Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents.

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

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

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.

SLN124, a GalNac-siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron-overload in a mouse model of ß-thalassaemia.

Beta-thalassaemia is an inherited blood disorder characterised by ineffective erythropoiesis and anaemia. Consequently, hepcidin expression is reduced resulting in increased iron absorption and primary iron overload. Hepcidin is under the negative control of transmembrane serine protease 6 (TMPRSS6) via cleavage of haemojuvelin (HJV), a co-receptor for the bone morphogenetic protein (BMP)-mothers against decapentaplegic homologue (SMAD) signalling pathway. Considering the central role of the TMPRSS6/HJV/hepcidin axis in iron homeostasis, the inhibition of TMPRSS6 expression represents a promising therapeutic strategy to increase hepcidin production and ameliorate anaemia and iron overload in ß-thalassaemia. In the present study, we investigated a small interfering RNA (siRNA) conjugate optimised for hepatic targeting of Tmprss6 (SLN124) in ß-thalassaemia mice (Hbbth3/+ ). Two subcutaneous injections of SLN124 (3 mg/kg) were sufficient to normalise hepcidin expression and reduce anaemia. We also observed a significant improvement in erythroid maturation, which was associated with a significant reduction in splenomegaly. Treatment with the iron chelator, deferiprone (DFP), did not impact any of the erythroid parameters. However, the combination of SLN124 with DFP was more effective in reducing hepatic iron overload than either treatment alone. Collectively, we show that the combination therapy can ameliorate several disease symptoms associated with chronic anaemia and iron overload, and therefore represents a promising pharmacological modality for the treatment of ß-thalassaemia and related disorders.

Combined chelation with high-dose deferiprone and deferoxamine to improve survival and restore cardiac function effectively in patients with transfusion-dependent thalassemia presenting severe cardiac complications.

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 < 0.001). There were no deaths, and all patients were discharged from hospital with good quality of life. In contrast, all the eight patients receiving DFO monotherapy died (P < 0.001). Accordingly, combined chelation therapy with high-dose L1 and DFO should be considered in patients with TDT presenting cardiac complications.

Effectiveness of deferiprone-loaded nanocarrier in experimentally induced rhabdomyolysis: A dose-comparison study.

Herein, the efficacy of free deferiprone (DFP) and DFP-loaded starch/polyethylene glycol/polyacrylic acid (St/PEG/PAAc) nanogel [Nano-DFP] in modulating the biochemical changes induced by glycerol model of rhabdomyolysis (RBD) in male rats was investigated. In this respect, gamma radiation-induced crosslinking was used to produce St/PEG/PAAc nanogel particles, and then, it was used as a nanocarrier for DFP as an attempt to overcome the poor bioavailability and short half-life of DFP. St/PEG/PAAc nanogel was characterized by Fourier transform infrared, dynamic light scattering and Transmission electron microscopy. Free DFP was administered to rats in two doses; 25 and 50 mg following RBD induction, while the loaded nanogel was administered at a dose of 25 mg. The liver and kidney functions were then fully assessed in association with the histological tissue examination of both organs and the femur muscle. Both doses of DFP significantly antagonized the RBD-induced changes in most of the assessed organs functions. The higher dose of DFP, however, showed a statistically more pronounced modulation of RBD effects on each of kidney, liver and skeletal muscles. Nano-DFP; at 25 mg dose, resulted in a statistically significant correction of most of the RBD-related biomarkers with a comparable magnitude to the higher DFP dose rather than the corresponding lower one.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Iron chelation by deferiprone does not rescue the Niemann-Pick Disease Type C1 mouse model.

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.

Oral administration of the iron chelator deferiprone protects against loss of retinal ganglion cells in a mouse model of glaucoma.

Glaucoma is a progressive neurodegenerative process affecting the retinal ganglion cells (RGCs) and the optic nerve. Oxidative stress has been implicated in glaucoma pathogenesis, and iron is a potent generator of oxidative stress. The oral iron chelator deferiprone (DFP) is protective against retinal degenerations associated with oxidative stress. To test whether DFP could be protective in glaucoma, we used microbead injections to induce elevated intraocular pressure (IOP) in a cohort of 3-month old C57BL/6J mice. One eye of each animal was injected with magnetic microbeads resulting in ocular hypertension for >7 weeks while the fellow eye was injected with saline and served as a normotensive internal control. While half of the cohort received oral DFP (1 mg/ml in the drinking water), the other half did not and served as controls. After 8 weeks, Brn3a immunolabeling of flat-mounted retinas was used for manual RGC quantification. Axon counts were obtained from thin sections of optic nerves using the AxonJ plugin for ImageJ. DFP administration was protective against RGC and optic nerve loss in the setting of elevated IOP. These results suggest that iron chelation by DFP may provide glaucoma neuroprotection.

Deferiprone ameliorates memory impairment in Scopolamine-treated rats: The impact of its iron-chelating effect on ß-amyloid disposition.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive and memory problems. Scopolamine (SCOP) is a natural anticholinergic drug that was proven to cause memory impairment in rats. Chelating agents are potential neuroprotective and memory enhancing agents as they can trap iron that enters in pathological deposition of ß-amyloid (Aß) which is a hallmark in AD and memory disorders. This study investigated the potential neuroprotective and memory enhancing effects of the iron chelating drug, Deferiprone. Three doses (5, 10, and 20 mg/kg) were administered to rats treated with SCOP (1.14 mg/kg/day). Systemic administration of SCOP for seven days caused memory impairment which manifested as decreased time spent in platform quadrant in Morris water maze test, decreased retention latencies in passive avoidance test, and increased acetylcholinesterase (AChE) activity, Aß, and free iron deposition. It was observed that pretreatment with Deferiprone increased platform quadrant time in Morris water maze and increased retention latencies in the passive avoidance test. It also attenuated the increase in AChE activity and decreased Aß and iron deposition. Overall, Deferiprone (10 mg/kg) was determined as the most effective dose. Therefore, this study suggests neuroprotective and memory enhancing effects for Deferiprone in SCOP-treated rats which might be attributed to its iron chelating action and anti-oxidative effect.

Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis.

Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.

A case of post-splenectomy transfusion-dependent homozygous beta-thalassemia major complicated with myocardial siderosis and osteoporosis and usage of iron-chelating therapy with deferiprone in pregnancy.

Beta-thalassemia major is a subtype component of hemoglobinopathies; autosomal recessive disorders complicated with anemia that affect at least 50,000 babies each year. It contributes to problems in reproductive entities such as infertility due to iron deposition in the endocrine organs, which leads to malfunction of the hypothalamus-pituitary axis. Due to this, there have been very few pregnancies discovered and reported with this type of condition as they usually required an ovulation-induction agent with assisted reproductive technique to achieved pregnancy. We report a successful spontaneous pregnancy in a woman with beta-thalassemia major who underwent splenectomy with lifelong transfusion-dependence complicated with myocardial siderosis and osteoporosis. The close monitoring and regular blood transfusion are a core of successful support to this type of pregnancy. The unintentional consumption of Fosamax, hydroxyurea and deferiprone (Ferriprox) up till 20 weeks of gestation did not show any adverse effects on fetal well-being. As expected, this pregnancy ended with the preterm delivery via cesarean section due to intrauterine growth restriction with oligohydramnios, and currently, this child is thriving. We concluded that pregnancy is not a contraindication in beta-thalassemia major; complex individual care is needed to achieve a safe outcome for the mother.

Prospects for the introduction of targeted antioxidant drugs for the prevention and treatment of diseases related to free radical pathology.

INTRODUCTION: Oxidative stress toxicity (OST) has been implicated in almost all pathological conditions. Despite the widespread use of natural antioxidants, no pharmaceutical antioxidants have yet been developed or prescribed in medical practise. Antioxidant drugs such as Deferiprone and N-acetylcysteine can target essential pathways of OST in many pathological conditions. The pharmacological parameters required by antioxidant drugs in relation to the OST target characteristics include the determination of the therapeutic index, ADMET and drug interactions. Antioxidant drug development efforts are currently targeting the treatment of severe diseases with no proven effective therapies. AREAS COVERED: This article addresses the damaging effects of OST, prospects for the development of pharmaceutical antioxidants and clinical studies using other drugs with antioxidant potential. EXPERT OPINION: Effective antioxidant therapeutic strategies should include the design of protocols for the inhibition of OST through iron chelation, administration of synthetic and natural antioxidants and enhancement of the antioxidant defences by increasing the production of endogenous antioxidants and activation of antioxidant mechanisms. Different therapeutic strategies apply in the use of antioxidant drugs for one or more targets, for prevention, treatment, or of post-treatment effects and for systematic, long-term or short-term applications. The design of new antioxidant drugs and effective protocols which can include Deferiprone and N-acetylcysteine combinations, could lead to the development of a new class of therapeutics for clinical use.

Deferiprone exerts a dose-dependent reduction of liver iron in adults with iron overload.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The present study failed to demonstrate that the use of deferiprone at >90 mg/kg/d was associated with increased risk of agranulocytosis or neutropenia, but did demonstrate more effective liver iron control in iron overload patients.

Therapeutic mechanism of combined oral chelation therapy to maximize efficacy of iron removal in transfusion-dependent thalassemia major - a pilot study.

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.

Deferiprone has anti-inflammatory properties and reduces fibroblast migration in vitro.

Normal wound healing is a highly regulated and coordinated process. However, tissue injury often results in inflammation with excessive scar tissue formation after 40-70% of operations. Here, we evaluated the effect of the iron chelator deferiprone on inflammation and the migration of primary nasal fibroblasts and primary human nasal epithelial cells (HNECs) in vitro. The cytotoxicity of deferiprone was examined by the lactate dehydrogenase assay on primary nasal fibroblasts and air-liquid interface (ALI) cultures of HNECs. Wound closure was observed in scratch assays by using time-lapse confocal scanning laser microscopy. Interleukin-6 (IL-6) and type I and III collagen protein levels were determined by ELISA. Intracellular Reactive Oxygen Species (ROS) activity was measured by utilizing the fluorescent probe H2DCFDA. Deferiprone at 10 mM concentration was non-toxic to primary fibroblasts and HNECs for up to 48 hours application. Deferiprone had significant dose-dependent inhibitory effects on the migration, secreted collagen production and ROS release by primary nasal fibroblasts. Deferiprone blocked Poly (I:C)-induced IL-6 production by HNECs but did not alter their migration in scratch assays. Deferiprone has the potential to limit scar tissue formation and should be considered in future clinical applications.

Single-center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox.

BACKGROUND: Iron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as "last resort" therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic. METHODS AND FINDINGS: Under an IRB-approved study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox. RESULTS: Although deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2-18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1-6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron. CONCLUSIONS: Deferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the effectiveness of deferiprone. Exposure to deferiprone, over six years while the drug was unlicensed, in the face of ineffectiveness and serious toxicities, demands review of the standards of local medical practice. The limited scope of regulatory approval of deferiprone, worldwide, should restrict its exposure to the few patients genuinely unable to tolerate the two effective, first-line therapies.

Pantoprazole reduces serum ferritin in patients with thalassemia major and intermedia: A randomized, controlled study.

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±613µg/mL to 1197±956µg/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±7.3ms to 24.1±6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7±2.3ms to 9.8±2.6ms). 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.