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Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was −4.04 (0.48) mg/g dry weight for deferiprone vs −4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, −0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Deferiprone (DFP) and deferasirox (DFX) are the most well-known, efficacious and safe chelators to reduce the serum ferritin (SF) level in multi transfused thalassemic children, although there are few reports available for assessing the efficacy between DFP and DFX. We compared the efficacy of DFP vs. DFX as iron chelating drugs in β-thalassemia major (β-TM) patients. Pediatric patients diagnosed to carry β-TM, aged between 2 and 10 years, were recruited. A suitable data collection form and questionnaire were used. Paired and unpaired t-tests were used to compare the safety and efficacy of the chelating drugs DFP and DFX. The mean SF level at the 12th month was found to be 3016.73 ± 670.04 ng/mL (p = 0.002) in the DFX-treated group, which was quite significant in contrast to DFP response, where the value was 3204.06 ± 690.15 ng/mL (p = 0.14). There is no statistically significant (p = 0.15) difference on relative changes of the left ventricular ejection fraction (LVEF), between these two groups. The adverse effects were transient and none of them required stoppage of therapy. Deferasirox is more effective when compared to DFP in reducing chelating drug-related complications and iron overload specially in multiple transfusion dependent β-TM patients.

Friedreichs Ataxia is an autosomal recessive genetic disease causing the defective gene product, frataxin. A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated prooxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, we suggest the rationale for planning combination strategies based on the three mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in FRDA patients, calling attention to clinical practitioners of the importance to implement clinical trials. Copyright © 2020. Published by Elsevier Inc.

Background Each year nearly 10,000 children with thalassaemia major are born in India, but among them, very few are optimally managed mainly in urban regions even though the Government of India has incorporated their care and treatment in the 12th Five-Year Plan. Data on prescribing patterns and drug-related problems (DRPs) in paediatric thalassaemia patients in India are limited. Methods In this prospective interventional study, the medications prescribed were recorded after reviewing the treatment charts, thalassaemia register, thalassaemia card, nurses’ notes, as well as discharge summaries. When DRPs and/or medication errors were identified, the same was discussed with the concerned health care professionals and suitable suggestions were made at the earliest. Results Out of the enrolled 54 patients, only 94% (n = 51) of the patients received iron chelation therapy with deferasirox and/or deferiprone, Folic acid tablet was prescribed for 100% of the patients (n = 54). Five percent of patients (n = 3) had undergone splenectomy and was prescribed with amoxicillin prophylactically. There were a total of 16 DRPs and 15 medication errors were identified and suitable measurements were taken to solve these problems. Conclusions The prescribing patterns, DRPs and medication errors in transfusion-dependent paediatric thalassaemia patients were discussed in this study. Our study was effective in identifying and solving the DRPs and medication problems that occurred in thalassaemia patients.

The accumulation of neurofibrillary tangles (NFTs), which is composed of abnormally hyperphosphorylated tau aggregates, is the classic neuropathology associated with cognitive dysfunction in tauopathies such as Alzheimer’s disease (AD). However, there is an emerging theory suggesting that dysregulation in cerebral iron may contribute to NFT formation. Iron is speculated to bind to tau and induce conformational changes of the protein, potentially leading to subsequent aggregation and cognitive decline. Deferiprone (DFP) is a clinically available iron chelator, which has demonstrated potential therapeutic advantages of chelating iron in neurodegenerative disorders, and is currently in clinical trials for AD. However, its effect on tau pathology remains unclear. Here, we report the effects of short-term DFP treatment (4 weeks, 100 mg/kg/daily, via oral gavage) in a mixed-gender cohort of the rTg((tauP301L))4510 mouse model of tauopathy. Our results revealed that DFP improved Y-maze and open field performance, accompanied by a 28% decrease in brain iron levels, measured by inductively coupled plasma mass spectrometry (ICP-MS) and reduced AT8-labeled p-tau within the hippocampus in transgenic tau mice. This data supports the notion that iron may play a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders that can be modulated by the clinically available metal chelator DFP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00972-w.

Background: Thalassemia is a chronic disease requiring lifelong treatment. The adherence to regular iron chelation therapy is important to ensure complication-free survival and good quality of life. The study aim to assess the adherence to iron chelation therapy (ICT) in patients with transfusion-dependent thalassemia (TDT), evaluate various causes of non-adherence and study the impact of non-adherence on the prevalence of complications secondary to iron overload. Materials and Methods: Patients with TDT on ICT for > 6 months were enrolled in the study. Hospital records were reviewed for demographic details, iron overload status, treatment details, and the prevalence of complications. A study questionnaire was used to collect information on adherence to ICT, knowledge of patients, and the possible reasons for non-adherence. Results: A total of 215 patients with a mean age of 15.07+7.68 years and an M: F ratio of 2.2:1 were included in the study. Non-adherence to ICT was found in 10.7% of patients. Serum ferritin levels were significantly higher in the non-adherent group (3129.8+1573.2 µg/l) than the adherent population (2013.1+1277.1 µg/l). Cardiac as well as severe liver iron overload was higher in the non-adherent patients. No correlation was found between disease knowledge and adherence to ICT. Difficulties in drug administration and many medicines to be taken daily were statistically significant reasons for non-adherence. There was no difference in the co-morbidities arising due to the iron overload in the two groups. Conclusion: Nearly 11% of patients with TDT were non-adherent to ICT. Non-adherence results in higher iron overload.

Mucormycosis is an ailment that originates from a saprophyte. Mucorales are a group of a growing number of members who have mucormycosis. The environmental contamination with fungal spore and now in COVID-19 the high use of steroid, which increases the occasion of mucor. It is a worldwide infectious disease as well as there is no vaccine to treat mucormycosis. Therapies for mucormycosis involve a coordinated surgical and medical approach. Antifungal therapy, iron sequestration, and adjunctive therapy are the various therapies to treat mucormycosis that will discuss in the article. Also the pathogenesis, identification of mucormycosis will review here.

Objective: The current iron chelation therapy regimens include deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) in transfusion-dependent patients. Compliance with iron-chelating therapy is one of the significant determinants of mortality and morbidities related to iron loading in chronically transfused patients. This survey aims to compare the compliance and the satisfaction of DFO, DFP, and DFX formulations in patients who have iron-overloading in three hematology centers from Turkey. Moreover, bioequivalent (generic) formulations of dispersible DFX tablet compared with the original formulation in terms of taste and treatment compliance. Patients and Methods: A written questionnaire with a list of pre-set questions was applied to measure patient-reported outcomes to a total of 85 patients, where 77 had beta-thalassemia major, 7 had beta-thalassemia intermedia, and 1 had sickle cell anemia diagnoses. Results: The patients’ median age at enrollment was 15 years (range 7 – 42). The compliance was below 50% in 8 (18.6%), 4 (16%), and 5 (6.7%) in patients receiving DFO, DFP, and DFX, respectively. Additionally the compliance was below 80% in 16 (37.2%), 9 (36%), and 17 (22.6%) in patients receiving DFO, DFP, and DFX, respectively. It was found that 39 (47%) patients had compliance problems due to the dispersible DFX tablet formulations’ taste, except combination therapies. There was no difference between the currently used oral chelators in terms of taste and treatment compliance. Conclusion: This study draws attention to compliance problems in patients with iron-loading anemias, partly due to the unpleasant taste of DFX. Improving patient satisfaction and compliance with iron-chelator therapy may reduce complications of iron overload.

Iron overload–induced cardiomyopathy is the leading cause of death in patients with transfusion-dependent thalassemia (TDT). The mortality is extremely high in these patients with severe cardiac complications, and how to rescue them remains a challenge. It is reasonable to use combined chelation with deferiprone (L1) and deferoxamine (DFO) because of their shuttle and synergistic effects on iron chelation. Here, seven consecutive patients with TDT who had severe cardiac complications between 2002 and 2019 and received combined chelation therapy with oral high-dose L1 (100 mg/kg/day) and continuous 24-h DFO infusion (50 mg/kg/day) in our hospital were reported. Survival for eight consecutive patients receiving DFO monotherapy for their severe cardiac complications between 1984 and 2001 was compared. We found that combined chelation therapy with high-dose L1 and DFO was efficient to improve survival and cardiac function in patients with TDT presenting severe cardiac complications. Reversal of arrhythmia to sinus rhythm was noted in all patients. Their 1-month follow-up left ventricular ejection fraction increased significantly (P

To assess the efficacy and safety of dual oral iron chelation therapy (deferiprone and deferasirox) in decreasing iron overload status, using serum ferritin and liver and cardiac MRI as indicators, in transfusion dependent thalassemic children. This was a prospective observational study conducted in a tertiary care hospital for a period of one year. Children with thalassemia between 2 and 18 y of age with serum ferritin above 1500 ng/ml were started on oral deferiprone and deferasirox. They were followed up for one year. Serum ferritin and MRI quantification of liver and cardiac iron concentration was done at enrolment and end of 12 mo. They were also monitored monthly for any adverse effects. Twenty one thalassemic children with mean age of 7.8 y (range 4–12 y) and a mean ferritin value of 3129 + 1231.5 ng/ml were enrolled. Mean serum ferritin decreased by 1226.3 ng/ml (p = 0.047, 95% CI =10.2, 1504.3) with 16.8% fall from baseline. The reduction in ferritin correlated significantly with the initial ferritin level (spearman’s rho = 0.742, p = 0.001). Mean liver iron concentration and myocardial iron concentration did not change significantly. Red color urine, transient rise in creatinine and liver enzymes were noted during the study period. Combined oral chelation with deferiprone and deferasirox significantly decreases the serum ferritin level in children with severe iron overload. The drugs were tolerated well without any serious adverse effects.

Background: Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators. Aim: To assess the effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*. Patients and methods: Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) – with deferiprone, and 8 (17.3%) – with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA. Results: In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 – 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014. Conclusion: A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring.

BACKGROUND: Iron overload is the main cause of oxidative stress in beta-thalassemia (βT) by the increased production of free radicals and reactive oxygen species. Antioxidants counteract the toxic effects of oxidative stress. AIM: This study aims to evaluate the total antioxidant capacity (TAC) and the possible impact of splenectomy, iron chelators, and hydroxyurea (hydra) on serum level of TAC. MATERIALS AND METHODS: Fifty children and adolescents with βT were studied in comparison to 25 healthy age- and sex-matched subjects. Complete medical history, clinical examination, and laboratory assessment of serum TAC, ferritin, hepcidin, and hemoglobin (Hb) were carried out. RESULTS: There was no statistically significant difference between the three groups; thalassemia major (TM), thalassemia intermedia (TI), and controls as regard age and sex. β-TM patients had significantly higher serum ferritin, serum hepcidin, and serum TAC (p < 0.000, 0.002, and 0.000, respectively) than controls. β-TI patients had significantly higher serum ferritin and serum TAC (p < 0.000) than controls. Serum TAC was lower in children with splenectomy, but this difference was not statistically significant. In addition, we observed no statistically significant difference in serum TAC of patients under different (deferasirox or deferiprone) medication. Serum TAC concentration was significantly higher in patients taking hydroxyurea (hydra) (p < 0.010). CONCLUSIONS: The study showed an increased level of serum TAC in patients with β-T in comparison with controls. Serum TAC was also increased in those taking hydroxyurea, however, it was low in βT patients under regular chelation therapy, while splenectomy had no significant effect on serum TAC.

Hemochromatosis is an imbalance of excessive serum iron and is a life-threatening condition if left untreated. Due to different causes, primary and secondary hemochromatosis have different patient care considerations for the infusion nurse. Understanding the pathophysiology and how the body absorbs iron is imperative for providing the highest quality care. Since primary (hereditary) hemochromatosis originates from a gene mutation, and secondary (acquired) from excessive intake, the treatment and education must be adjusted accordingly to deliver successful outcomes for both diagnoses.

Niemann-Pick Disease Type C (NP-C) is a fatal lysosomal storage disorder with progressive neurodegeneration. In addition to the characteristic cholesterol and lipid overload phenotype, we previously found that altered metal homeostasis is also a pathological feature. Increased brain iron in the Npc1-/- mouse model of NP-C may potentially contribute to neurodegeneration, similar to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Deferiprone (DFP) is a brain penetrating iron chelator that has demonstrated effectiveness in preventing neurological deterioration in Parkinson's disease clinical trials. Therefore, we hypothesized that DFP treatment, targeting brain iron overload, may have therapeutic benefits for NP-C. Npc1-/- mice were assigned to four experimental groups: (1) pre-symptomatic (P15) + 75 mg/kg DFP; (2) pre-symptomatic (P15) + 150 mg/kg DFP; (3) symptomatic (P49) + 75 mg/kg DFP; (4) symptomatic (P49) + 150 mg/kg DFP. Our study found that in Npc1-/- mice, DFP treatment did not offer any improvement over the expected disease trajectory and median lifespan. Moreover, earlier treatment and higher dose of DFP resulted in adverse effects on body weight and onset of ataxia. The outcome of our study indicated that, despite increased brain iron, Npc1-/- mice were vulnerable to pharmacological iron depletion, especially in early life. Therefore, based on the current model, iron chelation therapy is not a suitable treatment option for NP-C.

Spinal laminectomy is a common procedure performed to relieve neural compression in patients suffering from myelopathy or radiculopathy. However, up to 40% of patients suffer from persistent post-operative pain and disability, a condition known as Failed Back Surgery Syndrome (FBSS). Excessive scarring in the surgical bed is implicated as a cause. Hydrogels have been proposed to prevent adhesion formation post-laminectomy; however, their efficacy has not been proven. This study uses Chitogel complexed with the iron chelator Deferiprone (Def) to prevent adhesion formation in a sheep laminectomy model.Fifteen Adult Merino sheep (Ovis Aries, 1-5 yrs old) underwent laminectomy at lumbar levels 1-5 and had hydrated aluminum silicate (kaolin) applied to promote adhesion formation. Subjects were randomised to receive at each laminectomy level no-treatment control, Chitogel, Chitogel with Def at 20 mM or 40 mM or Carboxy-methyl-cellulose and Polyethylene oxide (CMC/PEO) gel. The animals were recovered for 3 months post-surgery, followed by assessment with Magnetic Resonance Imaging (MRI) and histopathology of the spinal tissues for evaluating the presence and extent of adhesions.MRI and Histology assessment indicated that Kaolin induced severe inflammation with adhesion formation. Chitogel with and without 20 mM Def decreased inflammation (p 0.01) and trended to reduce adhesions (p 0.1). Chitogel with Def 40 mM was not significantly dis-similar to CMC/PEO and did not reduce inflammation or adhesions compared to no-treatment control.Chitogel in combination with Def 20 mM is safe and effective in decreasing the inflammatory process and may possibly reduce post-operative adhesions following laminectomy.

BACKGROUND Arthropathies and bone deformities are well known to occur in patients with thalassemia major and have been attributed to the disease or to its therapy. Before the advent of chelation therapy, these children developed widened diploic space and "hair-on-end" pattern in skull, "cobweb" pattern in the pelvis, and the lack of the normal concave outline in the long bones because of extensive marrow proliferation. After the introduction of iron-chelation therapy, these patients were noted to develop metaphyseal abnormalities and vertebral changes resembling spondylo-metaphyseal dysplasia. Only one study has shown some association of deferiprone (chelating agent) use with distal ulnar changes in these children. Our study was done to describe the skeletal changes and deformities in wrist joints of children with transfusion-dependent thalassemia and correlate them with age, mean pretransfusion hemoglobin level, mean serum ferritin level, and type and duration of chelation therapy in these children. METHODS A total of 60 children with transfusion-dependent thalassemia from the thalassemia daycare center were examined. These children were divided into 3 groups on the basis of their age (group A: 2 to 6 y, group B: 6 to 10 y, and group C: 10 to 14 y). Detailed history, including treatment history, number of blood transfusions received over the last 1 year, clinical examination, and radiologic assessment of both forearm with wrists were done. RESULTS The clinical and radiologic differences in radial and ulnar lengths increased significantly with the increasing age of these patients, the ulna being short. There was some correlation between increasing negative ulnar variance and distal radial articular angle with deferiprone consumption. CONCLUSION Chelation therapy, particularly with deferiprone, may cause distal ulnar growth arrest causing ulnar shortening and progressive radial bowing in these children. LEVEL OF EVIDENCE Level IV-case series.

Background: Beta-thalassemia is a hereditary haemoglobinopathy caused by defective hemoglobin (Hb) β-globin synthesis, leading to excess α-globin chains that cause hemolysis and impair erythropoiesis. Ischemia modified albumin (IMA) is not a signal protein and not generated in pro-inflammatory state alone but rather an end product of oxidative stress. Objectives: The aim of the study was to evaluate ischemia modified albumin (IMA) and C-reactive protein (CRP) in children with β-thalassemia major and its relation to different iron chelators. Patients and Methods: The study was carried on 40 children diagnosed as beta-thalassemia major recruited from the outpatient clinic and the pediatric department, at Al-Zahraa University Hospital, Faculty of medicine for Girls, Al-Azhar University and EL Minia Insurance Hospital. They were 20 male and 20 female, aged from 4 - 11 years. Another 40 apparently healthy children age and sex matched as control group. CRP and IMA were determined for all participants. Results: There were significant increases in serum CRP, IMA and ferritin levels in patients group compared to control group. There were significant decreases of IMA and CRP levels of thalassemic patients on chelation deferiprone (DFP) compared to deferasirox (DFX) P-value (Conclusion: IMA, CRP and Serum ferritin were higher in children with β-thalassemia major than controls. Moreover, IMA and CRP levels in thalassemic children on deferiprone (DFP) were significantly lower compared with children on deferasirox (DFX). So it could be considered as useful markers in the follow up assessment of thalassemic patients for early detection of complications.

Background: Thalassemia is a blood disease charac­­terized by the most frequently found auto­somal recessive hereditary hemolytic anemia. It requires repeated blood trans­fusions for life. Routine blood transfusion can cause complica­tions in the form of accumu­lation of ferritin in the tissue. Iron chelation therapy is considered effective for treating body iron deposits. How­ever, iron chelation therapy has the side effect of decreasing levels of other im­­­­portant minerals such as zinc (Zn). This study aimed to examine plasma zinc difference in children with Thalasse­mia β major received deferiprone or deferasirox zinc. Subjects and Method: This was a cross sec­tional study conducted at Dr. Moewardi Hospital, Surakarta, from February to April 2017. A sample of 40 children with thalassemia β major aged 3 to 18 years who received deferiprone iron chelation and defe­rasirox at least 6 months was selected by consecutive sampling. The dependent variable was serum zinc levels. The independent vari­ables were iron ­deferip­rone and deferasirox. Plasma zinc levels were measured by atomic absorption spectroscope. The data were analyzed by t test. Results: Zinc levels in patients with deferiprone therapy (Mean= 54.50; SD= 11.02) were lower than defera­sirox therapy (Mean= 60.95; SD= 20.71), but statistically not significant (p= 0.229). Conclusion: Zinc levels in patients with deferi­prone therapy are lower than deferasirox therapy, but not statistically significant. Keyword s : zinc, deferiprone, deferasirox, children with thalassemia β major Correspondence: Wahyu Kusumawardhani. Department of Pedi­a­trics, Faculty of Medicine, Universitas Sebelas Maret/ Dr. Moewardi Hospital, Surakarta, Cen­tral Java. Phone/ Fax: 0271-633348. Email: dha­nisurya­diraja­@gmail.com Indonesian Journal of Medicine (2020), 05(02): 102-108 https://doi.org/10.26911/theijmed.2020.05.02.02

Bismuth is a heavy metal with antibacterial properties that has a long history of medicinal use. The results reported here suggest that bismuth(III) (chelated with deferiprone) could be used in aquaculture systems to treat bacterial disease outbreaks, greatly reducing antibiotic use. We tested bismuth susceptibility in a collection of aquaculture bacterial pathogens. In the presence of bismuth concentrations ranging from 1.3 to 13 µM, most bacteria started showing a drastic decrease in their growth ability, although with high inter- and intraspecific variability. The minimal inhibitory concentrations of bismuth ranged from 13 to more than 780 µM, depending on bacterial species and strain. The results of in vivo assays suggest that low concentrations of bismuth could be especially effective to treat vibriosis caused by Vibrio anguillarum, since bismuth greatly reduced mortality in experimentally infected fish without any observable side effects. A bismuth therapy, alone or combined with other antimicrobials, could contribute to reduce the use of antibiotics in aquaculture.

Beta thalassemias are autosomal recessive hemoglobin disorders related to a defect in the beta-globin chain production. Most of the major forms of beta-thalassemia are transfusion dependent leading to iron overload. Today, three iron chelators are available in France. We report the case of a patient suffering from β+ major transfusion-dependent thalassemia who presented with severe skin reactions to deferoxamine and deferasirox as well as with agranulocytosis after deferiprone administration. The patient benefited from successful tolerance induction to deferasirox. With the increasing number of children suffering from iron overload, we believe that our protocol can be useful to pediatric hematology teams confronted with multiple iron chelator reactions.

INTRODUCTION: Because of iron overload complications, thrombosis and infectious predisposition, patients with severe forms of thalassemia are likely to be at increased risk of COVID-19 complications. RESULTS: A national survey conducted during the year 2020 across the French reference centers for hemoglobinopathies identified 16 cases of COVID-19 confirmed by RT-PCR in beta-thalassemia patients. Their age ranged from 11 months to 60 years. 15 patients were transfusion-dependent and 6 were splenectomized. Concerning iron overload related complications, none had diabetes or cirrhosis and only one had experienced heart failure. All 4 pediatric patients were pauci-symptomatic during the viral episode. Three patients (41, 49 and 57 years old) developed COVID-19 pneumonia requiring oxygen therapy without the need for mechanical ventilation. Neutropenia (absolute neutrophils count

Aim: Complications due to iron overload exert a problematic situation in patients with thalassemia. Proton pump inhibitors (PPIs) like pantoprazole are effective agents to reduce acid gastric acid secretion and perhaps to interrupt iron absorption in conditions with increased iron absorption. Our purpose was to study effects of pantoprazole addition to chelators on iron levels in patients with thalassemia major and intermedia. Methods: This randomized, controlled, and single center trial was performed on 60 patients with thalassemia major and intermedia in Amir Kabir hospital, Iran. Patients were randomized 1:1 to pantoprazole group (iron chelator plus pantoprazole) or control group (iron chelator) for 6 months. Serum ferritin was measured by ELISA. Iron content was measured by magnetic resonance imaging; heart T2* and liver T2*. Results: After 6 months of treatment, a significant reduction was seen in serum ferritin levels in the pantoprazole group (1444 ± 613 μg/mL to 1197 ± 956 μg/mL; P < 0.001). A further reduction was seen in patients with thalassmeia intermedia. There were no significant changes in myocardial T2* values in pantoprazole group compared to control group (23.6 ± 7.3 ms to 24.1 ± 6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7 ± 2.3 ms to 9.8 ± 2.6 ms). However, between-group difference was significant (P < 0.05). Conclusion: Pantoprazole therapy for 6 months has benefits for reducing serum ferritin in patients with thalassemia major and intermedia. Pantoprazole addition to iron chelators seems safe. © 2019 Societe francaise de pharmacologie et de therapeutique

Objective Deferiprone is an iron chelator that has recently been used to treat patients with infratentorial superficial siderosis (iSS). It is considered to have a generally favourable safety profile but concerns have been raised due to the risk of agranulocytosis. We aimed to evaluate the safety and tolerability of oral deferiprone as a treatment for patients with iSS. Methods We present a case series of 10 consecutive patients presenting with classical iSS treated with deferiprone. Results Ten patients were followed up for a mean period of 2.3 years (range 0.5–5.5 years). Four patients (40%) were withdrawn from treatment because of treatment-related side effects. The reasons for treatment discontinuation were neutropenic sepsis (n = 3) and fatigue (n = 1). In 2 out of the 3 cases of neutropenic sepsis, patients initially developed neutropenia without sepsis. The mean time to neutropenic sepsis following deferiprone was 1.2 years (range 0.3–2.5) with mean neutrophil count of 0.4 (range 0.3–0.5). Six patients (60%) reported no change in neurological function while on treatment, and four patients (40%) reported that their condition deteriorated. Conclusions Deferiprone was poorly tolerated, with 40% of patients withdrawing from treatment, most commonly due to neutropenic sepsis, after an average of 2 years on treatment. This study increases the number of reported cases of agranulocytosis in patients with iSS treated with deferiprone. Clinicians treating iSS patients with deferiprone should be aware that this drug has a potentially life-threatening side effect of neutropenic sepsis, and should ensure that appropriate haematological monitoring is in place.

Objectives: Iron overload might lead to bone loss in transfusion-dependent beta-thalassemia (TDT) patients. To investigate the role of iron chelation therapy (ICT) on bone mineral density (BMD) of TDT patients suffering from iron overload, the authors compared the efficacy of five different iron chelation regimens through assessing serum ferritin and BMD.Methods: In 256 consecutive TDT patients, BMD was measured by dual-energy X-ray absorptiometry in lumbar spine and femoral neck regions. Treatment outcome of five iron chelation regimens including Deferoxamine (DFO), Deferiprone (DFP), Deferasirox (DFX), and combination therapy was evaluated to compare the mean differences of serum ferritin and BMD indices pre- and post-treatment during 12-months follow-up period.Results: No significant difference was observed in DXA characteristics and serum ferritin level changes between ICT groups, but combination of DFO and DFX had the best outcome in improving bone mass through assessing each group individually.Conclusion: Combination therapy with DFX and DFO had the highest impact on reducing serum ferritin, however insignificant, and improving bone loss in both lumbar spine and femoral neck in comparison with other regimens. A randomized prospective clinical trial is advised to accurately assess the efficacy of iron chelation regimens on BMD measurements of TDT patients.

Brain iron overload is chronic and slow progressing and plays an important role in the pathogenesis of neurodegenerative disorders. Magnetic resonance imaging (MRI) is a useful noninvasive tool for determining liver iron content, but it has not been proven to be adequate for evaluating brain iron overload. We evaluated the usefulness of MRI-derived parameters to determine brain iron concentration in β-thalassemic mice and the effects of the membrane permeable iron chelator, deferiprone. Sixteen β-thalassemic mice underwent 1.5T MRI of the brain that included a multiecho T2*-weighted sequence. Brain T2* values ranged from 28 to 31ms for thalassemic mice. For the iron overloaded thalassemic mice, brain T2* values decreased, ranging from 8 to 12ms, which correlated with the iron overload status of the animals. In addition, brain T2* values increased in the group with the treatment of deferiprone, ranging from 18 to 24ms. Our results may be useful to understand brain pathology in iron overload. Moreover, data could lead to an earlier diagnosis, assist in following disease progression, and demonstrate the benefits of iron chelation therapy.

While doses of deferiprone up to 75 mg/kg/d have been demonstrated to be effective in cardiac iron removal, their efficacy in the reduction of liver iron has been equivocal. The aim of this study was to evaluate the effect of deferiprone dose on liver iron concentrations in adult iron overload patients.A single-centered, retrospective, cohort observational study was conducted involving 71 patients exposed to deferiprone doses up to 113 mg/kg/d between January 2009 and June 2015 for a median of 33 months.At the end of the study period, liver iron measured by R2 MRI was reduced by a mean 1.7 mg/g dw. A dose effect was observed, with incremental reductions of 2.8 mg/g dw in end of study LIC for every 10 mg/kg/d higher dose of deferiprone (P 0.001). A dose effect was also observed in end of study ferritin and cardiac iron concentration measured by T2* MRI (P 0.0001 and P = 0.048, respectively). No associations between adverse effects and deferiprone dose were observed, but there was a trend toward higher rates of agranulocytosis at higher doses and two of three hereditary hemochromatosis patients developed this complication.The present study failed to demonstrate that the use of deferiprone at90 mg/kg/d was associated with increased risk of agranulocytosis or neutropenia, but did demonstrate more effective liver iron control in iron overload patients.

Objectives Three iron chelators are used to treat transfusion-dependent beta-thalassemia: desferrioxamine (DFO), deferasirox (DFX), and deferiprone (DFP). Compliance is low for DFO as it cannot be administered orally. Combined administration of DFP and DFX is orally available, however, the therapeutic mechanism is unknown. This pilot study investigated the iron removal mechanisms of DFX and DFP treatment in patients with transfusion-dependent thalassemia major. Methods Each patient received three treatments sequentially: (1) DFX monotherapy, (2) DFP monotherapy, and (3) DFX/DFP combination therapy with a four-day washout period between each treatment. Urine and stool specimens were collected to determine the primary outcome of iron excretion volumes. Results The mean iron excretion was seven times higher after combination therapy with DFX and DFP. Monotherapies also increased excretions volumes, though to a significantly lesser degree. Combined administration of DFX and DFP achieves maximum iron removal in transfusion-dependent thalassemia major compared to monotherapy with either drug. Conclusions We suggest combination therapy in chronic severe iron overload cases, especially for patients in poor compliance with DFO/DFP combination therapy or those exhibiting poor iron removal from DFX or DFP monotherapy.

Superficial siderosis is a rare neurodegenerative disease caused by hemosiderin deposition on the brain surface. Although the efficacy of the iron chelator—deferiprone—in superficial siderosis has recently been documented, a comparative study of patients who underwent surgical ablation of their bleeding source and subsequently received treatment with or without deferiprone has not yet been conducted. Fifteen postoperative patients with superficial siderosis were recruited, and seven patients were administered deferiprone (combination therapy group). Quantitative changes in the hypointense signals on T2*-weighted magnetic resonance images were acquired; additionally, cerebellar ataxia was assessed (International Cooperative Ataxia Rating Scale score and Scale for the Assessment and Rating of Ataxia). Audiometry was performed and the results were compared with those of patients who did not receive deferiprone (surgical treatment group; controls). Significant improvements in signal contrast ratios were noted in the lateral orbitofrontal gyrus, superior temporal lobe, insular lobe, brainstem, lingual gyrus, and cerebellar lobe in the combination therapy group. The scores of patients in the combination therapy group on the cerebellar ataxia scales significantly improved. The degree of signal improvement in the cerebellar lobe correlated with the improvement of cerebellar ataxia scores. Early deferiprone administration after disease onset and long-term administration were correlated with greater signal improvements on magnetic resonance imaging. No adverse effects were observed in the clinical or laboratory parameters. Deferiprone administration significantly improved radiological and clinical outcomes in patients with postoperative superficial siderosis. Earlier and longer courses of deferiprone could result in better patient prognosis.

Superficial siderosis describes haemosiderin deposition on the surface of the brain. When present on infratentorial structures, it can cause ataxia, sensorineural hearing loss and pyramidal signs. There is no proven treatment and patients experience slow progression of symptoms. Iron-chelating agents have been suggested as a therapeutic option and deferiprone is suited as it crosses the blood-brain barrier. However, deferiprone is reported to have a 1–2% risk of agranulocytosis. We performed a systematic review on treatment of infratentorial superficial siderosis with deferiprone based on PRISMA guidelines. Studies were included if in English or an English language translation was available, were about human subjects and referred to patients with ataxia. Studies were excluded if they did not possess an English translation, included animal studies or did not have ataxia. Studies were excluded if they discussed cerebral amyloid angiopathy or siderosis of other regions. Eleven papers were included. We identified 69 patients. Seventeen patients (25%) discontinued the drug. The most encountered adverse effect was anaemia (21.7%). Neutropaenia was observed in 8.7% and agranulocytosis in 5.8% of patients. Clinically, response varied, and stability or improvement was seen across neurological domains in 6 studies while 5 showed a mixed response. On imaging, 13 (28.9%) patients improved, 24 (53.3%) stabilised and 8 (17.8%) deteriorated. A prospective international centralised register of patients should be developed to inform the design and conduct of a multicentre, placebo-controlled, randomised clinical trial to evaluate the efficacy of deferiprone. The evidence from this systematic review is that deferiprone is a promising intervention.

Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.

Objectives: Assess the safety and efficacy of deferiprone (DFP) in chronically transfused, iron-overloaded patients with sickle cell disease (SCD) or other anemias. Methods: FIRST was a multicenter, 1-year, noninferiority trial of DFP vs deferoxamine (DFO). Patients ≥2 years of age were randomly assigned 2:1 to receive DFP or DFO. Those who completed FIRST could enter FIRST-EXT, a 2-year extension in which all patients received DFP. Thus, the baseline was the start of FIRST for patients randomized to DFP (up to 3 years for the DFP-DFP group), and the start of FIRST-EXT for patients randomized to DFO in FIRST (up to 2 years for the DFO- DFP group). In both studies, efficacy endpoints were yearly changes from baseline in liver iron concentration (LIC), cardiac MRI T2*, and serum ferritin (SF) level. All adverse drug reactions (ADRs) for both studies were recorded. Results: In FIRST, patients (N = 228) were 46.9% female, mean age was 16.9 (standard deviation [SD] 9.6; range 3–59) years, 84.2% had SCD and 15.8% had other anemias. At 1 year, there were no significant (p > 0.05) differences in change in LIC, cardiac MRI T2*, or SF measures between the DFP and DFO intent-to-treat groups. Common ADRs (≥5% of patients) in the DFP group were abdominal pain, vomiting, pyrexia, increased alanine transaminase, increased aspartate aminotransferase, neutropenia, nausea, and chromaturia; in the DFO group, they were pyrexia and injection site pain. Serious ADRs in the DFP group were neutropenia (2.6%), increased transaminases (1.3%), and agranulocytosis, sickle cell crisis, epididymitis, Propionibacterium infection, bacterial sinusitis (infections not associated with neutropenia), vascular device infection, and migraine (0.7% each); in the DFO group, they were abdominal pain, arthritis, and headache (1.3% each). 134 Patients continued to FIRST-EXT (n = 89 DFP-DFP; n = 45 DFO-DFP): 60.4% were male, mean age was 16.2 (SD 8.6; range 4–47) years, 85.8% had SCD and 14.2% had other anemias. At baseline, all patients had elevated LIC with a mean (SD) of 14.93 (7.61) mg/g dry weight (dw), all had normal cardiac iron with a mean (SD) MRI T2* of 32.69 (17.66) ms, and all but 1 had elevated SF with a mean (SD) of 3894 (2591) μg/L. LIC decreased with mean (SD) reductions of -2.64 (4.64), -3.91 (6.38), and -6.64 (7.72) mg/g dw after 1, 2, and 3 years, respectively (p < 0.01 for all years). Cardiac iron remains in the normal range for all patients. SF levels declined with mean (SD) changes from baseline to years 1, 2, and 3 of -1 (1986), -771 (2171), and -1016 (3617) μg/L, respectively (p < 0.05 for years 2 and 3). No new ADRs (observed in 30.6% of patients) were reported. One patient withdrew due to ADRs of thrombocytopenia and neutropenia, which resolved. Another patient withdrew due to generalized edema and died for reasons unknown 17 days after withdrawal from the study. Discussion/Conclusion: DFP effectively controlled iron burden in chronically transfused patients with SCD and other anemias, and it was noninferior to DFO. DFP use was associated with reductions in LIC and SF levels. Cardiac MRI T2* remained normal. DFP was well tolerated in patients who received up to 3 years of treatment, with no new safety concerns. We thank Dr. M Badr, Dr. B Inusa, Dr. AAM Adly, Dr. Y Kilinc, C Fradette, and NT Temin for their contribution to the studies. Sponsored by Chiesi Global Rare Diseases; medical writing support provided by Oxford PharmaGenesis Inc., and funded by Chiesi.

Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in some organs including the liver, glands, brain, heart, gastrointestinal tract and lung. Iron chelation therapy could be con-sidered an effective approach for removing excess iron. Deferoxamine, deferiprone and deferasirox are three common iron chelators in clinical practice but cause several side effects. In this context, the use of curcumin, a dietary phytochemical derived from turmeric, as a natural and safe antioxi-dant with iron-chelating activity may be a useful strategy for the management of iron overload. This review focuses on the deleterious effect of iron accumulation in different organs of the body as well as the therapeutic potential of curcumin against iron-induced toxicity.

Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

Raffaele Nuzzi,1 Giada Geronazzo,1,2 Federico Tridico,1 Alessia Nuzzi,3 Paolo Caselgrandi,1 Antonio Giulio Piga4 1Eye Clinic Section, Department of Surgical Sciences, University of Turin, Turin, Italy; 2Regional Reference Centre for Diagnosis and Cure of Hemoglobinopathies, S. Luigi Gonzaga University Hospital, University of Turin, Orbassano (TO), Italy; 3Department of Clinical Sciences and Community Health, Eye Clinic San Giuseppe Hospital, IRCCS Multimedica, University of Milan, Milan, Italy; 4Head of Regional Reference Centre for Diagnosis and Cure of Hemoglobinopathies, S. Luigi Gonzaga University Hospital, University of Turin, Orbassano (TO), ItalyCorrespondence: Raffaele NuzziEye Clinic Section, Department of Surgical Sciences, University of Turin, Via Cherasco 23, Turin, 10126, ItalyEmail prof.nuzzi_raffaele@hotmail.itBackground: 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.Keywords: iron chelation, ocular adverse effects, deferiprone, deferasirox, deferoxamine

Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway. 196

Introduction Adhesions are often considered to be an inevitable consequence of abdominal and pelvic surgery, jeopardizing the medium and long-term success of these procedures. Numerous strategies have been tested to reduce adhesion formation, however, to date, no surgical or medical therapeutic approaches have been successful in its prevention. This study demonstrates the safety and efficacy of Chitogel with Deferiprone and/or antibacterial Gallium Protoporphyrin in different concentrations in preventing adhesion formation after abdominal surgery. Materials and methods 112 adult (8–10 week old) male Wistar albino rats were subjected to midline laparotomy and caecal abrasion, with 48 rats having an additional enterotomy and suturing. Kaolin (0.005g/ml) was applied to further accelerate adhesion formation. The abrasion model rats were randomized to receive saline, Chitogel, or Chitogel plus Deferiprone (5, 10 or 20 mM), together with Gallium Protoporphyrin (250μg/mL). The abrasion with enterotomy rats were randomised to receive saline, Chitogel or Chitogel with Deferiprone (1 or 5 mM). At day 21, rats were euthanised, and adhesions graded macroscopically and microscopically; the tensile strength of the repaired caecum was determined by an investigator blinded to the treatment groups. Results Chitogel with Deferiprone 5 mM significantly reduced adhesion formation (p Conclusions Chitogel with Deferiprone 1 mM constitutes an effective preventative anti-adhesion barrier after abdominal surgery in a rat model. Moreover, this therapeutic combination of agents is safe and does not weaken the healing of the sutured enterotomy site.

Background Abnormally hyperphosphorylated tau is a defining pathological feature of tauopathies, such as Alzheimer's disease (AD), and accumulating evidence suggests a role for iron in mediating tau pathology that may lead to cognitive decline in these conditions. The metal chelator deferiprone (DFP), which has a high affinity for iron, is currently in clinical trials for AD and Parkinson's disease. However, the effect of DFP on tau pathology remains underexplored. Objective We aimed to investigate the impact of chronic DFP treatment on tau pathology using a well-characterized mouse model of tauopathy (rTg(tauP301L)4510). Methods Animals were treated daily with DFP (100 mg/kg) via oral gavage for 16 weeks. After 14 weeks, mice were tested in the Y-maze, open field, Morris water maze, and rotorod. At the end of the study, brain tissue was collected to examine metal levels (using inductively coupled plasma-mass spectrometry) and for western blot analysis of DFP on tau and iron associated pathways. Results DFP significantly reduced anxiety-like behavior, and revealed a trend toward improved cognitive function. This was accompanied by a decrease in brain iron levels and sarkosyl-insoluble tau. Our data also showed downregulation of the tau kinases glycogen synthase kinase 3β and cyclin dependent kinase-5 in DFP treated mice and an increase in the methylation of the catalytic subunit of protein phosphatase 2A. Conclusion These data support the hypothesis that suggests that iron plays a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders.

Objectives The main therapy of β-thalassemia major are blood transfusion and iron chelation drugs. However, those therapies also have some adverse effects and problems such as iron overload, transfusion reactions, nutritional deficiencies, and patient compliance problems. Those arising problems also have an impact on therapy cost. Hence, this study was designed to analyze drug utilization study and cost of therapy in β-thalassemia major adult patients at Dr. Soetomo General Hospital Surabaya. Methods This research was conducted in descriptive observational-retrospective design using secondary data obtained from patient’s medical records and billing registrations from January 1–December 31, 2019. Results There were 18 patients out of 233 patients that were analyzed. Deferasirox was the most administered drug with doses between 500 mg/day–1,500 mg/day while deferiprone was ranged between 1,500 and 4,500 mg/day. Patients also received transfusion reaction drugs with dexamethasone injection 5 mg/ml which was administered the most. The most administered supplement was folic acid 1 mg. Patients had an increase in serum ferritin due to low compliance. Deferasirox had the most adherence number of patients with decrease of serum ferritin. The two highest costs of direct medical components were top-up medicines and consumable medical supplies. Overall, the hospital gained profit from national health insurance claims. Conclusions The most administered chelating agent was deferasirox. Deferasirox also had the most adherence number of patients with decreased number of serum ferritin. However, deferasirox also yielded the highest cost. Yet, overall, the hospital gained profit from national health insurance claims.

Background: Iron extra load is an anticipated and lethal consequence of chronic blood transfusion in major beta-thalassemia patients; therefore it is necessary to use an efficient iron chelator drug to stimulate the evacuation of the surplus iron from the body. This trial was performed to compare myocardial and hepatic magnetic resonance imaging T2 (MRI T2*) results of beta-thalassemia patients treated by Deferasirox or combination of Deferoxamine and Deferiprone. Material and Methods: In this clinical trial, 44 patients who were on combination therapy with Deferiprone and Deferoxamine and complied with the inclusion criteria were randomized to either case (Deferasirox) or control (combined therapy) groups. Twenty-two patients in the case group received Deferasirox. For 22 patients in the control group, prior treatment with Deferiprone and Deferoxamine was continued. Myocardial and hepatic MRI T2* results were assessed before and after the study. Moreover, serum ferritin level (SFL) was evaluated every 3 months. Results: SFL at the start of the study did not differ significantly in two groups (2158.1± 1012.2 μg/L in the control group vs. 2145.5±1121.4 μg/L in the case group) (P=0.08). SFL at the end of the study did not differ significantly in two groups (2204.4±1143.5 μg/L in the control group vs. 2347.2±1236.6 μg/L in the case group), either (P=0.12). In each group, myocardial and hepatic MRI T2 at the start and at the end of the trial did not differ significantly (P>0.1). Conclusion: Myocardial and hepatic MRI T2*results were better in the control (combination therapy) group than those in the case (Deferasirox) group. Major beta-thalassemia patients replied to combined treatment better than Deferasirox.

Murine hematopoietic-acute radiation syndrome (H-ARS) survivors of total body radiation (TBI) have a significant loss of heart vessel endothelial cells, along with increased tissue iron, as early as 4 months post-TBI. The goal of the current study was to determine the possible role for excess tissue iron in the loss of coronary artery endothelial cells. Experiments utilized the H-ARS mouse model with gamma radiation exposure of 853 cGy (LD50/30) and time points from 1 to 12 weeks post-TBI. Serum iron was elevated at 1 week post-TBI, peaked at 2 weeks, and returned to non-irradiated control values by 4 weeks post-TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number. Perls’ Prussian Blue staining used to detect iron deposition in heart tissue sections showed myocardial iron was present as early as 2 weeks following irradiation. Pretreatment of mice with the iron chelator deferiprone decreased tissue iron, but not serum iron, at 2 weeks. Coronary artery endothelial cell density was significantly decreased as early as two weeks vs. non-irradiated controls (P

Background Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts. Objectives The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo. Methods We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis. Results In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses. Conclusions The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.

Background Aceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. The effects of iron chelation on neurological outcomes have only been described in case studies, and are inconsistent. Aggregated case reports were analyzed to help delineate the disease-modifying potential of treatment. Methods Data on clinical manifestations, treatment and neurological outcomes of treatment were collected from three neurologically symptomatic Dutch patients, who received deferiprone with phlebotomy as a new therapeutic approach, and combined with other published cases. Neurological outcomes of treatment were compared between patients starting treatment when neurologically symptomatic and patients without neurological manifestations. Results Therapeutic approaches for aceruloplasminemia have been described in 48 patients worldwide, including our three patients. Initiation of treatment in a presymptomatic stage of the disease delayed the estimated onset of neurological manifestations by 10 years (median age 61 years, SE 5.0 vs. median age 51 years, SE 0.6, p = 0.001). Although in 11/20 neurologically symptomatic patients neurological manifestations remained stable or improved during treatment, these patients were treated significantly shorter than patients who deteriorated neurologically (median 6 months vs. median 43 months, p = 0.016). Combined iron chelation therapy with deferiprone and phlebotomy for up to 34 months could be safely performed in our patients without symptomatic anemia (2/3), but did not prevent further neurological deterioration. Conclusions Early initiation of iron chelation therapy seems to postpone the onset of neurological manifestations in aceruloplasminemia. Publication bias and significant differences in duration of treatment should be considered when interpreting reported treatment outcomes in neurologically symptomatic patients. Based on theoretical grounds and the observed long-term safety and tolerability in our study, we recommend iron chelation therapy with deferiprone in combination with phlebotomy for aceruloplasminemia patients without symptomatic anemia.

The ongoing outbreak of novel coronavirus pneumonia (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) in China is lifting widespread concerns. Thus, therapeutic options are urgently needed, and will be discussed in this review. Iron-containing enzymes are required for viruses most likely including coronaviruses (CoVs) to complete their replication process. Moreover, poor prognosis occurred in the conditions of iron overload for patients upon infections of viruses. Thus, limiting iron represents a promising adjuvant strategy in treating viral infection through oral uptake or venous injection of iron chelators, or through the manipulation of the key iron regulators. For example, treatment with iron chelator deferiprone has been shown to prolong the survival of acquired immunodeficiency syndrome (AIDS) patients. Increasing intracellular iron efflux via increasing iron exporter ferroportin expression also exhibits antiviral effect on human immunodeficiency virus (HIV). The implications of other metals besides iron are also briefly discussed. For even though we know little about iron regulation in COVID-19 patients thus far, it could be deduced from other viral infections that iron chelation might be an alternative beneficial adjuvant in treating COVID-19.