Deferiprone-resveratrol hybrid attenuates iron accumulation, oxidative stress, and antioxidant defenses in iron-loaded human Huh7 hepatic cells.

Chronic liver diseases are complications of thalassemia with iron overload. Iron chelators are required to remove excessive iron, and antioxidants are supplemented to diminish harmful reactive oxygen species (ROS), purposing to ameliorate oxidative liver damage and dysfunctions. The deferiprone-resveratrol hybrid (DFP-RVT) is a synthetic iron chelator possessing anti-ß-amyloid peptide aggregation, anti-malarial activity, and hepatoprotection in plasmodium-infected mice. The study focuses on investigating the antioxidant, cytotoxicity, iron-chelating, anti-lipid peroxidation, and antioxidant defense properties of DFP-RVT in iron-loaded human hepatocellular carcinoma (Huh7) cells. In the findings, DFP-RVT dose dependently bound Fe(II) and Fe(III) and exerted stronger ABTS•- and DPPH•-scavenging (IC50 = 8.0 and 164 µM, respectively) and anti-RBC hemolytic activities (IC50 = 640 µM) than DFP but weaker than RVT (p < 0.01). DFP-RVT was neither toxic to Huh7 cells nor PBMCs. In addition, DFP-RVT diminished the level of redox-active iron (p < 0.01) and decreased the non-heme iron content (p < 0.01) in iron-loaded Huh7 cells effectively when compared without treatment in the order of DFP-RVT > RVT ∼ DFP treatments (50 µM each). Moreover, the compound decreased levels of hepatic ROS in a dose-dependent manner and the level of malondialdehyde, which was stronger than DFP but weaker than RVT. Furthermore, DFP-RVT restored the decrease in the GSH content and GPX and SOD activities (p < 0.01) in iron-loaded Huh7 cells in the dose-dependent manner, consistently in the order of RVT > DFP-RVT > DFP. Thus, the DFP-RVT hybrid possesses potent iron chelation, antioxidation, anti-lipid peroxidation, and antioxidant defense against oxidative liver damage under iron overload.

The Oxidative Stress Response Highly Depends on Glucose and Iron Availability in Aspergillus fumigatus.

Pathogens have to cope with oxidative, iron- and carbon(glucose)-limitation stresses in the human body. To understand how combined iron-carbon limitation alters oxidative stress responses, Aspergillus fumigatus was cultured in glucose-peptone or peptone containing media supplemented or not with deferiprone as an iron chelator. Changes in the transcriptome in these cultures were recorded after H2O2 treatment. Responses to oxidative stress were highly dependent on the availability of glucose and iron. Out of the 16 stress responsive antioxidative enzyme genes, only the cat2 catalase-peroxidase gene was upregulated in more than two culturing conditions. The transcriptional responses observed in iron metabolism also varied substantially in these cultures. Only extracellular siderophore production appeared important regardless of culturing conditions in oxidative stress protection, while the enhanced synthesis of Fe-S cluster proteins seemed to be crucial for oxidative stress treated iron-limited and fast growing (glucose rich) cultures. Although pathogens and host cells live together in the same place, their culturing conditions (e.g., iron availability or occurrence of oxidative stress) can be different. Therefore, inhibition of a universally important biochemical process, like Fe-S cluster assembly, may selectively inhibit the pathogen growth in vivo and represent a potential target for antifungal therapy.

The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group.

BACKGROUND: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. METHODS: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. RESULTS: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1-2. CONCLUSIONS: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

Efficacy and Safety of Combined Deferiprone and Deferasirox in Iron-Overloaded Patients: A Systematic Review.

Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an optimal chelating regimen. Deferasirox (DFX) and deferiprone (DFP) are two oral iron chelators, and combination usage demonstrated effectiveness as an alternative to monotherapies in patients with a limited response to monotherapy. The present systematic review aimed to assess the evidence regarding the outcomes of combined DFP and DFX in iron-overloaded patients. An online search was conducted in PubMed, Scopus, Web of Science, and CENTRAL databases. Interventional and observational studies that assessed the outcomes of combined DFP and DFX in iron-overloaded patients were included. Eleven studies (12 reports) were considered in this meta-analysis. The studies included dual iron chelation strategies for a number of diagnoses. Single-arm studies (n =7) showed a reduction of serum ferritin, which reached the level of statistical significance in three studies. Likewise, most studies reported a numerical reduction in liver iron concentration (LIC) and increased cardiac MRI-T2* values after chelating therapy. Alternatively, comparative studies showed no significant difference in post-treatment serum ferritin between DFX plus DFP and DFX/DFP plus deferoxamine (DFO). The adherence to combination therapy was good to average in nearly 66.7-100% of the patients across four studies. One study reported a poor adherence rate. The combined regimen was generally tolerable, with no reported incidence of serious adverse events among the included studies. In conclusion, the DFP and DFX combination is a safe and feasible option for iron overload patients with a limited response to monotherapy.

Combination chelation therapy.

Combination chelation therapies are considered in transfusion-dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or intensification of iron chelation therapy is required for the rapid reduction of excess iron to avoid permanent organ damage. Combination chelation may provide a more flexible approach for individualizing chelation therapy, thereby improving tolerability, adherence, and quality of life. In principle, iron chelators can be combined with an infinite number of dosing regimens; these involve simultaneous or sequential exposure to the chelators on the same day or alternating the drugs on different days. Clinical studies have established the safety and efficacy of chelation combinations. However, real-life data with combination therapies indicate the significance of compliance for a meaningful reduction in iron overload compared to monotherapies.

The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases.

The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.

A novel C19ORF12 mutation in two MPAN sisters treated with deferiprone.

BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare and devastating disease caused by pathogenic mutations in C19orf12 gene. MPAN is characterized by pathological iron accumulation in the brain and fewer than 100 cases of MPAN have been described. Although the diagnosis of MPAN has achieved a great breakthrough with the application of the whole exome gene sequencing technology, the therapeutic effect of iron chelation therapy in MPAN remains controversial. CASE PRESENTATION: We reported that two sisters from the same family diagnosed with MPAN had dramatically different responses to deferiprone (DFP) treatment. The diagnosis of MPAN were established based on typical clinical manifestations, physical examination, brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF) and gene sequencing results. The clinical presentations of the two sisters with MPAN due to novel gene locus mutations were similar to those previously reported. There is no other difference in basic information except that the proband had a later onset age and fertility history. Both the proband and his second sister were treated with deferiprone (DFP), but they had dramatically different responses to the treatment. The proband's condition deteriorated sharply after treatment with DFP including psychiatric symptoms and movement disorders. However, the second sister of the proband became relatively stable after receiving the DFP treatment. After four years of follow-up, the patient still denies any new symptoms of neurological deficits. CONCLUSION: The findings of this study enriched the MPAN gene database and indicated that DFP might ameliorate symptom progression in patients without severe autonomic neuropsychiatric impairment at the early stage of the disease.

Clinical Challenges with Iron Chelation in Beta Thalassemia.

Conventional therapy for severe thalassemia includes regular red cell transfusions and iron chelation therapy to prevent and treat complications of iron overload. Iron chelation is very effective when appropriately used, but inadequate iron chelation therapy continues to contribute to preventable morbidity and mortality in transfusion-dependent thalassemia. Factors that contribute to suboptimal iron chelation include poor adherence, variable pharmacokinetics, chelator adverse effects, and difficulties with precise monitoring of response. The regular assessment of adherence, adverse effects, and iron burden with appropriate treatment adjustments is necessary to optimize patient outcomes.

Chelation Combination-A Strategy to Mitigate the Neurotoxicity of Manganese, Iron, and Copper?

The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox-DFOA and the tetrathiomolybdate-DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations.

Effects of subacute cadmium exposure and subsequent deferiprone treatment on cadmium accumulation and on the homeostasis of essential elements in the mouse brain.

INTRODUCTION: Cadmium (Cd) is а hazardous multi-organ toxin. In this study, we provide the first results about the effect of oral administration of deferiprone (DFP) on Cd accumulation and on the homeostasis of essential elements in the brain of Cd-exposed mice. METHODS: Adult Institute of Cancer Research (ICR) male mice were randomized into four experimental groups: untreated controls - administered distilled water for 28 days; Cd-exposed group - exposed to 18 mg/kg body weight (b.w.) Cd(II) acetate for 14 days followed by the administration of distilled water for two weeks; Cd + DFP (low dose) - Cd-intoxicated mice subsequently treated with 19 mg/kg b.w. DFP for two weeks; and Cd + DFP (high dose) - Cd-exposed mice administered high-dose DFP (135 mg/kg b.w.) for 14 days. Brains were subjected to inductively coupled plasma-mass spectrometry (ICP-MS) and histological analysis. RESULTS: The results revealed that exposure of mice to Cd for 14 days significantly increased Cd concentration and significantly decreased magnesium (Mg), phosphorus (P), and zinc (Zn) contents in the brain compared to untreated controls. This effect was accompanied by necrotic-degenerative changes in both the cerebrum and cerebellum. Oral administration of low-dose DFP to Cd-exposed mice decreased the concentration of the toxic metal in the brain by 16.37% and restored the concentration of the essential elements to normal control values. Histological analysis revealed substantially improved cerebral and cerebellar histoarchitectures. In contrast, oral administration of high-dose DFP increased Cd content and significantly decreased selenium (Se) concentration in the brain. Necrotic neurons and Purkinje cells were still observed in the cerebral and cerebellar cortices. CONCLUSION: The results demonstrated that oral administration of DFP at low doses has a better therapeutic potential for the treatment of Cd-induced brain damage compared to high doses.

Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.

Neurodegeneration with brain iron accumulation (NBIA) comprises various rare clinical entities with brain iron overload as a common feature. Magnetic resonance imaging (MRI) allows diagnosis of this condition, and genetic molecular testing can confirm the diagnosis to better understand the intracellular damage mechanism involved. NBIA groups disorders include: pantothenate kinase-associated neurodegeneration (PKAN), mutations in the gene encoding pantothenate kinase 2 (PANK2); neuroferritinopathy, mutations in the calcium-independent phospholipase A2 gene (PLA2G6); aceruloplasminemia; and other subtypes with no specific clinical or MRI specific patterns identified. There is no causal therapy, and only symptom treatments are available for this condition. Promising strategies include the use of deferiprone (DFP), an orally administered bidentate iron chelator with the ability to pass through the blood-brain barrier. This is a prospective study analysis with a mean follow-up time of 5.5 ± 2.3 years (min-max: 2.4-9.6 years) to define DFP (15 mg/kg bid)'s efficacy and safety in the continuous treatment of 10 NBIA patients through clinical and neuroradiological evaluation. Our results show the progressive decrease in the cerebral accumulation of iron evaluated by MRI and a substantial stability of the overall clinical neurological picture without a significant correlation between clinical and radiological findings. Complete ferrochelation throughout the day appears to be of fundamental importance considering that oxidative damage is generated, above, all by non-transferrin-bound iron (NTBI); thus, we hypothesize that a (TID) administration regimen of DFP might better apply its chelating properties over 24 h with the aim to also obtain clinical improvement beyond the neuroradiological improvement.

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology.

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a "magic bullet" drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.

Characterisation of individual ferritin response in patients receiving chelation therapy.

AIMS: To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. METHODS: Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. RESULTS: An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079-0.0131] vs. 0.0013 [90% CI: 0.0008-0.0018] L/mg mo). In addition to drug-specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. CONCLUSION: Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug-induced changes in iron elimination rate and ferritin production. The use of a semi-mechanistic parameterisation allowed us to disentangle disease-specific factors from drug-specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.

The pharmacokinetic and safety profile of single-dose deferiprone in subjects with sickle cell disease.

Patients with sickle cell disease (SCD) who undergo repeated blood transfusions often develop iron overload. Deferiprone (Ferriprox®) is an oral iron chelator indicated for the treatment of transfusional iron overload due to thalassemia syndromes and has been recently approved as a treatment for iron overload in adult and pediatric patients with SCD and other anemias. The present study aims to characterize the pharmacokinetic (PK) profile of deferiprone (DFP) in adult subjects with SCD. In this phase I, open-label study, subjects with SCD were administered a single 1500 mg dose of DFP. Blood and urine samples were collected for PK assessments of DFP and its main metabolite, deferiprone 3-O-glucuronide (DFP-G). Eight subjects were enrolled and completed the study. Following drug administration, serum levels of DFP and DFP-G rose to maximum concentrations at 1.0 and 2.8 h post-dose, respectively. The half-lives of DFP and DFP-G were 1.5 and 1.6 h, respectively. The majority of administered drug was metabolized and excreted as DFP-G, with less than 4% excreted unchanged in urine up to 10 h post-dose. Subjects received a safety assessment 7 (± 3) days post-dose. Two subjects reported mild adverse events unrelated to the study drug, and no other safety concerns were reported. The PK profile of DFP in SCD subjects is consistent with previous reports in healthy adult volunteers, suggesting no special dosing adjustments are indicated for this population. These findings provide valuable insight for treating iron overload in patients with SCD, who have limited chelation therapy treatment options (trial registration number: NCT01835496, date of registration: April 19, 2013).

Iron chelation therapy with deferiprone improves oxidative status and red blood cell quality and reduces redox-active iron in ß-thalassemia/hemoglobin E patients.

The oxidative status of twenty-three ß-thalassemia/hemoglobin E patients was evaluated after administration of 75 mg/kg deferiprone (GPO-L-ONE®) divided into 3 doses daily for 12 months. Serum ferritin was significantly decreased; the median value at the initial and final assessments was 2842 and 1719 ng/mL, respectively. Progressive improvement with significant changes in antioxidant enzyme activity, including plasma paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH), and in antioxidant enzymes in red blood cells (glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD)) were observed at 3-6 months of treatment. The levels of total GSH in red blood cells were significantly increased at the end of the study. Improved red blood cell membrane integrity was also demonstrated using the EPR spin labeling technique. Membrane fluidity at the surface and hydrophobic regions of the red blood cell membrane was significantly changed after 12 months of treatment. In addition, a significant increase in hemoglobin content was observed (6.6 ± 0.7 and 7.5 ± 1.3 g/dL at the initial assessment and at 6 months, respectively). Correlations were observed between hemoglobin content, membrane fluidity and antioxidant enzymes in red blood cells. The antioxidant activity of deferiprone may partly be explained by progressive reduction of redox active iron that catalyzes free radical reactions, as demonstrated by the EPR spin trapping technique. In conclusion, iron chelation therapy with deferiprone notably improved the oxidative status in thalassemia, consequently reducing the risk of oxidative-related complications. Furthermore, the improvement in red blood cell quality may improve the anemia situation in patients.

Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy.

The blood-brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski's rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron chelators employed N-aliphatic alcohols modification of deferiprone were reasonably designed in this work. The chelators not only meet Lipinski's rule for BBB permeability, but also ensure the iron affinity. The results of solution thermodynamics demonstrated that the pFe3+ value of N-hydroxyalkyl substituted deferiprone is between 19.20 and 19.36, which is comparable to that of clinical deferiprone. The results of 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays indicated that the N-hydroxyalkyl substituted deferiprone also possesses similar radical scavenging ability in comparison to deferiprone. Meanwhile, the Cell Counting Kit-8 assays of neuron-like rat pheochromocytoma cell-line demonstrated that the N-hydroxyalkyl substituted deferiprone exhibits extremely low cytotoxicity and excellent H2O2-induced oxidative stress protection effect. These results indicated that N-hydroxyalkyl substituted deferiprone has potential application prospects as chelating agents for Parkinson's disease chelation therapy strategy.

Long-Term Effects of Iron Chelating Agents on Ocular Function in Patients with Thalassemia Major.

BACKGROUND: The aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the onset of ocular alterations and the intake of iron chelating drugs. METHODS: A prospective cohort study was performed. Eighty-eight patients, composed of children and adults with thalassemia major (TM) who are taking or had taken iron chelating drugs (deferoxamine, deferiprone or deferasirox), have been initially enrolled in the study. The final sample featured 80 patients, including 18 children and 62 adults. These subjects received an eye examination to evaluate intraocular pressure (IOP), best corrected visual acuity (BCVA), the presence of refractive defects, cornea, anterior chamber, lens, fundus oculi, visual field and mean retinal nerve fiber layer (RNFL) thickness. Logistic regression model analysis was performed in order to assess any correlation. In addition, a literature search regarding the relation between iron chelating drugs and ocular adverse events was carried out to compare the results obtained with the evidence in the literature. RESULTS: Logistic regression did not report a significant correlation between the intake of iron chelating drugs and the onset of anterior ocular segment alterations, lens opacities, retinal diseases, optical neuropathies, astigmatism, visual field and RNFL thickness defects. Logistic regression returned a statistically significant correlation between myopia and iron chelation therapy (p-value 0.04; OR 1.05) and also between presbyopia and total duration of therapy with deferoxamine (p-value 0.03; OR 1.21). Although intraocular pressure levels remained within the normal range, a significant correlation with the length of deferoxamine therapy has been found (p-value 0.002; association coefficient -0.12). A negative correlation between deferiprone and presbyopia has also been observed. CONCLUSION: Iron chelation therapy is not associated with severe visual function alterations. Limitation of deferoxamine treatment can help prevent ocular complications. Deferiprone and/or deferasirox may be preferable, especially in patients over age 40 years.

Adherence to Iron Chelation Therapy and Its Determinants.

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.

Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis.

The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive neurodegenerative disorders unified by the accumulation of lysosomal auto-fluorescent material called lipofuscin. The only form that occurs via autosomal-dominant inheritance exhibits adult onset and is sometimes referred to as Parry type NCL. The manifestations may include behavioral symptoms followed by seizures, ataxia, dementia, and early death. Mutations in the gene DNAJC5 that codes for the presynaptic co-chaperone cysteine string protein-α (CSPα) were recently reported in sporadic adult-onset cases and in families with dominant inheritance. The mutant CSPα protein may lead to disease progression by both loss and gain of function mechanisms. Iron chelation therapy may be considered as a possible pharmaceutical intervention based on our recent mechanism-based proposal of CSPα oligomerization via ectopic Fe-S cluster-binding, summarized in this review.

Efficacy and Safety of Combined Oral Chelation with Deferiprone and Deferasirox on Iron Overload in Transfusion Dependent Children with Thalassemia - A Prospective Observational Study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.