiprone (DFP) are two oral iron chelators, and combination usage demonstrated effectiveness as an alternative to monotherapies in patients with a limited response to monotherapy. The present systematic review aimed to assess the evidence regarding the outcomes of combined DFP and DFX in iron-overloaded patients. An online search was conducted in PubMed, Scopus, Web of Science, and CENTRAL databases. Interventional and observational studies that assessed the outcomes of combined DFP and DFX in iron-overloaded patients were included. Eleven studies (12 reports) were considered in this meta-analysis. The studies included dual iron chelation strategies for a number of diagnoses. Single-arm studies (n =7) showed a reduction of serum ferritin, which reached the level of statistical significance in three studies. Likewise, most studies reported a numerical reduction in liver iron concentration (LIC) and increased cardiac MRI-T2* values after chelating therapy. Alternatively, comparative studies showed no significant difference in post-treatment serum ferritin between DFX plus DFP and DFX/DFP plus deferoxamine (DFO). The adherence to combination therapy was good to average in nearly 66.7-100% of the patients across four studies. One study reported a poor adherence rate. The combined regimen was generally tolerable, with no reported incidence of serious adverse events among the included studies. In conclusion, the DFP and DFX combination is a safe and feasible option for iron overload patients with a limited response to monotherapy.
PubMed: 38058350
DOI: 10.7759/cureus.48276 -
Brain & NeuroRehabilitation Nov 2023Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder characterized by progressive motor symptoms, such as dystonia and...
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder characterized by progressive motor symptoms, such as dystonia and spasticity. Classical PKAN is the most common subtype of neurodegeneration with brain iron accumulation (NBIA). Currently, there is no established treatment for PKAN. However, baclofen and botulinum toxin have been reported to improve motor symptoms and ease care in these patients. Additionally, Deferiprone is a well-tolerated iron chelator that has been shown to be effective in reducing brain iron accumulation. In this case report, we present the case of a seven-year-old boy who presented to our ward with spastic gait and extrapyramidal signs. Brain magnetic resonance imaging was performed, which showed features of neurodegeneration secondary to brain iron accumulation with a specific appearance of the eye-of-the-tiger sign. Genetic testing was positive for a homozygous mutation in PANK2, and the diagnosis of early-stage classical PKAN was made. This case report highlights the potent efficacy of baclofen, botulinum toxin, and deferiprone in slowing down the disease progression at an early stage and improving the severity of symptoms.
PubMed: 38047104
DOI: 10.12786/bn.2023.16.e25 -
Biomedicines Nov 2023The transition metal characteristics of iron allow it to play a fundamental role in several essential aspects of human life such as the transport of oxygen through... (Review)
Review
The transition metal characteristics of iron allow it to play a fundamental role in several essential aspects of human life such as the transport of oxygen through hemoglobin or the transport of electrons in the mitochondrial respiratory chain coupled to the synthesis of ATP. However, an excess or deficiency of iron is related to certain pathologies. The maintenance of iron homeostasis is essential to avoid certain pathologies related to iron excess or deficiency. The existence of iron deposits in postmortem tissues of Parkinson's patients has been interpreted as evidence that iron plays a fundamental role in the degenerative process of the nigrostriatal system in this disease. The use of iron chelators has been successful in the treatment of diseases such as transfusion-dependent thalassemia and pantothenate kinase-associated neurodegeneration. However, a clinical study with the iron chelator deferiprone in patients with Parkinson's disease has not shown positive effects but rather worsened clinical symptoms. This suggests that iron may not play a role in the degenerative process of Parkinson's disease.
PubMed: 38002094
DOI: 10.3390/biomedicines11113094 -
Scientific Reports Oct 2023NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms...
NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms of NMDA excitotoxicity will provide further insight into the mechanisms of many retinal diseases. To study mechanisms of NMDA excitotoxicity in vivo, we used an animal model in which NMDA (20 mM, 2 µL) was injected into the vitreous of mice. We also used high-throughput expression profiling, various animals with reduced expression of target genes, and animals treated with the oral iron chelator deferiprone. We found that the expression of many genes involved in inflammation, programmed cell death, free radical production, oxidative stress, and iron and calcium signaling was significantly increased 24 h after NMDA treatment. Meanwhile, decreased activity of the pro-inflammatory TNF signaling cascade and decreased levels of ferrous iron (Fe, required for free radical production) led to significant neuroprotection in NMDA-treated retinas. Since increased TNF signaling activity and high Fe levels trigger regulated necrosis, which, in turn, lead to inflammation, we proposed an important role in NMDA excitotoxicity of a positive feedback loop in which regulated necrosis promotes inflammation, which subsequently triggers regulated necrosis.
Topics: Mice; Animals; N-Methylaspartate; Retina; Retinal Diseases; Necrosis; Iron; Free Radicals; Inflammation
PubMed: 37891222
DOI: 10.1038/s41598-023-45855-0