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PloS One 2021There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major...
There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1-18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866-8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5-53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33-195), 130 (range:17-1012) and 147 (range:27.7-1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37-182), target ferritin level of <300ng/ml was achieved in 59(40%) while a level <500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months of IRT (range: 3-136). Patients in class III risk category and higher starting serum ferritin levels (>2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload.
Topics: Adolescent; Allografts; Benzoates; Child; Child, Preschool; Deferasirox; Female; Ferritins; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Iron; Iron Chelating Agents; Iron Overload; Male; Phlebotomy; Triazoles; beta-Thalassemia
PubMed: 33481797
DOI: 10.1371/journal.pone.0238793 -
Mediterranean Journal of Hematology and... 2020The Iron chelation is essential to prevent iron overload damage of vital organs, like heart, liver, and endocrine glands, in patients with transfusion-dependent...
OBJECTIVE
The Iron chelation is essential to prevent iron overload damage of vital organs, like heart, liver, and endocrine glands, in patients with transfusion-dependent thalassemia. The most common chelation regimens for β-thalassemia major (β-TM) patients used in China are a combination therapy of deferoxamine and deferiprone (DFO+DFP), deferoxamine (DFO) monotherapy, deferiprone (DFP) monotherapy and deferasirox (DFX) monotherapy. Such patients use iron chelators their whole lives, resulting in enormous treatment costs. This study analyses the cost-utility of these four regimens from the Chinese healthcare system perspective.
METHODS
A Markov decision model was used over a 5-year time horizon and was populated using clinical data from a systematic literature review. We obtained utility data from local and previous research. Costs were estimated using Chinese national sources.
RESULTS
From the base-case analysis results, DFP was the most cost-effective chelation regimen, followed by DFO, DFX, and DFO+DFP. DFP had 97.32%, 99.43%, and 58.04% likelihood of being cost-effective versus DFX, DFO+DFP, and DFO, respectively, at a payment threshold of 193,932.00 CNY/QALY (QALY, quality-adjusted life-year).
CONCLUSIONS
DFP was the most cost-effective chelation regimen for β-TM patients, followed by DFO, DFX, and DFO+DFP. Using DFP as the primary treatment regimen may potentially result in cost-savings and QALY gains for the Chinese healthcare system. To increase these benefits, the Chinese government should take measures to lower DFX and DFO drug costs, and Chinese clinicians should choose the cheaper DFX and DFO, increase the utility of DFO+DFP and reduce mortality and morbidity of DFP. Changes in influential parameters easily affect the results of DFX versus DFO+DFP and of DFP versus DFO; clinicians should focus on such parameters and adjust the regimens accordingly.
PubMed: 32395218
DOI: 10.4084/MJHID.2020.029 -
PeerJ 2023Recent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death-ferroptosis. This form of cell death is associated...
BACKGROUND
Recent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death-ferroptosis. This form of cell death is associated with a variety of diseases, including type 2 diabetes. We hypothesize that iron overload may play a role in driving glucose metabolism abnormalities by inducing endoplasmic reticulum stress that mediates ferroptosis in islet β cells. In this study, we tested this conjecture from and experiments.
METHODS
We established a mouse iron overload model by intraperitoneal injection of iron dextrose (50 mg/kg) and an iron overload cell model by treating MIN6 cells with ferric ammonium citrate (640 μmol/L, 48 h) . The iron deposition in pancreatic tissue was observed by Prussian blue staining, and the pathological changes in pancreatic tissues by HE staining and the protein expression level by pancreatic immunohistochemistry. In the cellular experiments, we detected the cell viability by CCK8 and observed the cellular ultrastructure by transmission electron microscopy. We also used MDA and ROS kits to detect the level of oxidative stress and lipid peroxidation in cells. Western blotting was performed to detect the expression levels of target proteins.
RESULTS
Iron overload induces MIN6 cell dysfunction, leading to increased fasting blood glucose, impaired glucose tolerance, and significantly decreased insulin sensitivity in mice. This process may be related to the ferroptosis of islet β cells and the activation of ASK1/P-P38/CHOP signaling pathway.
Topics: Mice; Animals; Ferroptosis; Diabetes Mellitus, Type 2; Iron Overload; Iron; Signal Transduction
PubMed: 37090106
DOI: 10.7717/peerj.15206 -
Journal of Ayub Medical College,... 2021Thalassemia major is the severe form of β thalassemia characterized by severe anaemia, hepatosplenomegaly and facioskeletal changes due to increased haemolysis of...
BACKGROUND
Thalassemia major is the severe form of β thalassemia characterized by severe anaemia, hepatosplenomegaly and facioskeletal changes due to increased haemolysis of defective red blood cells. In iron overload states, high levels of iron exceed the iron-carrying capacity of transferrin within the plasma, leading to the formation of nontransferrin-bound iron form. These nontransferrin-bound iron forms can be taken up into cells, including liver, heart, and endocrine cells leading to organ damage. To prevent complications associated with hemosiderosis, iron chelation therapy remains one of the main objectives of clinical management of the patients affected by Thalassemia Major.
METHODS
Thirty-seven patients were enrolled using non randomized convenience sampling technique after the written consent from patients. Patients age 2-30 years were enrolled in this study. Serum Ferritin, ALT, Serum Creatinine were checked at the start of the study, 3 months, 6months and then at the end of the study, i.e., at 9 months of the commencement of the study. They were also assessed for other side effects pertaining to oral tolerability of the drug like vomiting, nausea, GI upset, diarrhoea, urinary complaints or any other subjective complaint.
RESULTS
Of the 37 patients, 20 were male (54.1%) and 17 were female (45.9%). Mean age of the patients was 10.2 years (Min. 3 years, Max 21 years). The average serum Ferritin at baseline was noted as 3440 which increased after a period of 3 months, 6 months and 9 months with average of 3359, 3677 and 4394 respectively. After the period of 9 months largest 95% confidence interval of serum Ferritin levels was observed in the range of 3420.17 to 5368.63. In our study, 17 patients required alternative chelation (46%). These patients needed IV Deferioxamine because of the rising trend of Serum Ferritin after the study.
CONCLUSIONS
From the results of our study, we infer that oral Deferasirox is not an effective iron chelator. If the patients are taking oral deferasirox, their Serum Ferritin should be checked 3 monthlies. The drug is effective only in maintaining Serum Ferritin levels with levels less than 1500ng/ml. Intravenous Deferioxamine still should be preferred over oral iron chelators for effective control of iron overload and its complications.
Topics: Administration, Intravenous; Adolescent; Adult; Benzoates; Child; Child, Preschool; Deferasirox; Erythrocyte Count; Female; Hepatomegaly; Humans; Iron Chelating Agents; Male; Triazoles; Young Adult; beta-Thalassemia
PubMed: 34137530
DOI: No ID Found -
Clinical Ophthalmology (Auckland, N.Z.) 2021The aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the...
BACKGROUND
The aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the onset of ocular alterations and the intake of iron chelating drugs.
METHODS
A prospective cohort study was performed. Eighty-eight patients, composed of children and adults with thalassemia major (TM) who are taking or had taken iron chelating drugs (deferoxamine, deferiprone or deferasirox), have been initially enrolled in the study. The final sample featured 80 patients, including 18 children and 62 adults. These subjects received an eye examination to evaluate intraocular pressure (IOP), best corrected visual acuity (BCVA), the presence of refractive defects, cornea, anterior chamber, lens, fundus oculi, visual field and mean retinal nerve fiber layer (RNFL) thickness. Logistic regression model analysis was performed in order to assess any correlation. In addition, a literature search regarding the relation between iron chelating drugs and ocular adverse events was carried out to compare the results obtained with the evidence in the literature.
RESULTS
Logistic regression did not report a significant correlation between the intake of iron chelating drugs and the onset of anterior ocular segment alterations, lens opacities, retinal diseases, optical neuropathies, astigmatism, visual field and RNFL thickness defects. Logistic regression returned a statistically significant correlation between myopia and iron chelation therapy (p-value 0.04; OR 1.05) and also between presbyopia and total duration of therapy with deferoxamine (p-value 0.03; OR 1.21). Although intraocular pressure levels remained within the normal range, a significant correlation with the length of deferoxamine therapy has been found (p-value 0.002; association coefficient -0.12). A negative correlation between deferiprone and presbyopia has also been observed.
CONCLUSION
Iron chelation therapy is not associated with severe visual function alterations. Limitation of deferoxamine treatment can help prevent ocular complications. Deferiprone and/or deferasirox may be preferable, especially in patients over age 40 years.
PubMed: 34045846
DOI: 10.2147/OPTH.S300974 -
British Journal of Haematology Sep 2022Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available...
Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in β-thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24-h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24-h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones.
Topics: Adult; Calcium; Female; Humans; Hypercalciuria; Kidney Calculi; Prevalence; Risk Factors; beta-Thalassemia
PubMed: 35768889
DOI: 10.1111/bjh.18345 -
World Journal of Hepatology Nov 2021Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson's disease (WD), one of the common... (Review)
Review
Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson's disease (WD), one of the common causes of cirrhosis in children is treated primarily with copper chelating agents like D-penicillamine and trientine. D-Penicillamine though widely used due its high efficacy in hepatic WD is fraught with frequent adverse effects resulting discontinuation. Trientine, an alternative drug has comparable efficacy in hepatic WD but has lower frequency of adverse effects. The role of ammonium tetra-thiomolybdate is presently experimental in hepatic WD. Indian childhood cirrhosis is related to excessive copper ingestion, rarely seen in present era. D-Penicillamine is effective in the early part of this disease with reversal of clinical status. Iron chelators are commonly used in secondary hemochromatosis of liver in hemolytic anemias. There are strict chelation protocols during bone marrow transplant. The role of iron chelation in neonatal hemochromatosis is presently not in vogue due to its poor efficacy and availability of other modalities of therapy. Hereditary hemochromatosis is rare in children and the use of iron chelators in this condition is limited.
PubMed: 34904029
DOI: 10.4254/wjh.v13.i11.1552 -
Transplantation and Cellular Therapy Jan 2023During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT), non-transferrin-bound iron and its chelatable form, labile plasma... (Observational Study)
Observational Study
During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT), non-transferrin-bound iron and its chelatable form, labile plasma iron (LPI), regularly appear in the blood of patients at high levels of transferrin saturation (TfS). As these free iron species potentially favor infection and mediate transplantation-associated toxicities, chelation therapy could be an approach to improve outcome after transplantation. However, data addressing iron chelation in the immediate peritransplantation period are sparse. In this study, we investigated the influence of iron chelation with deferasirox during conditioning chemotherapy on the appearance of LPI, the incidence of infection and toxicities, and the tolerability of this treatment in the peritransplantation period. We conducted this single-center prospective observational study in 25 adults with iron overload (serum ferritin >1000 µg/L) undergoing allogeneic HSCT after myeloablative busulfan-based conditioning chemotherapy. Patients received iron chelation with deferasirox (14 mg/kg) from the start of conditioning until day 3 post-transplantation. Iron parameters, including LPI, were obtained at the chelator's trough level daily until day 0 and then on days 4, 7, and 14. Data on infection (bacteremia or invasive fungal disease) and toxicity, as well as the tolerability of deferasirox, were collected until the end of the follow-up period on day 28. Data were analyzed descriptively. TfS levels exceeded 70% in median on 6 days (range, 4 to 10 days) and in 63.6% (range, 36.4% to 90.9%) of the samples per patient, although in 19 of 25 patients (76%), no elevated LPI values were detected during the intake of deferasirox despite high TfS levels. Only 6 patients (24%) showed mildly increased LPI values (≤0.5 units) during the intake of deferasirox, 3 of whom had presented with elevated LPI values before the start of conditioning. Deferasirox was well tolerated, and no aggravation of toxicities was observed. Infection occurred in 5 patients (20%), including 3 of the 6 patients with elevated LPI values despite chelation therapy. In the present study, we demonstrate that iron chelation with deferasirox safely suppresses the appearance of LPI and might decrease the incidence of infection, whereas the impact on transplantation-associated toxicities remains to be elucidated.
Topics: Adult; Humans; Iron; Deferasirox; Ferritins; Iron Chelating Agents; Hematopoietic Stem Cell Transplantation
PubMed: 36241148
DOI: 10.1016/j.jtct.2022.10.002 -
Toxicological Research Apr 2023The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with...
The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD. Although repression of iron accumulation and oxidative stress in brains has been implicated in their marked neuroprotective potential, molecular mechanisms of iron chelator's neuroprotective function are largely unexplored. Here, we show that the iron chelator deferasirox provides cytoprotection against oxidative stress through enhancing parkin expression under basal conditions. Parkin expression is required for cytoprotection against oxidative stress in SH-SY5Y cells with deferasirox treatment as confirmed by abolished deferasirox's cytoprotective effect after parkin knockdown by shRNA. Similar to the previously reported parkin inducing compound diaminodiphenyl sulfone, deferasirox-mediated parkin expression was induced by activation of the PERK-ATF4 pathway, which is associated with and stimulated by mild endoplasmic reticulum stress. The translational potential of deferasirox for PD treatment was further evaluated in cultured mouse dopaminergic neurons. There was a robust ATF4 activation and parkin expression in response to deferasirox treatment in dopaminergic neurons under basal conditions. Consequently, the enhanced parkin expression by deferasirox provided substantial neuroprotection against 6-hydroxydopamine-induced oxidative stress. Taken together, our study results revealed a novel mechanism through which an iron chelator, deferasirox induces neuroprotection. Since parkin function in the brain is compromised in PD and during aging, maintenance of parkin expression through the iron chelator treatment could be beneficial by increasing dopaminergic neuronal survival.
PubMed: 37008698
DOI: 10.1007/s43188-022-00157-x -
Life (Basel, Switzerland) Jan 2021Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course...
Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine-DFO; deferiprone-DFP; and deferasirox-DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.
PubMed: 33466819
DOI: 10.3390/life11010057