Challenges and Opportunities of Deferoxamine Delivery for Treatment of Alzheimer's Disease, Parkinson's Disease, and Intracerebral Hemorrhage.

Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has also been implicated in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and secondary injury following intracerebral hemorrhage (ICH). Chelation of brain iron is thus a promising therapeutic strategy for improving behavioral outcomes and slowing neurodegeneration in the aforementioned disease states, though the effectiveness of DFO treatment is limited on several accounts. Systemically administered DFO results in nonspecific toxicity at high doses, and the drug's short half-life leads to low patient compliance. Mixed reports of DFO's ability to cross the blood-brain barrier (BBB) also appear in literature. These limitations necessitate novel DFO formulations prior to the drug's widespread use in managing neurodegeneration. Herein, we discuss the various dosing regimens and formulations employed in intranasal (IN) or systemic DFO treatment, as well as the physiological and behavioral outcomes observed in animal models of AD, PD, and ICH. The clinical progress of chelation therapy with DFO in managing neurodegeneration is also evaluated. Finally, the elimination of intranasally administered particles via the glymphatic system and efflux transporters is discussed. Abundant preclinical evidence suggests that intranasal DFO treatment improves memory retention and behavioral outcome in rodent models of AD, PD, and ICH. Several other biochemical and physiological metrics, such as tau phosphorylation, the survival of tyrosine hydroxylase-positive neurons, and infarct volume, are also positively affected by intranasal DFO treatment. However, dosing regimens are inconsistent across studies, and little is known about brain DFO concentration following treatment. Systemic DFO treatment yields similar results, and some complex formulations have been developed to improve permeability across the BBB. However, despite the success in preclinical models, clinical translation is limited with most clinical evidence investigating DFO treatment in ICH patients, where high-dose treatment has proven dangerous and dosing regimens are not consistent across studies. DFO is a strong drug candidate for managing neurodegeneration in the aging population, but before it can be routinely implemented as a therapeutic agent, dosing regimens must be standardized, and brain DFO content following drug administration must be understood and controlled via novel formulations.

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.

Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series.

Thalassemia syndromes are characterized by the inability to produce normal hemoglobin. Ineffective erythropoiesis and red cell transfusions are sources of excess iron that the human organism is unable to remove. Iron that is not saturated by transferrin is a toxic agent that, in transfusion-dependent patients, leads to death from iron-induced cardiomyopathy in the second decade of life. The availability of effective iron chelators, advances in the understanding of the mechanism of iron toxicity and overloading, and the availability of noninvasive methods to monitor iron loading and unloading in the liver, heart, and pancreas have all significantly increased the survival of patients with thalassemia. Prolonged exposure to iron toxicity is involved in the development of endocrinopathy, osteoporosis, cirrhosis, renal failure, and malignant transformation. Now that survival has been dramatically improved, the challenge of iron chelation therapy is to prevent complications. The time has come to consider that the primary goal of chelation therapy is to avoid 24-h exposure to toxic iron and maintain body iron levels within the normal range, avoiding possible chelation-related damage. It is very important to minimize irreversible organ damage to prevent malignant transformation before complications set in and make patients ineligible for current and future curative therapies. In this clinical case-based review, we highlight particular aspects of the management of iron overload in patients with beta-thalassemia syndromes, focusing on our own experience in treating such patients. We review the pathophysiology of iron overload and the different ways to assess, quantify, and monitor it. We also discuss chelation strategies that can be used with currently available chelators, balancing the need to keep non-transferrin-bound iron levels to a minimum (zero) 24 h a day, 7 days a week and the risk of over-chelation.

Analysis of Metabolomic Changes in Mesenchymal Stem Cells on Treatment with Desferrioxamine as a Hypoxia Mimetic Compared with Hypoxic Conditions.

Mesenchymal stem cells (MSCs) are commonly used in regenerative medicine, but their therapeutic effects vary depending on the culture environment. Hypoxic culturing can be used to maintain stem cells in an undifferentiated state, but is expensive and difficult to perform. The aim of this study was to determine the effectiveness of desferrioxamine (DFO), a hypoxia-mimetic reagent, as an alternative to hypoxic culturing by analyzing metabolic changes in MSCs under hypoxic conditions compared with changes induced by DFO. Low concentrations of DFO reduced mitochondrial activity and apoptosis. Therefore, low concentrations of DFO may be useful for MSC preconditioning. Metabolome analysis showed that both hypoxic treatment and DFO administration exhibited similar metabolite patterns except purine, pyrimidine, and tricarboxylic acid cycle (TCA) cycle related metabolites. Therefore, the use of DFO at low concentrations is a potential substitute for hypoxic culturing. These findings may form the foundation for the development of future regenerative therapies using MSCs. Stem Cells 2018;36:1226-1236.

Beliefs and Adherence Associated With Oral and Infusion Chelation Therapies in Jordanian Children and Adolescents With Thalassemia Major: A Comparative Study.

The researcher assessed the beliefs and adherence associated with both oral deferasirox and deferoxamine infusion chelation therapies among Jordanian children with thalassemia major, and compared the adherence levels between the recipients of each. In this descriptive cross-sectional study, 120 participants were recruited from 3 major thalassemia treatment clinics in Jordan using convenience sampling. Data were collected through questionnaires on demographic- and disease-related information, the beliefs about medicines, and a medication adherence report scale. Most participants showed a high adherence to deferoxamine infusion and oral deferasirox (87.20% and 89.08%, respectively), and believed in the necessity of deferoxamine for maintaining health (89.34%). However, 41.32% of the participants had strong concerns about deferoxamine use. While most participants believed in the need for oral deferasirox (89.84%), about 40.7% had strong concerns about its use. An independent samples t test showed no statistically significant difference in the adherence between the oral deferasirox and infusion deferoxamine recipients (t=1.048, DF=118, P=0.075). Jordanian children with thalassemia have positive beliefs and adherence to both oral and infusion chelation therapies. Health care providers should pay attention to patients' beliefs and discuss the major concerns pertaining to iron chelation therapy with them to enhance the continuity of adherence therapy.

A 1-year randomized trial of deferasirox alone versus deferasirox and deferoxamine combination for the treatment of iron overload in thalassemia major.

AIM: Iron chelators are extensively used to reduce iron overload. Our purpose was to compare effects of deferasirox versus deferasirox and deferoxamine in patients with thalassemia major. METHODS: This randomized and double blind trial was performed on 62 patients. Patients were assigned 1:1 to oral 30 mg/kg deferasirox daily or oral 30 mg/kg deferasirox daily plus SC 50 mg/kg deferoxamine for 5 days a week. Treatment continued for 12 months in both groups. RESULTS: Fifty-five patients completed the 1 year of treatment. Mean age was 24.5 years with an excess of females. Combined therapy caused a significant increase in myocardial T2* from 23.1 ± 7.5 ms at baseline to 27.1 ± 7.0 ms at 12 months (P < 0.05). This difference was statistically significant between 2 groups at 12 months (P = 0.01). Combined therapy and monotherapy had no significant effect on liver T2*. At 12 months, serum ferritin levels were reduced in two groups; however, the difference was significant (737 ± 459 µg/ml vs 1085 ± 919 µg/ml, P < 0.01). CONCLUSION: Our study indicates that combined treatment with deferasirox and deferoxmaine is more effective than deferasirox for reduction of iron over load in patients with thalassemia major.

Treatment With Topical Deferoxamine Improves Cutaneous Vascularity and Tissue Pliability in an Irradiated Animal Model of Tissue Expander-Based Breast Reconstruction.

PURPOSE: Postmastectomy radiation therapy is an important component of the multimodality approach to later-stage breast cancers. Unfortunately, despite its proven survival benefits, postmastectomy radiation therapy is deleterious to the skin and soft tissue, causing increased complications and worse aesthetic outcomes after breast reconstruction.There is currently no effective pharmaceutical agent to mitigate the soft tissue fibrosis and hypovascularity associated with soft tissue radiation. We hypothesized that a novel topical formulation of deferoxamine (DFX) will result in improved cutaneous vascularity and soft tissue pliability in an animal model of irradiated tissue expander-based breast reconstruction. METHODS: This study consisted of 16 hairless rats divided into 4 equal groups: a control group (expander only), a tissue expanded and irradiated group, a tissue expanded + DFX group, and a tissue expanded/irradiated/DFX group. A novel topical formulation of DFX consisted of reconstituted drug dissolved in agents designed to enhance dermal penetrance. Vessels per high-power field (vHPF) were quantified histologically; micro-computed tomography angiography was used to assess vessel volume fraction (VVF) and vessel length density. RESULTS: Irradiated skin had less vascularity compared with control (3.81 vHPF vs 8.25 vHPF, P = 0.03; 0.79% VVF vs 1.53% VVF, P = 0.06). Treatment of irradiated skin with topical DFX reversed these effects, resulting in vascular findings similar to the control group histologically (7.94 vHPF vs 8.25 HPF, P = 0.985) and via micro-computed tomography angiography (1.05% VVF vs 1.53% VVF, P = 0.272). Similarly, radiation resulted in less volume expansion compared with controls (0.72 vs 0.8 mL, P = 0.04), whereas treatment with topical DFX reversed this effect, allowing for an expansion volume similar to the control group (0.81 vs 0.80 mL, P = 0.999). CONCLUSIONS: In an animal model of irradiated tissue expander-based breast reconstruction, treatment with topical DFX improved the cutaneous vascularity and tissue pliability, resulting in vascular density and final tissue expansion volumes similar to those found in the nonirradiated control group. Topical DFX may be an effective agent for the treatment of soft tissue radiation injury; future studies are indicated to further characterize this novel drug formulation.

Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice.

Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound healing. With this demographic growing rapidly, there is a need for effective treatments. We have previously demonstrated that defective hypoxia signaling through destabilization of the master hypoxia-inducible factor 1α (HIF-1α) underlies impairments in both aging and diabetic wound healing. To stabilize HIF-1α, we developed a transdermal delivery system of the Food and Drug Administration-approved small molecule deferoxamine (DFO) and found that transdermal DFO could both prevent and treat ulcers in diabetic mice. Here, we demonstrate that transdermal DFO can similarly prevent pressure ulcers and normalize aged wound healing. Enhanced wound healing by DFO is brought about by stabilization of HIF-1α and improvements in neovascularization. Transdermal DFO can be rapidly translated into the clinic and may represent a new approach to prevent and treat pressure ulcers in aged patients.

Pattern dystrophies in patients treated with deferoxamine: report of two cases and review of the literature.

BACKGROUND: Deferoxamine (DFO) is one of the most commonly used chelation treatments for transfusional hemosiderosis. Pattern dystrophies constitute a distinct entity of retinal disorders that has been occasionally identified in association with deferoxamine. CASE PRESENTATION: We report two cases of bilateral macular pattern dystrophy in transfusion dependent patients undergoing chronic chelation therapy with deferoxamine due to thalassemias. Our patients were evaluated with multimodal imaging and the results are presented. Both patients had normal cone and rod responses in the full-field electroretinogram and continued the prescribed chelation therapy, after hematology consult. The patients were followed up every 3 months for 2 and 4 years respectively for possible deterioration. Their best corrected visual acuity remained stable with no anatomic change on Optical Coherence Tomography findings. CONCLUSION: Multimodal imaging of our patients allowed a better evaluation and possibly earlier detection of the DFO-related changes. Screening and close follow up of patients under chronic chelating therapy is important in order to promptly diagnose and manage possible toxicity either with discontinuation of the offending agent or dose modification.

Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

Topical Deferoxamine Alleviates Skin Injury and Normalizes Atomic Force Microscopy Patterns Following Radiation in a Murine Breast Reconstruction Model.

BACKGROUND: Breast cancer is most commonly managed with a combination of tumor ablation, radiation, and/or chemotherapy. Despite the oncologic benefit of these treatments, the detrimental effect of radiation on surrounding tissue challenges the attainment of ideal breast reconstruction outcomes. The purpose of this study was to determine the ability of topical deferoxamine (DFO) to reduce cutaneous ulceration and collagen disorganization following radiotherapy in a murine model of expander-based breast reconstruction. METHODS: Female Sprague-Dawley rats (n = 15) were divided into 3 groups: control (expander), XRT (expander + radiation), and DFO (expander + radiation + deferoxamine [DFO]). Expanders were placed in a submusculocutaneous plane in the right upper back and ultimately filled to 15 mL. Radiation was administered via a fractionated dose of 28 Gy. Deferoxamine was delivered topically for 10 days following radiation. After a 20-day recovery period, skin ulceration and dermal type I collagen organization were analyzed. RESULTS: Compared with control, the XRT group demonstrated a significant increase in skin ulceration (3.7% vs 43.3%, P = 0.00) and collagen fibril disorganization (26.3% vs 81.8%, P = 0.00). Compared with the XRT group, treatment with topical DFO resulted in a significant reduction in ulceration (43.3% vs 7.0%, P = 0.00) and fibril disorganization (81.8% vs 15.3%, P = 0.00). There were no statistical differences between the control and DFO groups in skin ulceration or collagen disorganization. CONCLUSIONS: This study suggests topical DFO is capable of reducing skin ulceration and type I collagen fibril disorganization following radiotherapy. This novel application of DFO has potential to enhance expander-based breast reconstruction outcomes and improve quality of life for women suffering the devastating effects of breast cancer.

Effects of amniotic membrane extract and deferoxamine on angiogenesis in wound healing: an in vivo model.

OBJECTIVE: Angiogenesis, formation of new vessels from pre-existing vessels, is an essential part of wound healing. We aimed to compare amniotic membrane extract with deferoxamine in angiogenesis and to assess any synergistic effect. METHOD: We examined four groups of rats (five per group): control, deferoxamine, amniotic membrane extract, and deferocxamine and amniotic membrane extract in combination. A distal-based skin flap was created. Deferoxamine (100mg/kg), amniotic membrane extract (0.1mg/ml), and the combination of both were injected subcutaneously every other day in 10 separate points (0.1 ml at each point) in the skin flap. On day 11, the animals were euthanised for histopathological evaluation. RESULTS: Results indicated that the amniotic membrane extract raised the angiogenic markers, particularly new vessel numbers (p<0.008) and CD31+ compared with controls (p <0.003), and deferoxamine increased new vessel numbers and Von Willebrand factor (vWF) significantly compared with controls (p<0.008). There was an increase in angiogenic factors in the combined group, however, this was not statistically significant difference was observed. There was no difference between amniotic membrane extract and deferoxamine. CONCLUSION: Amniotic membrane extract or deferoxamine could be used interchangeably in angiogenesis within wound healing due to their high safety and availability.

Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload.

Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] ≥56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* ≥10 ms and ≥10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227.

Deferasirox for managing iron overload in people with thalassaemia.

BACKGROUND: Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusions. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone are effective; however, a review of the effectiveness and safety of the newer oral chelator deferasirox in people with thalassaemia is needed. OBJECTIVES: To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and iron overload. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 August 2016.We also searched MEDLINE, Embase, the Cochrane Library, Biosis Previews, Web of Science Core Collection and three trial registries: ClinicalTrials.gov; the WHO International Clinical Trials Registry Platform; and the Internet Portal of the German Clinical Trials Register: 06 and 07 August 2015. SELECTION CRITERIA: Randomised controlled studies comparing deferasirox with no therapy or placebo or with another iron-chelating treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. MAIN RESULTS: Sixteen studies involving 1807 randomised participants (range 23 to 586 participants) were included. Twelve two-arm studies compared deferasirox to placebo (two studies) or deferoxamine (seven studies) or deferiprone (one study) or the combination of deferasirox and deferoxamine to deferoxamine alone (one study). One study compared the combination of deferasirox and deferiprone to deferiprone in combination with deferoxamine. Three three-arm studies compared deferasirox to deferoxamine and deferiprone (two studies) or the combination of deferasirox and deferiprone to deferiprone and deferasirox monotherapy respectively (one study). One four-arm study compared two different doses of deferasirox to matching placebo groups.The two studies (a pharmacokinetic and a dose-escalation study) comparing deferasirox to placebo (n = 47) in people with transfusion-dependent thalassaemia showed that deferasirox leads to net iron excretion. In these studies, safety was acceptable and further investigation in phase II and phase III studies was warranted.Nine studies (1251 participants) provided data for deferasirox versus standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared. In the phase III study, similar or superior efficacy for the intermediate markers ferritin and liver iron concentration (LIC) could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg per day and 51.6 mg per day respectively. The pooled effects across the different dosing ratios are: serum ferritin, mean difference (MD) 454.42 ng/mL (95% confidence interval (CI) 337.13 to 571.71) (moderate quality evidence); LIC evaluated by biopsy or SQUID, MD 2.37 mg Fe/g dry weight (95% CI 1.68 to 3.07) (moderate quality evidence) and responder analysis, LIC 1 to < 7 mg Fe/g dry weight, risk ratio (RR) 0.80 (95% CI 0.69 to 0.92) (moderate quality evidence). The substantial heterogeneity observed could be explained by the different dosing ratios. Data on mortality (low quality evidence) and on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was better with deferasirox among those who had previously received deferoxamine treatment, RR 2.20 (95% CI 1.89 to 2.57) (moderate quality evidence). The rate of discontinuations was similar for both drugs (low quality evidence).For the remaining comparisons in people with transfusion-dependent thalassaemia, the quality of the evidence for outcomes assessed was low to very low, mainly due to the very small number of participants included. Four studies (205 participants) compared deferasirox to deferiprone; one of which (41 participants) revealed a higher number of participants experiencing arthralgia in the deferiprone group, but due to the large number of different types of adverse events reported and compared this result is uncertain. One study (96 participants) compared deferasirox combined with deferiprone to deferiprone with deferoxamine. Participants treated with the combination of the oral iron chelators had a higher adherence compared to those treated with deferiprone and deferoxamine, but no participants discontinued the study. In the comparisons of deferasirox versus combined deferasirox and deferiprone and that of deferiprone versus combined deferasirox and deferiprone (one study, 40 participants), and deferasirox and deferoxamine versus deferoxamine alone (one study, 94 participants), only a few patient-relevant outcomes were reported and no significant differences were observed.One study (166 participants) included people with non-transfusion dependent thalassaemia and compared two different doses of deferasirox to placebo. Deferasirox treatment reduced serum ferritin, MD -306.74 ng/mL (95% CI -398.23 to -215.24) (moderate quality evidence) and LIC, MD -3.27 mg Fe/g dry weight (95% CI -4.44 to -2.09) (moderate quality evidence), while the number of participants experiencing adverse events and rate of discontinuations (low quality evidence) was similar in both groups. No participant died, but data on mortality were limited due to a follow-up period of only one year (moderate quality evidence). AUTHORS' CONCLUSIONS: Deferasirox offers an important treatment option for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy and will translate to similar benefits in the long term, as has been shown for deferoxamine, needs to be confirmed. Data from randomised controlled trials on rare toxicities and long-term safety are still limited. However, after a detailed discussion of the potential benefits and risks, deferasirox could be offered as the first-line option to individuals who show a strong preference for deferasirox, and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine.

ELECTRORETINOGRAPHIC AND VISUAL-EVOKED POTENTIAL CHANGES IN RELATION TO CHELATION MODALITY IN CHILDREN WITH THALASSEMIA.

PURPOSE: To evaluate possible benefits of using electrophysiological investigations for detecting retinal and visual pathway changes and correlating them with chelation modality in children with thalassemia. METHODS: This study included 60 patients on single oral iron chelator (deferasirox) (Group 1), 60 on deferoxamine chelator (Group 2), and 60 controls (Group 3). Participants underwent full ophthalmologic examination, pattern visual-evoked potential, pattern electroretinogram, and multifocal electroretinogram. RESULTS: Fundus showed no abnormalities. Multifocal electroretinogram mean P1 amplitude showed statistically significant differences in all 5 rings, amplitudes being significantly lower in Groups 1 and 2 than Group 3; moreover, significantly lower in Group 2 than Group 1. There was a statistically significant difference between groups regarding P50 wave latency and N35-P50 of pattern electroretinogram amplitude (P < 0.001 and P < 0.001, respectively). However, there were no statistically significant differences between groups regarding N95 wave of pattern electroretinogram and pattern visual-evoked potential waves' amplitude and latency. Multiple regression analyses illustrated that chelator was the most important determinant for multifocal electroretinogram and P50 parameters. CONCLUSION: Preclinical electrophysiologic changes existed in thalassemics, more obvious in those on deferoxamine. Electrophysiologic studies analysis denotes an early toxic macular insult rather than optic nerve affection. Thus, regular follow-up using multifocal electroretinogram and pattern electroretinogram is recommended.

Decorporation of Iron Metal Using Dialdehyde Cellulose-Deferoxamine Microcarrier.

Deferoxamine iron chelator has a limited therapeutic index due to rapid clearance from blood and possesses dose-limiting toxicity. Therefore, an intravenous deferoxamine delivery system based on dialdehyde cellulose (DAC) polymer was developed and its efficacy and toxicity were tested in iron-overloaded animals. The amino groups of deferoxamine were conjugated to free aldehyde moieties of dialdehyde cellulose via Schiff base reaction to form dialdehyde cellulose-deferoxamine (DAC-DFO) conjugate and characterized by Fourier transform infrared spectrophotometer, scanning electron microscope, and X-ray diffraction. The toxicity of prepared formulation was analyzed by XTT cell viability assay and LD50 study in mice. The change in serum iron levels, after intravenous administration of formulation, was observed in iron-overloaded rats. The DAC-DFO conjugate was tagged with Tc-99m to study the blood kinetics and observe change in blood circulation time. DAC-DFO conjugate was dispersible in water at concentration ∼75 mg/ml. In vitro cytotoxicity assay and LD50 study in mice indicated significantly enhanced safety of covalently bound deferoxamine (at >1000 mg/kg body weight compared to free drug at ∼270 mg/kg dose). A preliminary scintigraphy imaging and blood clearance study, with technetium-99m, indicated prolonged circulation of conjugated DFO in rabbit blood. A single dose of formulation injected into iron overloaded animals was found to maintain the normal serum iron levels until 10 days. The polymeric conjugate was effective in maintaining normal serum iron levels until 10 days at a dose of 100 mg/kg body weight.

Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating disease that affects over 30,000 Americans per year. Previous animal studies have explored the therapeutic effects of deferoxamine (DFX) via its iron-chelating properties after SAH, but none have assessed the necessity of microglial/macrophage heme oxygenase-1 (HO-1 or Hmox1) in DFX neuroprotection, nor has the efficacy of an intracerebroventricular (ICV) administration route been fully examined. We explored the therapeutic efficacy of systemic and ICV DFX in a SAH mouse model and its effect on microglial/macrophage HO-1. METHODS: Wild-type (WT) mice were split into the following treatment groups: SAH sham + vehicle, SAH + vehicle, SAH + intraperitoneal (IP) DFX, and SAH + ICV DFX. For each experimental group, neuronal damage, cognitive outcome, vasospasm, cerebral and hematogenous myeloid cell populations, cerebral IL-6 concentration, and mitochondrial superoxide anion production were measured. HO-1 co-localization to microglia was measured using confocal images. Trans-wells with WT or HO-1(-/-) microglia and hippocampal neurons were treated with vehicle, red blood cells (RBCs), or RBCs with DFX; neuronal damage, TNF-α concentration, and microglial HO-1 expression were measured. HO-1 conditional knockouts were used to study myeloid, neuronal, and astrocyte HO-1 involvement in DFX-induced neuroprotection and cognitive recovery. RESULTS: DFX treatment after SAH decreased cortical damage and improved cognitive outcome after SAH yet had no effect on vasospasm; ICV DFX was most neuroprotective. ICV DFX treatment after SAH decreased cerebral IL-6 concentration and trended towards decreased mitochondrial superoxide anion production. ICV DFX treatment after SAH effected an increase in HO-1 co-localization to microglia. DFX treatment of WT microglia with RBCs in the trans-wells showed decreased neuronal damage; this effect was abolished in HO-1(-/-) microglia. ICV DFX after SAH decreased neuronal damage and improved cognition in Hmox1 (fl/fl) control and Nes (Cre) :Hmox1 (fl/fl) mice, but not LyzM (Cre) :Hmox1 (fl/fl) mice. CONCLUSIONS: DFX neuroprotection is independent of vasospasm. ICV DFX treatment provides superior neuroprotection in a mouse model of SAH. Mechanisms of DFX neuroprotection after SAH may involve microglial/macrophage HO-1 expression. Monitoring patient HO-1 expression during DFX treatment for hemorrhagic stroke may help clinicians identify patients that are more likely to respond to treatment.

A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in ß-thalassemia major (CORDELIA).

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 ß-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.

N-acetylcysteine plus deferoxamine for patients with prolonged hypotension does not decrease acute kidney injury incidence: a double blind, randomized, placebo-controlled trial.

BACKGROUND: The aim was to test the primary hypothesis that in patients suffering from shock, treatment with N-acetylcysteine (NAC) plus deferoxamine (DFX) decreases the incidence of acute kidney injury (AKI). METHODS: A double-blind, randomized, placebo-controlled trial was conducted in a general intensive care unit in an academic hospital. Patients were included if they had new-onset hypotension, defined as mean arterial blood pressure <60 mmHg or requirement for vasopressor medication. A loading dose of NAC or placebo of 50 mg/kg in 4 h was administered intravenously. After the loading dose, patients received 100 mg/kg/day for the next 48 h. DFX or placebo was administered once at 1000 mg at a rate of 15/mg/kg/h. The primary outcome was the incidence of AKI. RESULTS: A total of 80 patients were enrolled in the study. The incidence of AKI was 67 % in the placebo arm and 65 % in the treatment group (relative risk (RR) 0.89 (0.35-2.2)). Furthermore, NAC plus DFX was effective in decreasing the severity and duration of AKI, and patients in the treatment group had lower serum creatinine levels at discharge. No severe adverse event associated with treatment was reported. The effects of NAC plus DFX could be secondary to the attenuation of early inflammatory response and oxidative damage. CONCLUSION: The administration of NAC plus DFX to critically ill patients who had a new episode of hypotension did not decrease the incidence of AKI. TRIAL REGISTRATION: Clinicaltrials.gov NCT00870883 (Registered 25 March 2009.).

The Effects of Desferroxamine on Bone and Bone Graft Healing in Critical-Size Bone Defects.

BACKGROUND: Autogenous bone grafts are still the criterion standard treatment option in critical-size bone defect reconstructions, and many therapies can affect its incorporation. In this study, it was aimed to research the effects of desferroxamine (DFO) application on bone and bone graft healing due to the effects of osteoblast and osteoclast regulation and stimulation of angiogenesis. METHODS: Rat zygomatic arch critical-size bone defect model (5 mm) was used as the experimental model. Thirty-two Sprague-Dawley rats (64 zygomatic arches) were divided into 4 groups (16 zygomatic arches in each). In groups 1 and 2, defects were reconstructed with the bone grafts harvested from the other side, and the right arc was named as group 1, and the left was group 2. At group 1, 200 µM/300 µL dosage of DFO was injected at the zygomatic arch region starting at the seventh day preoperatively and lasting until the 45th day postoperatively. Group 2 animals were defined as the control group of group 1, and 0.9% NaCl injection was applied. In groups 3 and 4, there was no repair after the formation of defects, and the right arc region was treated with DFO, and left was treated with 0.9% NaCl for postoperative 45 days, respectively. Radiological (computed tomography), histological (hematoxylin-eosin), and biomechanical (3-point bending test) tests were used for the evaluation. RESULTS: In radiological evaluation, there was a statistically significant decrease (P < 0.05) in bone defect size in group 3 animals at the 4th, 8th, and 12th weeks, and bone graft volume showed a statistical difference at all weeks (P < 0.05). In histological evaluation, it was observed that there was an increase in osteoblast number and vascularity rates (P < 0.05) in the DFO-treated groups at all weeks. Biomechanical evaluation of the subjects showed increase in bone strength in group 1 animals at 12 weeks. CONCLUSIONS: In this study, it was shown that DFO treatment increased bone graft incorporation and healing in critical-size bone defects. In this aspect, we suggest that DFO can be used to increase graft incorporation in risky areas and reduce the defect size in patients who are not suitable for vascularized bone graft transfer.