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1.
BMC Res Notes ; 17(1): 163, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38872196

RESUMO

PURPOSE: This study aimed to evaluate the knowledge, attitude, and practice toward iron chelating agents (ICAs) in Iranian thalassemia major patients. METHODS: A total of 101 patients with thalassemia major were involved in this cross-sectional survey. A deep medication review was done, and participants' knowledge, attitude, and practice were evaluated by a validated instrument based on a 20-scoring system. RESULTS: Statistical analyses showed 52 patients (51.5%) had a poor knowledge level (scores < 10) about their medications, 37 (36.6%) had a moderate level (scores 10-15), and 12 (11.9%) had a satisfactory level (scores > 15). Seventy-seven (76.2%) patients have positive beliefs regarding the dependence of their current health status on taking iron chelators, and 63 (62.4%) believed that they would become very ill without taking medication. The results also showed that the mean practice score in patients who received deferoxamine was 5.81 ± 3.50; in the patients who received deferiprone and those who received deferasirox, the mean scores were 7.36 ± 5.15 and 14.94 ± 4.14. Also, the knowledge and practice level had a direct linear correlation based on the regression analyses (P < 0.001). CONCLUSION: In conclusion, results of the present research suggests that the patients' knowledge about the administration, adverse events, and necessity of ICAs was not satisfactory. Improving the knowledge of thalassemia patients toward their medicines through educational interventions is highly recommended to improve their practice level.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Quelantes de Ferro , Humanos , Quelantes de Ferro/uso terapêutico , Irã (Geográfico) , Masculino , Feminino , Adulto , Estudos Transversais , Adulto Jovem , Adolescente , Talassemia beta/tratamento farmacológico , Talassemia/tratamento farmacológico , Deferiprona/uso terapêutico , Deferasirox/uso terapêutico , Desferroxamina/uso terapêutico , Triazóis/uso terapêutico , Pessoa de Meia-Idade , Piridonas/uso terapêutico
2.
Pediatr Blood Cancer ; 71(8): e31035, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38753107

RESUMO

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.


Assuntos
Transfusão de Sangue , Terapia por Quelação , Quelantes de Ferro , Sobrecarga de Ferro , Talassemia beta , Humanos , Talassemia beta/terapia , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Quelantes de Ferro/uso terapêutico , Criança , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Terapia por Quelação/métodos , Pré-Escolar , Desferroxamina/uso terapêutico , Deferiprona/uso terapêutico , Piridonas/uso terapêutico , Piridonas/efeitos adversos
3.
J Labelled Comp Radiopharm ; 67(8): 280-287, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38744538

RESUMO

A key aspect for the applicability of 89Zr-radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the siderophore desferrioxamine (DFO), Fe-DFO-N-suc-TFP-ester and p-NCS-Bz-DFO, are most often used for clinical 89Zr-immuno-PET. The use of Fe-DFO-N-suc-TFP-ester is advantageous with regard to higher radiolysis stability and more facile assessment of radiochemical purity as well as chelator-to-mAb ratio. However, not all mAbs withstand the Fe-removal step at relatively low pH (4-4.5) using EDTA, which is needed after conjugation to allow 89Zr labeling. In this study, it was investigated whether hydroxybenzyl ethylenediamine (HBED) or the clinically approved deferiprone (DFP) can serve as an alternative for EDTA to establish a pH-independent mild method for Fe-removal and thereby broaden the applicability of Fe-DFO-N-suc-TFP-ester. Carrier-added [59Fe]Fe-DFO-N-suc-TFP-ester was used for mAb modification to enable direct tracking of the Fe-removal efficiency under various conditions. Whereas incomplete Fe-removal with HBED was observed at pH 5 or higher, Fe-removal with DFP was possible at a broad pH range (4-9). This provides a mild, pH-independent method for Fe-removal, improving the applicability and attractiveness of Fe-DFO-N-suc-TFP-ester for 89Zr-mAb preparation.


Assuntos
Desferroxamina , Ferro , Tomografia por Emissão de Pósitrons , Radioisótopos , Zircônio , Zircônio/química , Desferroxamina/química , Radioisótopos/química , Ferro/química , Tomografia por Emissão de Pósitrons/métodos , Piridonas/química , Deferiprona/química , Imunoconjugados/química , Compostos Radiofarmacêuticos/química , Anticorpos Monoclonais/química
4.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731873

RESUMO

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.


Assuntos
Quelantes de Ferro , Sobrecarga de Ferro , Humanos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologia , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/metabolismo , Ferro/metabolismo , Animais , Deferiprona/uso terapêutico , Deferiprona/farmacologia
5.
Blood Cells Mol Dis ; 107: 102859, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38820707

RESUMO

We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.


Assuntos
Transfusão de Sangue , Deferasirox , Deferiprona , Desferroxamina , Quelantes de Ferro , Ferro , Piridonas , Talassemia beta , Humanos , Quelantes de Ferro/uso terapêutico , Talassemia beta/mortalidade , Talassemia beta/terapia , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Feminino , Masculino , Adulto , Estudos Retrospectivos , Desferroxamina/uso terapêutico , Deferiprona/uso terapêutico , Ferro/metabolismo , Deferasirox/uso terapêutico , Piridonas/uso terapêutico , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/tratamento farmacológico , Benzoatos/uso terapêutico , Ferritinas/sangue , Adolescente , Triazóis/uso terapêutico , Adulto Jovem , Criança , Resultado do Tratamento , Pessoa de Meia-Idade , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Estudos de Coortes
8.
Br J Pharmacol ; 181(16): 2833-2850, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38653449

RESUMO

BACKGROUND AND PURPOSE: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. KEY RESULTS: The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. CONCLUSIONS AND IMPLICATIONS: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.


Assuntos
Deferiprona , Eritropoetina , Hematínicos , Hemoglobinas , Ratos Sprague-Dawley , Proteínas Recombinantes , Hemoglobinas/metabolismo , Animais , Eritropoetina/farmacologia , Eritropoetina/administração & dosagem , Ratos , Proteínas Recombinantes/administração & dosagem , Masculino , Deferiprona/farmacologia , Deferiprona/administração & dosagem , Hematínicos/farmacologia , Hematínicos/administração & dosagem , Humanos , Piridonas/farmacologia , Piridonas/administração & dosagem , Ferro/metabolismo , Eritropoese/efeitos dos fármacos , Modelos Biológicos , Hormônios Peptídicos/farmacologia , Hormônios Peptídicos/administração & dosagem
9.
Am J Hematol ; 99(6): 1031-1039, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38429922

RESUMO

Patients with sickle cell disease (SCD) and other anemias who receive blood transfusions are at risk of organ damage due to transfusional iron overload. Deferiprone is an iron chelator with a well-established safety and efficacy profile that is indicated for the treatment of transfusional iron overload. Here, we report safety data from the large-scale, retrospective Ferriprox® Total Care Registry, which involved all patients with SCD taking deferiprone following the 2011 approval of deferiprone in the United States through August 2020. A total of 634 patients who had initiated deferiprone treatment were included. The mean (SD) duration of deferiprone exposure in the registry was 1.6 (1.6) years (range 0 to 9.7 years). In the overall patient population (N = 634), 64.7% (n = 410) of patients reported a total of 1885 adverse events (AEs). In subgroup analyses, 54.6% (n = 71) of pediatric patients and 67.3% (n = 339) of adult patients reported AEs. The most common AEs reported in patients receiving deferiprone were sickle cell crisis (22.7%), nausea (12.1%), vomiting (8.7%), abdominal discomfort (5.4%), and fatigue (5.4%). Neutropenia was reported in four (0.6%) patients and severe neutropenia/agranulocytosis (defined as absolute neutrophil count <0.5 × 109/L) was reported in two (0.3%) patients. Of patients with evaluable data, all cases of neutropenia and severe neutropenia/agranulocytosis resolved with deferiprone discontinuation. Results from the nearly 10 years of real-world data collected in the Ferriprox® Total Care Registry demonstrate that deferiprone is safe and well tolerated in patients with SCD or other anemias who have transfusional iron overload.


Assuntos
Anemia Falciforme , Deferiprona , Quelantes de Ferro , Sistema de Registros , Humanos , Deferiprona/uso terapêutico , Deferiprona/efeitos adversos , Anemia Falciforme/tratamento farmacológico , Masculino , Criança , Adulto , Feminino , Adolescente , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/administração & dosagem , Estudos Retrospectivos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Pré-Escolar , Adulto Jovem , Pessoa de Meia-Idade , Lactente
10.
Adv Sci (Weinh) ; 11(17): e2400862, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38408138

RESUMO

Hematoma, a risk factor of implant-associated infections (IAIs), creates a Fe-rich environment following implantation, which proliferates the growth of pathogenic bacteria. Fe metabolism is a major vulnerability for pathogens and is crucial for several fundamental physiological processes. Herein, a deferiprone (DFP)-loaded layered double hydroxide (LDH)-based nanomedicine (DFP@Ga-LDH) that targets the Fe-rich environments of IAIs is reported. In response to acidic changes at the infection site, DFP@Ga-LDH systematically interferes with bacterial Fe metabolism via the substitution of Ga3+ and Fe scavenging by DFP. DFP@Ga-LDH effectively reverses the Fe/Ga ratio in Pseudomonas aeruginosa, causing comprehensive interference in various Fe-associated targets, including transcription and substance metabolism. In addition to its favorable antibacterial properties, DFP@Ga-LDH functions as a nano-adjuvant capable of delaying the emergence of antibiotic resistance. Accordingly, DFP@Ga-LDH is loaded with a siderophore antibiotic (cefiderocol, Cefi) to achieve the antibacterial nanodrug DFP@Ga-LDH-Cefi. Antimicrobial and biosafety efficacies of DFP@Ga-LDH-Cefi are validated using ex vivo human skin and mouse IAI models. The pivotal role of the hematoma-created Fe-rich environment of IAIs is highlighted, and a nanoplatform that efficiently interferes with bacterial Fe metabolism is developed. The findings of the study provide promising guidance for future research on the exploration of nano-adjuvants as antibacterial agents.


Assuntos
Antibacterianos , Biofilmes , Ferro , Infecções Relacionadas à Prótese , Pseudomonas aeruginosa , Biofilmes/efeitos dos fármacos , Camundongos , Ferro/metabolismo , Animais , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/microbiologia , Deferiprona/farmacologia , Modelos Animais de Doenças , Cefiderocol , Infecções por Pseudomonas/tratamento farmacológico , Humanos , Nanomedicina/métodos
11.
BMJ Open ; 14(2): e077342, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38331857

RESUMO

INTRODUCTION: Despite the improvement in medical management, many patients with transfusion-dependent ß-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent ß-thalassaemia with very high iron overload. METHODS AND ANALYSIS: This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent ß-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals. TRIAL REGISTRATION NUMBER: The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).


Assuntos
Sobrecarga de Ferro , Talassemia beta , Adulto , Adolescente , Humanos , Deferasirox/uso terapêutico , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Talassemia beta/complicações , Talassemia beta/tratamento farmacológico , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Triazóis/efeitos adversos , Piridonas , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Quelantes de Ferro/efeitos adversos , Ferro/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Health Qual Life Outcomes ; 22(1): 14, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38302961

RESUMO

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.


Assuntos
Quelantes de Ferro , Talassemia , Humanos , Quelantes de Ferro/uso terapêutico , Deferasirox , Deferiprona , Desferroxamina/uso terapêutico , Qualidade de Vida , Piridonas/efeitos adversos , Benzoatos/efeitos adversos , Triazóis/efeitos adversos , Talassemia/tratamento farmacológico , Terapia por Quelação , Ferritinas , Avaliação de Resultados em Cuidados de Saúde
13.
CNS Neurosci Ther ; 30(2): e14607, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38334258

RESUMO

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.


Assuntos
Doença de Parkinson , Humanos , Deferiprona/uso terapêutico , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Ferro , Substância Negra
14.
Neuropharmacology ; 246: 109837, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38184274

RESUMO

BACKGROUND: Current antidepressants have limitations due to insufficient efficacy and delay before improvement in symptoms. Polymorphisms of the serotonin transporter (5-HTT) gene have been linked to depression (when combined with stressful life events) and altered response to selective serotonergic reuptake inhibitors. We have previously revealed the antidepressant-like properties of the iron chelator deferiprone in the 5-HTT knock-out (KO) mouse model of depression. Furthermore, deferiprone was found to alter neural activity in the prefrontal cortex of both wild-type (WT) and 5-HTT KO mice. METHODS: In the current study, we examined the molecular effects of acute deferiprone treatment in the prefrontal cortex of both genotypes via phosphoproteomics analysis. RESULTS: In WT mice treated with deferiprone, there were 22 differentially expressed phosphosites, with gene ontology analysis implicating cytoskeletal proteins. In 5-HTT KO mice treated with deferiprone, we found 33 differentially expressed phosphosites. Gene ontology analyses revealed phosphoproteins that were predominantly involved in synaptic and glutamatergic signalling. In a drug-naïve cohort (without deferiprone administration), the analysis revealed 21 differentially expressed phosphosites in 5-HTT KO compared to WT mice. We confirmed the deferiprone-induced increase in tyrosine hydroxylase serine 40 residue phosphorylation (pTH-Ser40) (initially revealed in our phosphoproteomics study) by Western blot analysis, with deferiprone increasing pTH-Ser40 expression in WT and 5-HTT KO mice. CONCLUSION: As glutamatergic and synaptic signalling are dysfunctional in 5-HTT KO mice (and are the target of fast-acting antidepressant drugs such as ketamine), these molecular effects may underpin deferiprone's antidepressant-like properties. Furthermore, dopaminergic signalling may also be involved in deferiprone's antidepressant-like properties.


Assuntos
Antidepressivos , Ferro , Humanos , Animais , Camundongos , Deferiprona , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transdução de Sinais , Quelantes de Ferro/farmacologia , Camundongos Knockout
15.
Exp Neurol ; 374: 114703, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38281588

RESUMO

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.


Assuntos
Barreira Hematoencefálica , Sobrecarga de Ferro , Humanos , Recém-Nascido , Ratos , Animais , Barreira Hematoencefálica/metabolismo , Animais Recém-Nascidos , Ratos Sprague-Dawley , Regulação para Cima , Deferiprona/metabolismo , Deferiprona/farmacologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/metabolismo , Estresse Oxidativo , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Homeostase , Ferritinas/metabolismo , Proteínas de Junções Íntimas/metabolismo
16.
Ecotoxicol Environ Saf ; 272: 116027, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38295733

RESUMO

Deferiprone, generally, is considered an important chelating agent for Fe3+ 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 Ca2+, Mg2+, Cd2+ and Pb2+ was studied by potentiometry and 1H NMR spectroscopy, in KCl aqueous solutions at different ionic strength values (0.1 ≤ I/mol dm-3 ≤ 1.0) and T = 298.15 K. The same speciation model featured by the ML, ML2, ML3 and ML(OH) (M = metal and L = deferiprone or DFP) species was obtained for Cd2+ and Pb2+; the formation constants calculated at infinite dilution are: logTß = 7.23±0.02, 12.47±0.03, 16.70±0.04, and -2.53±0.04, respectively for Cd2+ and 9.91±0.01, 15.99±0.02, 19.93±0.05 and 0.99±0.02 for Pb2+. Only two species, namely ML and ML2, were determined for Ca2+ and Mg2+, 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 M2+ were evaluated by determining the pL0.5 and pM parameters at different pHs and ionic strengths. The results suggest that deferiprone has the best complexing and sequestering ability toward Pb2+, followed by Cd2+, Mg2+ and Ca2+, respectively. 1H NMR studies confirmed the DFP affinity for Cd2+ and Pb2+, 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 Pb2+ accumulation or overload from environmental and biological matrices.


Assuntos
Cádmio , Chumbo , Deferiprona , Cádmio/química , Cátions , Modelos Teóricos , Quelantes/química
17.
Blood Transfus ; 22(1): 75-85, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37146300

RESUMO

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.


Assuntos
Sobrecarga de Ferro , Talassemia , Talassemia beta , Humanos , Pré-Escolar , Ferro/uso terapêutico , Deferasirox , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Quelantes de Ferro/uso terapêutico , Piridonas/uso terapêutico , Talassemia beta/diagnóstico por imagem , Talassemia beta/tratamento farmacológico , Benzoatos/uso terapêutico , Triazóis/uso terapêutico , Quimioterapia Combinada , Sobrecarga de Ferro/diagnóstico por imagem , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Pâncreas/diagnóstico por imagem
18.
Auris Nasus Larynx ; 51(2): 271-275, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37903661

RESUMO

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.


Assuntos
Sobrecarga de Ferro , Ototoxicidade , Talassemia beta , Adulto , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Talassemia beta/complicações , Talassemia beta/tratamento farmacológico , Talassemia beta/epidemiologia , Deferasirox/uso terapêutico , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/etiologia , Seguimentos , Estudos Retrospectivos , Ototoxicidade/complicações , Ototoxicidade/tratamento farmacológico , Benzoatos/uso terapêutico , Triazóis/uso terapêutico , Piridonas/uso terapêutico , Quelantes de Ferro/uso terapêutico , Ferro/uso terapêutico , Audição
19.
Int J Mol Sci ; 24(23)2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38069073

RESUMO

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.


Assuntos
Sobrecarga de Ferro , Talassemia beta , Humanos , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Piridonas/efeitos adversos , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/induzido quimicamente , Terapia por Quelação/métodos , Ferro/metabolismo , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Quimioterapia Combinada
20.
Elife ; 122023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38153418

RESUMO

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 Pcbp1 and Ncoa4 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.


Assuntos
Anemia , Sobrecarga de Ferro , Humanos , Camundongos , Animais , Eritropoese , Deferiprona , Sobrecarga de Ferro/complicações , Ferro , Camundongos Transgênicos , Ferritinas , Quelantes de Ferro/farmacologia
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