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Key Points: Question: Does therapy with edetate disodium (EDTA)–based chelation reduce major adverse cardiovascular events compared with placebo infusions among patients with diabetes and prior myocardial infarction (MI)? Findings: EDTA-based chelation did not reduce major adverse cardiovascular events compared with placebo infusion, with a hazard ratio of 0.93 (95% CI, 0.76-1.16; P =.53). Chelation infusions did reduce the median blood lead levels from 9.0 μg/L at baseline to 3.5 μg/L at infusion 40 (P <.001). Meaning: Among patients with diabetes and prior MI, EDTA-based chelation decreased median blood lead levels by 61% from baseline but did not reduce major adverse cardiovascular events. Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)–based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI). Objective: To replicate the finding of TACT in individuals with diabetes and previous MI. Design, Setting, and Participants: A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons. Interventions: Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study. Main Outcomes and Measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion. Results: Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P =.53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 μg/L at baseline to 3.46 μg/L at infusion 40 (P <.001). Corresponding levels in the placebo group were 9.3 μg/L and 8.7 μg/L, respectively. Conclusions and Relevance: Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI. Trial Registration: ClinicalTrials.gov Identifier: NCT02733185 This randomized clinical trial assesses whether edetate disodium–based chelation infusions decrease cardiovascular disease events compared with placebo among patients with diabetes and prior myocardial infarction. [ABSTRACT FROM AUTHOR]

BackgroundAimMethodsResultsConclusionWilson disease is an autosomal recessive disorder owing to defective copper metabolism which causes abnormal accumulation of copper and damage to the liver, brain, kidneys and other organs.To describe the clinical features, laboratory investigations and outcome of Wilson disease in children.A retrospective observational study was conducted in the paediatric department of a tertiary- care hospital in South India by reviewing medical records between January 2018 and March 2023. The diagnosis of Wilson disease was confirmed by the presence of low serum ceruloplasmin and/or high urine copper excretion in combination with clinical and ophthalmological features.A total of 32 cases were analysed. The mean (SD) age at presentation was 110 (36) months with a M:F ratio of 1.6:1. Isolated hepatic involvement was seen in 19 (60%) patients while 13 (40%) patients had a neurological presentation, either as an isolated entity or in combination with hepatic manifestations. Low serum ceruloplasmin levels were detected in 31 (96%) patients. Urine copper levels were elevated in all patients. Twenty-one patients were commenced on D penicillamine while 11 patients were treated with a combination chelation therapy with zinc. Eighteen patients (56%) were on regular follow-up.The clinical presentation of Wilson disease in children is diverse, varying from the more common hepatic or neurological manifestations to the less common atypical forms of the disease. Diagnosis is based on clinical and ophthalmological features in combination with biochemical abnormalities in the form of low ceruloplasmin and high urinary copper. The majority of patients can be medically managed with chelation therapy. [ABSTRACT FROM AUTHOR]

\nObjectives: This study aimed to evaluate the distribution of genotypes and iron metabolism imbalance in transfusion-dependent thalassemia patients. Methods: Genotype analysis was conducted on 84 thalassemia patients requiring transfusion, and retrospective analysis of iron overload was performed on 48 transfusion-dependent patients. Results: Among the 84 thalassemia cases requiring transfusion, six mutations of α-thalassemia were identified, including --SEA, αCS, -α3.7, -α4.2, αQS, and αWS. Nine mutations of β-thalassemia were also found, with CD41-42 being the most common. Of the 48 transfusion-dependent patients, 40 (83.3%) had iron overload with serum ferritin (SF) levels above 1,000 ng/mL. The recent SF level was lower than 3 years ago, but the overall ferritin level remains elevated. Conclusions: β-thalassemia was the predominant type among transfusion-dependent thalassemia patients, with CD41-42/-28, CD41-42/IVS-II-654, and CD17/IVS-II-654 being the most common genotypes. Proper blood transfusion and iron chelation therapy are essential for managing transfusion-dependent thalassemia. While some patients show a reduction in SF levels after 3 years of treatment, there are still individuals who exhibit elevated levels necessitating ongoing management. This study is a retrospective research that investigates the genotype distribution and iron metabolic imbalance in thalassemia patients requiring blood transfusion. Eighty-four thalassemia patients needing transfusion were enrolled in the study and underwent genotype analysis. Among these patients, 56 were transfusion-dependent and 28 were non-transfusion-dependent. Of the 56 transfusion-dependent patients, 48 were observed for 3 years, and their iron overload status was analyzed in this study. Our research found that among the 84 thalassemia patients needing transfusion, there were six types of α-thalassemia deletions and nine types of β-thalassemia mutations. Among the 56 transfusion-dependent patients, three types of α-thalassemia genotypes and 15 types of β-thalassemia genotypes were identified. Among the 48 transfusion-dependent thalassemia patients observed for 3 years, 40 patients exhibited iron overload with SF levels exceeding 1,000 ng/mL. The recent SF levels were lower than those 3 years ago. Our study found that β-thalassemia is the most common type of transfusion-dependent thalassemia. Standard blood transfusion and iron chelation therapy are necessary for transfusion-dependent thalassemia patients. While some patients show a reduction in SF levels after 3 years of treatment, there are still individuals who exhibit elevated levels necessitating ongoing management. [ABSTRACT FROM AUTHOR]

Systematic transfusions coupled with iron chelation therapy have substantially improved the life expectancy of thalassemia patients in developed nations. As the human organism does not have a protective mechanism to remove excess iron, iron overload is a significant concern in thalassemia, leading to organ damage, especially in the heart and liver. Thus, iron chelation therapy is crucial to prevent or reverse organ iron overload. There are three widely used iron chelators, either as monotherapy or in combination. The choice of iron chelator depends on several factors, including local guidelines, drug availability, and the individual clinical scenario. Despite treatment advancements, challenges persist, especially in resource-limited settings, highlighting the need for improved global healthcare access. This review discusses clinical management, current treatments, and future directions for thalassemia, focusing on iron overload and its complications. Furthermore, it underscores the progress in transforming thalassemia into a manageable chronic condition and the potential of novel therapies to further enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Background. Patients with β‐thalassemia major depend on lifelong transfusion, resulting in tissue iron overload. This longitudinal retrospective observational study aims to assess myocardial and liver iron overload using magnetic resonance imaging (MRI) and investigate the lag between myocardial and liver iron unloading in β‐thalassemia patients undergoing chelation therapy. Methods. Beta‐thalassemia major patients with at least two MRI studies between 2016 and 2020 were enrolled. Myocardial and liver iron overload were defined as T2∗ less than 20 and 2.1, respectively. Outcomes included mortality, myocardial and liver T2∗ changes, and systolic dysfunction assessed by cardiac MRI. Results. Fifty‐five patients with a mean age of 24.62 ± 7.94 years, a mean follow‐up duration of 24.3 ± 12.9 months, and a mean ferritin level of 1475.75 ± 771.12 ng/mL were enrolled. All of the abovementioned patients only took deferoxamine as the iron‐chelating medication. Mortality occurred in three patients (5.5%) during follow‐up. Liver T2∗ significantly increased (p value <0.05), while myocardial T2∗ showed a nonsignificant increase. Iron unloading of the myocardium was not significantly different from that of the liver and did not result in a significant lag (56% vs. 44%; p value = 0.419). Baseline myocardial T2∗ correlated with extramedullary hematopoiesis, weekly number of deferoxamine injections (p value <0.01), timing between the transfusions, and serum ferritin (p value <0.05). Conclusion. Liver T2∗ reduced during deferoxamine chelation therapy, while myocardial T2∗ remained unchanged. No significant lag was observed between myocardial and liver iron unloading. Further studies are required to elucidate these findings. [ABSTRACT FROM AUTHOR]

Primary Familial Intrahepatic Cholestasis type 3 is an exceedingly rare genetic cholestatic disorder characterized by the defective hepatocanaliculr bile acid transport leading to progressive liver disease. In this case report, we describe the course of treatment for a 12-year-old kid diagnosed with Wilson disease based on Leipzig score and copper investigations. The child did not improve with chelation therapy and was subsequently genetically classified as PFIC-3. This case highlighted the caveats in Wilson disease diagnostic scoring system. The diagnostic odyssey, therapeutic interventions, and outcome of this case underscore the intricate interplay between clinical suspicion, investigative strategies, and the pivotal role of genetic testing to elucidate rare liver disorders in children. [ABSTRACT FROM AUTHOR]

Background: Thalassemia is a genetic blood disorder in children that results in the production of abnormal hemoglobin, leading to severe anemia and the need for frequent blood transfusions. Without proper management, these transfusions can cause iron overload in the body, which can damage vital organs such as the heart and liver. Therapy with oral iron chelators is crucial for these children, as it helps to remove the excess iron and prevent potential complications. The aim of this study was to assess and compare the effectiveness and safety of oral iron chelators, both when administered alone and in combination, in children with thalassemia who receive several blood transfusions. Materials and Methods: The study was carried out in the Department of Pediatrics, Sri Balaji Medical College and Hospital, over a period of ¬¬¬¬24 months. The study included 75 children with thalassemia who had undergone several transfusions and were receiving daily treatment with iron chelation. Results: The current study included 75 children with thalassemia who had received multiple blood transfusions. For duration of 12 months, they received daily iron chelation therapy with either deferiprone alone (Group 1), deferasirox alone (Group 2), or a combination of the two (Group 3). The serum ferritin levels were found to be reduced in all 3 groups, however the difference was not significant. The hepatic T2- MRI values had increased from baseline to folloup, however the difference was significant only in Group 3. The reduction of cardiac T2* MRI value was significantly reduced in Group 3 from baseline to follow-up. Conclusion: This study concluded that deferiprone and deferasirox were effective and safe when administered alone in children with thalassemia who had received several transfusions. [ABSTRACT FROM AUTHOR]

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent β-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time. [ABSTRACT FROM AUTHOR]

Arsenic (As) poisoning has become a global public problem threatening human health. Chelation therapy (CT) is the preferred treatment for arsenic poisoning. Nevertheless, efficient and safe arsenic removal in vivo remains a daunting challenge due to the limitations of chelators, including weak affinity, poor cell membrane penetration, and short half-life. Herein, a mercapto-functionalized and size-tunable hierarchical porous Zr-MOF (UiO-66-TC-SH) is developed, which possesses abundant arsenic chemisorption sites, effective cell uptake ability, and long half-life, thereby efficiently removing toxic arsenic in vivo. Moreover, the strong binding affinity of UiO-66-TC-SH for arsenic reduces systemic toxicity caused by off-target effects. In animal trials, UiO-66-TC-SH decreases the blood arsenic levels of acute arsenic poisoning mice to a normal value within 48 h, and the efficacy is superior to clinical drugs 2,3-dimercaptopropanesulfonic acid sodium salt (DMPS). Meanwhile, UiO-66-TC-SH also significantly mitigates the arsenic accumulation in the metabolic organs of chronic arsenic poisoning mice. Surprisingly, UiO-66-TC-SH also accelerates the metabolism of arsenic in organs of tumor-bearing mice and alleviates the side effects of arsenic drugs antitumor therapy. Arsenic (As) contamination has become a global problem threatening public health. The present clinical chelation therapy (CT) still has some limitations, including the weak affinity, poor cell membrane permeability and short half-life of hydrophilic chelators. Herein, a metal−organic framework (MOF)-based multieffective arsenic removal strategy in vivo is proposed for the first time. Mercapto-functionalized and size-tunable hierarchical porous Zr-MOF nanoantidote (denoted as UiO-66-TC-SH) is accordingly designed and synthesized. After injection, UiO-66-TC-SH can form Zr− O −As bonds and As− S bonds with arsenic, thus enhancing arsenic adsorption capacity, cycling stability and systemic safety simultaneously. The acute arsenic poisoning model results indicate that UiO-66-TC-SH shows superior efficacy to the clinical drug sodium dimercaptopropanesulfonate (DMPS). More meaningfully, we find that UiO-66-TC-SH also accelerates the metabolism of arsenic in organs of tumor-bearing mice and alleviates side effects of arsenic drugs anti-tumor therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Iron overload is a significant complication commonly observed in individuals with ß-thalassemia, resulting from enhanced iron absorption due to ineffective erythropoiesis and frequent blood transfusions. Iron overload can lead to severe tissue damage and organ dysfunction, significantly impacting the quality of life for those affected. Additionally, recent research indicates that iron overload may also adversely impact mitochondrial function, further exacerbating the pathophysiology of this disease. Excessive iron accumulation in mitochondria can impair the electron transport chain, reduce adenosine tri phosphate synthesis, and increase the generation of reactive oxygen species, resulting in elevated tissue damage and clinical complications. Emerging evidence suggests that specific mitochondrial DNA (mtDNA) mutations may further contribute to the severity of iron overload in ß-thalassemia patients. Currently, the clinical management of iron overload in patients with ß-thalassemia primarily relies on conventional iron chelation therapies, aiming to reduce iron burden and prevent tissue damage. However, cases involving mtDNA mutations introduce additional complexities, necessitating personalized treatment approaches. Advances in gene therapy and mitochondrial replacement strategies offer promising avenues for potential targeted interventions. This review provides a comprehensive overview of the mechanisms underlying iron overload in ß-thalassemia and its association with mtDNA mutations. It discusses the clinical manifestations, diagnostic challenges, and current treatment options for managing iron overload, while also highlighting emerging research directions and potential therapeutic targets for improved patient care. Ultimately, a better understanding of the complex interplay between iron overload and mtDNA mutations in ß-thalassemia will pave the way for innovative strategies to alleviate the disease burden. [ABSTRACT FROM AUTHOR]

Background: β-thalassemia syndromes are a group of hereditary blood diseases characterized by reduced or absent β-globin chain synthesis, resulting in reduced hemoglobin in red blood cells. Pulmonary dysfunction ranging from restrictive to obstructive was reported among those with β- thalassemia. Aim of the work: to evaluate the pulmonary functions in patients with β-thalassemia. Patients and Methods: We conducted a cross-sectional study that included 60 ß-thalassemia patients following up at the Hematology Outpatient Clinic of Cairo University Children’s Hospital. They all underwent assessment of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), maximal expiratory flow (MEF) and peak expiratory flow (PEF) using spirometry and assessment of resistance (R) and reactance (Z) to different frequencies by impulse oscillometry (IOS). Results: The mean ± SD age of the studied group was 10.63 ± 3.53 years. Of them, 32 (53.3%) were females and 28 (46.7%) were males. 39 (65%) were transfusion dependent, 23 (38.3%) were compliant to chelation therapy and only 8 (13.3%) did not need chelation therapy. 30 (50%) patients showed restrictive pattern in spirometry (FVC80%”) and 15 (50%) of them also showed abnormal high impulse IOS to 5 and 20HZ (readings above 150%). The non-compliant patients had airway obstructive pattern by spirometry MEF50 (p=0.075), and higher IOS resistance pattern to R5Hz (p= 0.007), R20Hz (p=0.007) and X5Hz (p= 0.003). Higher airway resistance on IOS (0.0001) was associated with transfusion dependency, and need for chelation therapy (p=0.039). Poor compliance to chelation therapy correlated with spirometry restrictive pattern (p=0.0006). Conclusion: Restrictive lung disease is a common pulmonary dysfunction among children with ß-thalassemia. Compliance to adequate chelation therapy decreases the incidence of pulmonary dysfunction.

Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an "iron-phagy" nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment. Our research applied nanotechnology for constructing an autophagy-inhibition prodrug micelle (HTH)-based nano-delivery system (Dp44mT@HTH), for targeted and controlled release of Dp44mT (an iron chelator), in study of the iron chelation antitumor therapy. We advanced this "iron-phagy" strategy to induce irreversible mitochondrial impairments and toxic stacks via disrupting respiratory chain and inhibiting the autophagy-removal of impaired mitochondria, thus leading to tumor cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Cuproptosis, a newly characterized form of regulated cell death driven by copper accumulation, has emerged as a significant mechanism underlying various non-cancerous diseases. This review delves into the complex interplay between copper metabolism and the pathogenesis of conditions such as Wilson's disease (WD), neurodegenerative disorders, and cardiovascular pathologies. We examine the molecular mechanisms by which copper dysregulation induces cuproptosis, highlighting the pivotal roles of key copper transporters and enzymes. Additionally, we evaluate the therapeutic potential of copper chelation strategies, which have shown promise in experimental models by mitigating copper-induced cellular damage and restoring physiological homeostasis. Through a comprehensive synthesis of recent advancements and current knowledge, this review underscores the necessity of further research to translate these findings into clinical applications. The ultimate goal is to harness the therapeutic potential of targeting cuproptosis, thereby improving disease management and patient outcomes in non-cancerous conditions associated with copper dysregulation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite prolonged life expectancy in patients with beta-thalassemia due to modern chelation therapy and planned blood transfusions, they still suffer from multisystem complications of this chronic hemolytic anemia, including endocrine system dysfunction. Under-recognized parathyroid hormone (PTH) dysfunction in these patients can manifest as bone pain and fractures. OBJECTIVE: The objective of the study was to evaluate PTH in patients with beta-thalassemia >10 years of age. METHODS: A cross-sectional study was performed on 76 randomly selected patients >10 years old with beta-thalassemia (including both thalassemia major and thalassemia intermedia) in the Al-Kut Hereditary Blood Disease Center in Wasit province, Iraq. The study covered the period from November 2021 to April 2022. Data were collected from patients’ files after written consent, including sex, age, ferritin level, mean hemoglobin level, type of chelation therapy, frequency of transfusion, mean calcium level, and whether the patients were splenectomized or not. RESULTS: Of the 76 patients enrolled in the study, 39 (51.3%) were males. There were 63 (82.9%) who had thalassemia major. The majority of cases (n = 55, 71%) were from the age group >15 years. Fifteen (19.7%) patients had low PTH levels. The age group >15 years had a higher frequency of having low PTH levels (P = 0.01 and Pearson factor - 0.29). The study found a positive correlation between low calcium and low PTH levels (P = 0.001, Pearson factor = 0.1). High ferritin levels had no significant correlation with PTH levels (P = 0.4). CONCLUSIONS: Beta-thalassemia patients can have a low PTH level. It can occur more often in patients >15 years old, which necessitates close monitoring for older thalassemia patients. A declining calcium level in these patients can correlate with a low PTH level.

Background Aims: Hepcidin is low in β-thalassemia patients, suggesting a critical role in iron accumulation. Hepcidin has not been assessed in Jordanian thalassemia patients. There is variation in the response of superoxide dismutase (SOD) to iron overload and it has not been correlated with hepcidin. Thus, the aim of this study was to assess serum hepcidin and SOD in patients diagnosed with β-thalassemia intermedia and major, and to examine the correlation between hepcidin and SOD in those patients. Subjects and Methods: Sixty patients with β-thalassemia aged 2–25 years were recruited from the Thalassemia Unit of the Zarqa New Governmental Hospital. The patients were classified according to two forms of thalassemia and assessed for serum levels of hepcidin and SOD. Statistical analysis was performed to investigate the differences between the patients of the two forms, compare the levels of hepcidin and SOD with the normal reference ranges, and calculate their correlation coefficients. Results: The study sample included 31 thalassemia intermedia patients and 29 patients with thalassemia major who are 33 females and 27 males. All patients had significantly deficient hepcidin (2.21±0.16 ng/ml) and increased serum SOD (3.13±0.14 ng/ml) levels compared to normal values. Ferritin was very high (3036.9±309.7 ng/ml) in all patients and highest in adult patients and those with thalassemia major. No significant correlations were found between hepcidin or SOD and ferritin (p> 0.05). Only in child patients was hepcidin positively correlated with SOD (r=0.848, p=0.033). Conclusions: Jordanian β-thalassemia patients had hepcidin deficiency, contributing to iron accumulation. SOD had a significant protective role against oxidation in β-thalassemia. Chelation therapy is inadequate to treat iron overload, which is still the predominant contributor to health complications in thalassemia. Therefore, the use of hepcidin agonists could be a beneficial treatment of excess iron. [ABSTRACT FROM AUTHOR]

Extramedullary hematopoiesis (EMH) serves as a compensatory mechanism in chronic hemolytic anemias, such as thalassemia, and can result in spinal cord compression. This case report highlights a 36-year-old woman with transfusion-dependent β-thalassemia (TDT) who presented with lower extremity motor deficiency, pelvic paresthesia, and bladder dysfunction. The patient had a history of lower back pain, bilateral lower limb weakness, and demonstrated poor compliance with iron chelation therapy. MRI findings indicated spinal cord compression attributable to extramedullary hematopoiesis. Due to the infeasibility of surgical intervention, the patient underwent hypertransfusion and iron chelation therapy. While neurological symptoms improved, urinary retention persisted. The patient continues to receive iron chelation treatment and undergo transfusions. Managing extramedullary hematopoiesis in thalassemia necessitates an individualized treatment approach. [ABSTRACT FROM AUTHOR]

Periodontitis development arises from the intricate interplay between bacterial biofilms and the host's immune response, where macrophages serve pivotal roles in defense and tissue homeostasis. Here, we uncover the mitigative effect of copper chelator Tetrathiomolybdate (TTM) on periodontitis through inhibiting cuproptosis, a newly identified form of cell death which is dependent on copper. Our study reveals concurrent cuproptosis and a macrophage marker within murine models. In response to lipopolysaccharide (LPS) stimulation, macrophages exhibit elevated cuproptosis-associated markers, which are mitigated by the administration of TTM. TTM treatment enhances autophagosome expression and mitophagy-related gene expression, countering the LPS-induced inhibition of autophagy flux. TTM also attenuates the LPS-induced fusion of autophagosomes and lysosomes, the degradation of lysosomal acidic environments, lysosomal membrane permeability increase, and cathepsin B secretion. In mice with periodontitis, TTM reduces cuproptosis, enhances autophagy flux, and decreases Ctsb levels. Our findings underscore the crucial role of copper-chelating agent TTM in regulating the cuproptosis/mitophagy/lysosome pathway during periodontitis inflammation, suggesting TTM as a promising approach to alleviate macrophage dysfunction. Modulating cuproptosis through TTM treatment holds potential for periodontitis intervention. [ABSTRACT FROM AUTHOR]

This paper describes a procedure for the estimation of 241Am and 239Pu activity present in the human tissue by measuring the depth of contaminant using a portable Planar High Purity Germanium detector (HPGe). The ratios of photopeak counts of X-rays or gammas obtained with the detector coupled to collimator are calculated for the estimation of depth of the contaminant and the optimum one is determined. Since Minimum Detectable Activities (MDA) for the detector coupled to a collimator are higher than that of bare detector, activity must be estimated using bare detector, after locating the contaminant. Two methods are described for the estimation of plutonium coexisting with 241Am: (i) Abundance and isotopic correction for 239Pu (ii) and 239Pu:241Am ratio. The procedure to estimate 239Pu when plutonium isotopes alone are present is also established. An optimum monitoring period to detect the minimum value of intake for both radionuclides corresponding to chelation therapy and excision is also derived. [ABSTRACT FROM AUTHOR]

Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75–100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM. [ABSTRACT FROM AUTHOR]

Summary: Background: Despite numerous studies, the true scenario of hearing loss in beta‐thalassaemia remains rather nebulous. Materials and methods: Pure tone audiometry, chelation therapy, demographics and laboratory data of 376 patients (mean age 38.5 ± 16.6 years, 204 females, 66 non‐transfusion‐dependent) and 139 healthy controls (mean age 37.6 ± 17.7 years, 81 females) were collected. Results: Patient and control groups did not differ for age (p = 0.59) or sex (p = 0.44). Hypoacusis rate was higher in patients (26.6% vs. 7.2%; p < 0.00001), correlated with male sex (32.6% in males vs. 21.8% in females; p = 0.01) and it was sensorineural in 79/100. Hypoacusis rate correlated with increasing age (p = 0.0006) but not with phenotype (13/66 non‐transfusion‐dependent vs. 87/310 transfusion‐dependent patients; p = 0.16). Sensorineural‐notch prevalence rate did not differ between patients (11.4%) and controls (12.2%); it correlated with age (p = 0.01) but not with patients' sex or phenotype. Among adult patients without chelation therapy, the sensorineural hypoacusis rate was non‐significantly lower compared to chelation‐treated patients while it was significantly higher compared to controls (p = 0.003). Conclusions: Sensorineural hypoacusis rate is high in beta‐thalassaemia (about 21%) and it increases with age and in males while disease severity or chelation treatment seems to be less relevant. The meaning of sensorineural‐notch in beta‐thalassaemia appears questionable. [ABSTRACT FROM AUTHOR]

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative–nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative–nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO−) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•−) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN. [ABSTRACT FROM AUTHOR]

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

Inhibition of intraerythrocytic iron uptake by plasmodium parasites is a viable alternative antimalarial mode of action to that adopted by artemisinins, since microorganisms require iron for growth and replication, but this has received less research attention. Against this backdrop, an in silico study on bis-thiosemicarbazones (TSCs) with significant antiplasmodial properties as Fe(III)-selective chelators and inhibitors of hemozoin formation is undertaken herein using density functional theory (DFT), molecular docking and molecular dynamics (MD) simulations. From the large contrasts in calculated binding energies for Fe(III) and Fe(II) sequestration in aqueous solution at DSD-BLYP/def2-TZVPD level of theory (−1162.99 to −1187.64 kcal mol−1 and −671.75 to −687.60 kcal mol−1, respectively), the TSCs are potential Fe(III)-selective chelators as desired for chelation therapy. Based on their satisfactory oral bioavailability profiles, the TSCs are found to be adequately drug-like. They are therefore expected to easily penetrate parasitized erythrocytes and inhibit the growth/development of plasmodium parasites by scavenging and externalizing intraerythrocytic ferric iron. Moreover, docking and adsorption studies of these TSCs onto the (001) face of the β-hematin crystal have yielded favorable binding free energies (−9.874 to −11.83 kcal mol−1) and negative adsorption energies (−84.61 to −109.80 kcal mol−1), respectively. The adsorption energies obtained herein are either comparable or more negative than those obtained in previous studies for well-known antimalarial drugs. Therefore, besides Fe(III)–chelation, the antiplasmodial activities of the TSCs studied are also attributable to inhibition of β-hematin/hemozoin formation, which has a cascade effect on plasmodium parasite survival. From our findings, in vitro β-hematin inhibition assays on these TSCs are recommended. [ABSTRACT FROM AUTHOR]

OBJECTIVE The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022. METHODS Drug shortage data were retrieved from the University of Utah Drug Information Service from January 1, 2001, through December 31, 2022. Shortages of first- and second-line lead chelators were analyzed. Drug class, formulation, administration route, shortage reason, shortage duration, generic status, single-source status, and presence of temporally overlapping shortages were examined. Total shortage months, percentages of study period on shortage, and median shortage durations were calculated. RESULTS Thirteen lead chelator shortages were reported during the study period. Median duration was 7.4 months and the longest shortage (24.8 months) involved calcium disodium edetate. Calcium disodium edetate and dimercaprol had the greatest number of shortages, 4 each, and 61.5% of shortages involved parenteral medications. Median shortage duration was 14.2 months for parenteral agents and 2.2 months for non-parenteral agents. All shortages involved generic, single-source products. Supply/demand and manufacturing problems were the most common shortage reasons provided. Overlapping shortages occurred for 3.7% of the study period. Median shortage duration increased from 3 to 11 months in the second half of the study period, and 61.5% of shortages occurred in the second half of the study period. CONCLUSIONS All chelators experienced multiple shortages, which became increasingly frequent and prolonged over time. Concurrent shortages occurred, potentially hampering substitution between different agents. Health care stakeholders must build supply chain resilience and develop guidelines regarding how to modify chelation therapy based on shortage conditions. [ABSTRACT FROM AUTHOR]

Chronic lead exposure induces ROS accumulation which causes physiological disorders. Chelation therapy has been widely used to overcome lead poisoning since it exerts only a few side effects. Nano chitosan prevents lead poisoning by inhibiting ROS. This study examined the pharmacokinetics of nano chitosan in chronic lead-induced toxicity animal models and the mechanism of action pathway using the bioinformatic approach, The area under the curve was estimated to be 12110.13 ± 7709.37 µg/mL hours using the pharmacokinetic model, and the Cmax was 82.34 ± 5.64 µg/mL. The Tmax and t½ calculations were 22.68 ± 11.67 and 80.47 ± 60.58 hours respectively. Chitosan nanoparticles regulated VEGFA, FGF2, and LGALS3 which plausibly played a substantial role in chronic lead exposure. However, chitosan is not suitable for oral administration due to its low gastrointestinal solubility. These characteristics make chitosan nanoparticles have the prospect of being developed as a supplement so that they can contribute to overcoming the negative impacts of chronic lead poisoning. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Heavy metals (HMs) are natural elements present in the Earth's crust, characterised by a high atomic mass and a density more than five times higher than water. Despite their origin from natural sources, extensive usage and processing of raw materials and their presence as silent poisons in our daily products and diets have drastically altered their biochemical balance, making them a threat to the environment and human health. Particularly, the food chain polluted with toxic metals represents a crucial route of human exposure. Therefore, the impact of HMs on human health has become a matter of concern because of the severe chronic effects induced by their excessive levels in the human body. Chelation therapy is an approved valid treatment for HM poisoning; however, despite the efficacy demonstrated by chelating agents, various dramatic side effects may occur. Numerous data demonstrate that dietary components and phytoantioxidants play a significant role in preventing or reducing the damage induced by HMs. This review summarises the role of various phytochemicals, plant and herbal extracts or probiotics in promoting human health by mitigating the toxic effects of different HMs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite prolonged life expectancy in patients with beta‑thalassemia due to modern chelation therapy and planned blood transfusions, they still suffer from multisystem complications of this chronic hemolytic anemia, including endocrine system dysfunction. Under‑recognized parathyroid hormone (PTH) dysfunction in these patients can manifest as bone pain and fractures. OBJECTIVE: The objective of the study was to evaluate PTH in patients with beta‑thalassemia >10 years of age. METHODS: A cross‑sectional study was performed on 76 randomly selected patients >10 years old with beta‑thalassemia (including both thalassemia major and thalassemia intermedia) in the Al‑Kut Hereditary Blood Disease Center in Wasit province, Iraq. The study covered the period from November 2021 to April 2022. Data were collected from patients’ files after written consent, including sex, age, ferritin level, mean hemoglobin level, type of chelation therapy, frequency of transfusion, mean calcium level, and whether the patients were splenectomized or not. RESULTS: Of the 76 patients enrolled in the study, 39 (51.3%) were males. There were 63 (82.9%) who had thalassemia major. The majority of cases (n = 55, 71%) were from the age group >15 years. Fifteen (19.7%) patients had low PTH levels. The age group >15 years had a higher frequency of having low PTH levels (P = 0.01 and Pearson factor ‑ 0.29). The study found a positive correlation between low calcium and low PTH levels (P = 0.001, Pearson factor = 0.1). High ferritin levels had no significant correlation with PTH levels (P = 0.4). CONCLUSIONS: Beta‑thalassemia patients can have a low PTH level. It can occur more often in patients >15 years old, which necessitates close monitoring for older thalassemia patients. A declining calcium level in these patients can correlate with a low PTH level. [ABSTRACT FROM AUTHOR]

Thalassemia is a chronic disease caused by impaired globin chain synthesis, leading to ineffective erythropoiesis, hemolysis, and chronic anemia. The treatment of patients with thalassemia, including blood transfusion combined with chelation therapy has progressed and improved their survival and prognosis. However, thalassemia-related psychological problems and impaired health-related quality of life (QoL) challenges still exist. Gender is one of the factors that has been suggested, to contribute to the disparities in psychological outcomes. This review article examined the evidence for gender differences in psychological disturbances and QoL in adolescent and adult patients with thalassemia. A non-systematic search of the literature was conducted in PubMed and Google Scholar for English full-text available from 2013 to 2023. We identified 23 studies with a sample size ≥ 100 that examined gender disparities in anxiety, depression, and QoL in adolescent and adult patients with thalassemia (mean prevalence of female = 53.1%; mean age = 28 years). Our review shows that there are gender disparities in psychological distress and QoL in adolescent and adult patients with thalassemia. Statistically significant gender differences were demonstrated in 62% of the psychological and QoL outcomes from 16 studies. Female patients had a higher prevalence of anxiety, depression, and poorer QoL in some studies. However, further studies with sufficient power and design are necessary to confirm the existence of gender disparities in psychological disturbances and QoL outcomes. [ABSTRACT FROM AUTHOR]

Objective: In thalassemia syndromes, iron accumulation due to transfusion or excessive iron absorption adversely affects many organ functions, including the endocrine system. Due to advances in effective transfusion and chelation therapy in recent years a significant increase as occured in the life expectancy and quality of life of patients. This situation has also led to an increase in patients’ expectation of having children. Methods: This study retrospectively, evaluates the transfusion characteristics, complications and conditions of the babies with regard to pre-pregnancy, pregnancy and delivery of our transfusion-dependent thalassemia patients who’ve had children and were monitored at the Istanbul University Medical Faculty, Department of Pediatric Hematology and Oncology. Results: The study includes 15 patients with a gestational age between 22-34 (28±3,9) years, five with thalassemia major, nine with thalassemia intermedia, and one with thalassemia trait and alpha triplication. While 14 patients came for regular follow-ups, one did not. The patients on a regular transfusion program had an increased frequency of transfusions throughout pregnancy; four patients with thalassemia intermedia, who had never undergone a transfusion before, were observed to have been included in a regular transfusion program starting with the 2nd trimester of pregnancy. None of the patients developed cardiac and/or thromboembolic complications. One patient diagnosed with thalassemia intermedia and one patient diagnosed with thalassemia major each had a stillborn baby, three patients diagnosed with thalassemia intermedia had preterm babies and four other patients had babies with intrauterine growth restrictions (IUGR). Conclusions: Thalassemia patients who are followed up with a regular multidisciplinary approach will be able to have a healthy pregnancy and children through the early recognition, prevention and treatment of complications. [ABSTRACT FROM AUTHOR]

The iron ion is an essential element for most forms of life, however, it can damage biological systems when found in free form. Chelation therapy is very important, but it is precarious. Caffeic and ferulic acid are antioxidant compounds with many properties described in research such as anti-inflammatory, antiobesogenic, antithrombotic, vasodilator, and anti-tumor. The aim of the study was to evaluate presenting an in silico approach on the toxicity and bioavailability of caffeic and ferulic acid, subsequently, evaluating them in an iron overload model in vivo and providing a pharmacophoric model through molecular docking. The predictive in silico test did not show relevant toxicity of the compounds, therefore, the in vivo test was performed. The rats received dextran iron and the test groups received caffeic and ferulic acid orally for six weeks. Biochemical, hematological parameters, and tissue oxidative stress marker were analyzed. The experimental model showed increased serum iron levels and changes in several serum parameters such as glucose (215.8 ± 20.3 mg/dL), ALT (512.2 ± 128.7 U/L), creatine kinase (186.8 ± 30.1 U/L), and creatine kinase isoform MB (373.3 ± 69.7 U/L). Caffeic acid and, to a lessed degree, ferullic acid, attenuated the effects of iron overload on the rat serum biochemical parameters. Docking showed a pharmacophoric model where carbonic anhydrase interacted with the test molecules and caffeic acid showed less energy expenditure in this interaction. The results illustrate a new therapeutic action of phenolic compounds on iron overload. The possible interference of carbonic anhydrase in iron metabolism needs to be elucidated. [ABSTRACT FROM AUTHOR]

Thalassemia is a genetic disease that significantly affects human health. The common treatment of thalassemia is the regular injection of red blood cell, which is associated with the accumulation of iron in different tissues of the body, and makes chelation therapy necessary. Deferiprone and deferoxamine are broadly used as iron chelating agents in the vast majority of thalassemia cases. In this study, an efficient method for the synthesis of deferiprone was used by reacting maltol with methylamine in a mixture of water and ethanol as solvent. The structure of deferiprone was assigned using different spectroscopic techniques such as IR, 1H-NMR, and 13C-NMR. The advantages of this pathway are simple, practical, one-pot cascade, mild condition and high yield. The statistics of the Ministry of Health of Iran show the growing trend of deferiprone drug consumption in the country. Therefore, the domestic preparation of this drug can help the pharmaceutical industry in order to reduce costs and make it available for target patients. [ABSTRACT FROM AUTHOR]

Thalassemia treatment still relies on supportive care, mainly including blood transfusion and iron chelation therapy. Iron chelation is considered the main factor responsible for the marked improvement in survival rates of thalassemic patients. Hemosiderosis may be prevented if appropriate chelation therapy is offered from early childhood, with timely dose adjustments according to changing body weight and close monitoring of organ iron load. With three iron chelators currently available, the choice of appropriate chelation, either as monotherapy or combined therapy, should be individualized depending on the iron overload of target organs, patient's age, presence of adverse events and compliance issues, given known limitations related to each agent's administration. [ABSTRACT FROM AUTHOR]

Background and Objectives Chelation therapy is essential for beta-thalassemia major. This study aims to determine the complications clinical and laboratory symptoms of monotherapy and combined treatment of iron chelators in beta-thalassemia major patients in Yasuj. Materials and Methods In this cross-sectional-descriptive-analytical study, 103 patients with beta-thalassemia major in Yasuj city were evaluated during 2021-2022. After collecting the demographic, clinical and laboratory information of the patients, the results were reported as mean ± standard deviation and percentage. The degree of statistical differences between ratios was calculated using the Kruskal-Wallis test. Results The average age of our patients was reported to be 24.74 ± 8.34 years. 54.4% (n = 56) of the study patients were men and 45.6% (n = 47) were women. The results of the present study showed that there was a statistically significant difference in mean ferritin among different study groups (p = 0.028). Patients treated with deferoxamine showed the highest mean serum ferritin (5925.5 ± 3397ng%) and patients who took deferoxamine together with deferiprone or deferasirox had a lower mean ferritin compared to deferoxamine alone (3348 ± 2560, 4269 ± 3322 ng%), respectively. Also, the present study showed that after taking iron removers, 47.6% of patients (n = 49) had no clinical complications and 52.4% (n = 54) had at least one complication. Conclusions Our results showed that Deferoxamine can have a great effect in reducing iron deposition and serum ferritin levels in combination with oral drugs. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of switching from deferasirox dispersible tablet (DT) to deferasirox film-coated tablet (FCT) on serum ferritin (SF) levels in transfusion-dependent patients. Materials and Methods: Patients who received regular erythrocyte transfusion and whose treatment was switched from DT to FCT were included in the study. FCT start date was taken as the index date. Patients were followed over 2 equal and long periods, both before and after index date. Results: Thirty-two patients were included, and the comparison periods ranged from 4 to 12 months. The SF values increased from a median of 1723 ng/mL (range 717-5369 ng/mL) to 1.853 ng/mL (range 924-5478 ng/mL) after switching from DT to FCT (P = .036). While there was a significant increase in median SF after switching in Turkish patients (1467 ng/mL to 1778 ng/ mL, P = .010) and patients ≥12 years (1598-1848 ng/mL, P = .009), there was an insignificant (P = .859) decrease in SF in immigrant children. Considering only the post-switch period, there was a non-significant increase in median SF in the entire cohort, while SF decreased significantly in immigrant children (P = .026). No serious side effects were observed in any patient that would cause discontinuation of treatment. Conclusion: Overall, higher SF value was observed with FCT compared to DT in short term. There were different results between patient groups. Our results suggest that FCT is more effective than DT in patients with high basal ferritin and who are actually incompatible with treatment and should be preferred first in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Beta thalassaemia is the most prevalent hereditary autosomal disorder, significantly impacting endocrine function during pubertal development. The pathology is rooted in the excessive deposition of iron in vital organs. If left untreated, this condition leads to serious morbidity and mortality. Hypogonadism stands as the most common endocrine complication. Aim: To observe pubertal development in girls with thalassaemia and evaluate the adequacy of chelation therapy in such patients by measuring levels of Follicle Stimulating Hormone (FSH), Luteinising Hormone (LH), oestrogen, and serum ferritin. Materials and Methods: A quasi-experimental study was conducted at the Thalassaemia Clinic at the Department of Obstetrics and Gynaecology, Burdwan Medical College, Purba Bardhaman, West Bengal, India involving 300 diagnosed Beta Thalassaemia Major (BTM) (case) patients aged 13 to 17 years over a period of one and a half years (January 2020 to June 2021). The girls in the study groups were sequentially enrolled from the Outpatient Department of the Thalassaemia Clinic after meeting inclusion and exclusion criteria. Demographic data, anthropometric measurements, and Sexual Maturity Rating (SMR) were recorded. Hormonal assays of serum FSH, LH, oestrogen, and serum ferritin levels were conducted. Thalassaemic girls with serum ferritin levels exceeding 500 ng/mL received chelation therapy. Serum ferritin levels were measured at two-month intervals for up to six months, with reassessment of serum FSH, LH, oestrogen, and ferritin levels at the end of the six-month period. Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) version 27.0, Microsoft excel spreadsheet, and Epi Info 7. Results: A total of 190 (63.3%) of the thalassaemic girls were aged 13 to 15 years, with a mean Body Mass Index (BMI) of 22.5000±2.6100 kg/m², and 74 of them (38.94%) experienced menarche in this age group. Out of 300 cases, 269 thalassaemic girls (89.6%) received chelation therapy, and 89 cases (33.09%) reached menarche after chelation therapy. A significant (p<0.0001) increase in mean LH and FSH levels was observed after chelation therapy. The mean ferritin level decreased from 3168.85 ng/mL to 2227.24 ng/mL following chelation therapy. Conclusion: Pubertal development failure is common in beta thalassaemic girls. Intervention in the form of adequate chelation therapy in girls with high serum ferritin levels yielded favourable outcomes, as evident from serum gonadotropin and oestrogen levels. [ABSTRACT FROM AUTHOR]

Objective: the study was conducted to identify the potential gap in patients' understanding, belief and behaviour towards thalassemia and its medications including iron chelation therapy (ICT). Methods: An observational cross-sectional study performed from Feb to March 2023 on patients admitted to thalassemia centre in Najaf. The study included male and female patients diagnosed with thalassemia, taking iron chelation therapy, and accepted to participate in this study. The data were obtained by using a pretested validated questionnaire focused on sociodemographic data and 20 items used to evaluate the knowledge, attitude, and practice level (KAP). Results: A total of 199 patients completed the study. About 73.9% of them had adequate knowledge, 78.4% showed positive attitude and 78.9% had good practice toward thalassemia and its therapy. However, 73% of them did not know that iron overload could cause diabetes and around 50% of them showed wrong belief toward importance of not missing medication doses. Additionally, third of patients experienced dose missing due to side effects. There were significant positive correlations among the total scores of patients KAP. All scores of KAP were significantly correlated with educational level while knowledge and practice scores were associated with the occupation as well as knowledge and attitude scores were also related to monthly income. Among remaining variables only male and urban residence were significantly linked to high knowledge score. Conclusions: The study revealed overall adequate knowledge, positive attitude and good practice toward thalassemia and its therapy. Also, the study identifying specific and essential gap in patients' awareness, belief and behaviour that need a tailored patients support and educational program. [ABSTRACT FROM AUTHOR]

Children with transfusion-dependent thalassemia experience stressful conditions related to chronic anemia, repeated blood transfusions, and iron chelation adherence. They are vulnerable to emotional and behavioral problems and psychosocial disturbances. An observational evaluation of psychosocial issues in children with TDTs aged 4–18 using Strengths and Difficulties Questionnaires (SDQ). Psychosocial part in children with TDTs often experiences difficulties in childhood under 10 years old, compared to adolescents (11–18 years) for emotional symptoms and conduct problems. Boys and girls had similar psychosocial problems regarding emotional symptoms, conduct problems, hyperactivity-inatttention, peer relationship problems, and prosocial behavior. In a quarter of cases, they had emotional symptoms, conduct, and hyperactivity-inattention issues, especially in younger children. Interestingly, younger children have more problems than adolescence in peer relations even though they are still under strict parental supervision. Difficulties in emotion, conduct, and hyperactivity would affect their relationship life. Children may try to be accepted by their social environment (prosocial) even though they realize that there are problems in their emotional life and peer relationships. Regular screening of the psychosocial aspects should be followed by counseling because regular transfusion and iron chelation are necessary for long-term management. [ABSTRACT FROM AUTHOR]

• Currently available conventional treatment modalities in β-thalassemia have posed many challenges and limitations. • There is a need for therapies that reduce patient reliance on RBC transfusions and iron chelation therapy. • Many novel therapies for β-thalassemia are now being tested in clinical trials. • These can be classified into three major categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the α/β globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. β-thalassemias are genetic disorders causing an imbalance in hemoglobin production, leading to varying degrees of anemia, with two clinical phenotypes: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Red blood cell transfusions and iron chelation therapy are the conventional treatment options for the management of β-thalassemia. Currently available conventional therapies in thalassemia have many challenges and limitations. Accordingly, multiple novel therapeutic approaches are currently being developed for the treatment of β-thalassemias. These strategies can be classified into three categories based on their efforts to address different aspects of the underlying pathophysiology of β-thalassemia: correction of the α/β globin chain imbalance, addressing ineffective erythropoiesis, and targeting iron dysregulation. Managing β- thalassemia presents challenges due to the many complications that can manifest, limited access and availability of blood products, and lack of compliance/adherence to treatment. Novel therapies targeting ineffective erythropoiesis and thus improving anemia and reducing the need for chronic blood transfusions seem promising. However, the complex nature of the disease itself requires personalized treatment plans for each patient. Collaborations and partnerships between thalassemia centers can also help share knowledge and resources, particularly in regions with higher prevalence and limited resources. This review will explore the different conventional treatment modalities available today for the management of β-thalassemia, discuss the unmet needs and challenges associated with them in addition to exploring the role of some novel therapeutic agents in the field. [ABSTRACT FROM AUTHOR]

Simple Summary: In our systematic review, we analyzed and summarized observational studies revealing a potential association between myelodysplastic syndromes (MDS) and hepcidin. The extensive studies available in this area enabled us to draw the conclusion that hepcidin has a potential importance in the pathophysiology of MDS and the prediction of poor MDS patient outcomes. A summary of the mechanisms leading to iron overload in MDS and the potential causes of elevated serum hepcidin levels are shown in a graphical abstract created with BioRender. It is important to note that this systematic review is based on a relatively small number of MDS patients and control participants. Hence, additional research is crucial for the further exploration of these findings. Iron overload emerges as a serious complication in myelodysplastic syndromes (MDS), particularly associated with frequent transfusions during the course of the disease. The discovery and description of hepcidin's mechanisms of action have contributed to a deeper understanding of iron metabolism. The existing literature reports a potential role of hepcidin in MDS, yet these data are fragmented and presented in an unstructured, somewhat chaotic manner. Hence, to address the existing data, we performed a systematic review of observational studies examining hepcidin levels in MDS. An extensive review of three bibliographic databases (Pubmed, Web of Science, and Scopus) enabled us to identify 12 observational studies. These studies focused primarily on adult patients with low-risk MDS who underwent transfusions and chelation therapy. An in-depth analysis of these manuscripts led to four main conclusions: (1) although high serum hepcidin levels are associated with MDS, most studies generally have not found a significant difference in these levels between patients and healthy individuals; (2) serum hepcidin levels are specific to MDS type; (3) serum hepcidin levels in MDS are strongly associated with transfusions and the genetic status of patients; and (4) high-risk MDS is associated with high serum hepcidin levels. While we have furnished a comprehensive summary of the significance of hepcidin in MDS, there are still gaps that future research should address. This pertains primarily to the capacity of hepcidin in predicting adverse outcomes for MDS patients and evaluating the efficacy of chelation therapy or the need for transfusion. [ABSTRACT FROM AUTHOR]

Cardiac contraction and relaxation require a substantial amount of energy provided by the mitochondria. The failing heart is adenosine triphosphate (ATP)- and creatine-depleted. Studies have found iron is involved in almost every aspect of mitochondrial function, and previous studies have shown myocardial iron deficiency in heart failure (HF). Many clinicians advocated intravenous iron repletion for HF patients meeting the conventional criteria for systemic iron deficiency. While clinical trials showed improved quality of life, iron repletion failed to significantly impact survival or significant cardiovascular adverse events. There is evidence that in HF, labile iron is trapped inside the mitochondria causing oxidative stress and lipid peroxidation. There is also compelling preclinical evidence demonstrating the detrimental effects of both iron overload and depletion on cardiomyocyte function. We reviewed the mechanisms governing myocardial and mitochondrial iron content. Mitochondrial dynamics (i.e., fusion, fission, mitophagy) and the role of iron were also investigated. Ferroptosis, as an important regulated cell death mechanism involved in cardiomyocyte loss, was reviewed along with agents used to manipulate it. The membrane stability and iron content of mitochondria can be altered by many agents. Some studies are showing promising improvement in the cardiomyocyte function after iron chelation by deferiprone; however, whether the in vitro and in vivo findings will be reflected on on clinical grounds is still unclear. Finally, we briefly reviewed the clinical trials on intravenous iron repletion. There is a need for more well-simulated animal studies to shed light on the safety and efficacy of chelation agents and pave the road for clinical studies. [ABSTRACT FROM AUTHOR]

Background and Aim: Kidney dysfunction is reported in significant number of beta thalassemia major children. The aim of this study was to determine the prevalence of glomerular dysfunction in beta-thalassemia major children on regular blood transfusion (BT) and chelation therapy, and to find the correlation between glomerular filtration rate (GFR) estimated by Schwartz formula and Technetium 99m diethylenetriaminepentaacetic acid (99mTc-DTPA) renogram with ferritin level and cumulative transfusion load. Materials and Methods: An observational cross-sectional study conducted was done on 110 children diagnosed with beta-thalassemia major receiving regular BT and chelation therapy. Clinical examination, biochemical investigations (serum creatinine, ferritin) and DTPA renal scan were done. Estimated GFR calculation was done by Schwartz method and 99mTc-DTPA scan. The normal values of GFR were taken from the standard value as per KDIGO guidelines. P < 0.05 was considered statistically significant. Results: The prevalence of glomerular dysfunction by Schwartz formula and DTPA renogram was 44% and 24%, respectively. The GFR calculation (Schwartz formula and DTPA renogram) were weakly positively correlated (r = 0.126, P = 0.547). There was significant association between GFR Schwartz and duration of iron chelation, as children with abnormal GFR had significantly more duration of iron chelation >5 years (28% vs. 4%, P = 0.003). GFR (Schwartz formula and DTPA renogram) showed no association with cumulative transfusion load and disease duration (P > 0.05). GFR Schwartz formula and GFR-DTPA showed no correlation with serum ferritin with r = 0.179, (P = 0.392) and r = 0.278 (P = 0.178). Conclusion: There is a significant derangement in the renal function of children of beta-thalassemia major on chronic BT and iron chelation therapy. GFR holds a direct correlation with the increasing duration of iron chelation. [ABSTRACT FROM AUTHOR]

Heavy metals are often found in soil and can contaminate drinking water, posing a serious threat to human health. Molecular pathways and curation therapies for mitigating heavy metal toxicity have been studied for a long time. Recent studies on oxidative stress and aging have shown that the molecular foundation of cellular damage caused by heavy metals, namely, apoptosis, endoplasmic reticulum stress, and mitochondrial stress, share the same pathways as those involved in cellular senescence and aging. In recent aging studies, many types of heavy metal exposures have been used in both cellular and animal aging models. Chelation therapy is a traditional treatment for heavy metal toxicity. However, recently, various antioxidants have been found to be effective in treating heavy metal-induced damage, shifting the research focus to investigating the interplay between antioxidants and heavy metals. In this review, we introduce the molecular basis of heavy metal-induced cellular damage and its relationship with aging, summarize its clinical implications, and discuss antioxidants and other agents with protective effects against heavy metal damage. [ABSTRACT FROM AUTHOR]

Background: Thalassemia has a high prevalence and carrier rate of 8-10% in Pakistan, repeated blood transfusions lead to iron deposition in organs. In this Prospective study, we have compared the efficacy of three chelation regimens being used in our country. It has been conducted at PBTS, Fatmid Foundation and Children Hospital Lahore. Methods: 60 thalassemia major patients, were divided into 3 groups according to their mode of chelation. Patients in group I were on oral iron chelator deferiprone, 7 days per week. Thalassemics in group II were on parenteral iron chelator deferoxamine given subcutaneously for 4 days a week, and group III patients were on combination therapy, deferiprone for 5 days & deferoxamine given twice weekly. The assessment of chelation was done by measurement of serum ferritin and 24-hour urinary iron excretion at the start of the study and then after six months of follow-up. To assess the hepatic iron, hepatic MRIs were also performed. Results: Ferritin levels were maximally decreased in group II, followed by group III, with no significant reduction in group I. However, a statistically significant difference in mean urinary iron excretion (increased) was seen in group III. The hepatic iron was very high in all three groups as shown by the hepatic MRI. Conclusion: Combination chelation therapy is the most effective chelation therapy in iron-overloaded patients. It helps to improve compliance and increases urinary iron excretion. Patients on DFX had the lowest degree of hepatic siderosis even though it was considerably higher than the normal population. [ABSTRACT FROM AUTHOR]

There is limited literature on managing chronic lead exposure from non-removable sources such as lead fragments. In this case report, we present the complexities and clinical considerations involved in treating an elderly patient who sustained a comminuted knee fracture due to a gunshot wound, complicated by retained lead fragments. This case highlights the absence of comprehensive guidelines for managing chronic lead exposure when complete fragment removal is impractical. It also emphasizes the importance of a multidisciplinary approach to decision-making, while considering patient autonomy in such unique clinical scenarios.

Severe hemolytic disease of the fetus and newborn (HDFN) requiring intrauterine transfusions (IUTs) may cause iron accumulation, resulting in liver damage, which may lead to cholestasis and coagulation disorders. In this article, we reported a case of a female neonate who underwent chelation therapy with a positive outcome, and we reviewed the English and Polish literature on chelation therapy in HDFN available in PubMed. The patient with maximum ferritin concentration above 33,511.2 ng/mL developed liver dysfunction with coagulation disorders requiring multiple transfusions of fresh frozen plasma (FFP), Octaplex® and cryoprecipitate, and hypoalbuminemia treated with numerous albumin infusions. Furthermore, severe cholestasis was observed with direct bilirubin levels up to 33.14 mg/dL. Additionally, the child developed transient myelosuppression with neutropenia, thrombocytopenia, and low reticulocyte count due to several blood transfusions. The differential diagnosis tests were conducted to rule out any causes of hepatic failure other than hemolytic disease of the newborn. This case proves that adequate treatment of severe HDFN with anemia requiring IUT and hepatic failure can lead to positive outcomes with no long-term consequences. [ABSTRACT FROM AUTHOR]

Simple Summary: The lysosomal lipid hydrolase acid ceramidase is upregulated in acute myeloid leukemia and promotes leukemic blast survival, underscoring its potential for therapeutic targeting. B-13 is an established ceramidase inhibitor with demonstrated efficacy in multiple solid cancers. Next-generation lysosome-localizing prodrugs of B-13 have been developed but have not been evaluated in AML. This study characterizes the in vitro anti-leukemic efficacy and cell death mechanisms of the B-13 analog and acid ceramidase inhibitor LCL-805 in acute myeloid leukemia. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This work describes an analysis, using a previously established chelation model, of the bioassay data collected from a worker who received delayed chelation therapy following a plutonium-238 inhalation. The details of the case have already been described in two publications. The individual was treated with Ca-DTPA via multiple intravenous injections and then nebulizations beginning several months after the intake and continuing for four years. The exact date and circumstances of the intake are unknown. However, interviews with the worker suggested that the intake occurred via inhalation of a soluble plutonium compound. The worker provided daily urine and fecal bioassay samples throughout the chelation treatment protocol, including samples collected before, during, and after the administration of Ca-DTPA. Unlike the previous two publications presenting this case, the current analysis explicitly models the combined biokinetics of the plutonium-DTPA chelate. Using the previously established chelation model, it was possible to fit the data through optimizing only the intake (day and magnitude), solubility, and absorbed fraction of nebulized Ca-DTPA. This work supports the hypothesis that the efficacy of the delayed chelation treatment observed in this case results mainly from chelation of cell-internalized plutonium by Ca-DTPA (intracellular chelation). It also demonstrates the validity of the previously established chelation model. As the bioassay data were modified to ensure data anonymization, the calculation of the "true" committed effective dose was not possible. However, the treatment-induced dose inhibition (in percentage) was calculated. [ABSTRACT FROM AUTHOR]