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Medicine Oct 2023This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209...
This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209 patients, independent of the chelation regimen, ferritin, cardiac T2* and liver iron concentration changes were evaluated. We defined chelation success (ChS) as no iron load in the heart and acceptable levels in the liver. Over 3 early magnetic resonance imagings, the same parameters were assessed in 2 subgroups, the only 2 that had sufficient patients continuing on 1 regimen and for a significant period of time, 1 on deferrioxamine (low iron load patients n = 41, Group A) and 1 on deferoxamine-deferiprone (iron overloaded n = 60, Group B). Finally, 28 deaths and causes were compared to those of an earlier period. The 209 patients significantly optimized those indices, while the number of patients with chelation success, increased from 6% to 51% (P < .0001). In group A, ChS after about 8 years increased from 21 to 46% (P = .006), while in Group B, from 0% to 60% (P < .001) after about 7 years. Deaths over the 2 periods showed significant reduction. Combined clearance of cardiac and liver iron (ChS) is feasible and should become the new target for all patients. This requires, serial magnetic resonance imagings and often prolonged intensified chelation for patients.
Topics: Humans; Iron Chelating Agents; beta-Thalassemia; Deferoxamine; Deferiprone; Chelation Therapy; Pyridones; Iron; Liver
PubMed: 37832083
DOI: 10.1097/MD.0000000000035455 -
Scientific Reports Jan 2022Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney...
Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. Thy-1.1 mice were injected with anti-Thy-1.1 monoclonal antibody (mAb) to induce proteinuria. Urine, blood and tissue were collected at day (D)1, D5, D8, D15 and D22 after mAb injection. Thy-1.1 mice were subjected to captopril (CA), iron-deficient (ID) diet or iron chelation (deferoxamine; DFO). MAb injection resulted in significant albuminuria at all time points (p < 0.01). Kidney iron loading, predominantly in distal tubules, increased in time, along with urinary kidney injury molecule-1 and 24p3 concentration, as well as kidney mRNA expression of Interleukin-6 (Il-6) and Heme oxygenase-1 (Ho-1). Treatment with CA, ID diet or DFO significantly reduced kidney iron deposition at D8 and D22 (p < 0.001) and fibrosis at D22 (p < 0.05), but not kidney Il-6. ID treatment increased kidney Ho-1 (p < 0.001). In conclusion, kidney iron accumulation coincides with progression of tubulointerstitial injury in this model of FSGS. Reduction of iron loading halts disease progression. However, targeted approaches to prevent excessive kidney iron loading are warranted to maintain the delicate systemic and cellular iron balance.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Deferoxamine; Disease Models, Animal; Female; Glomerulosclerosis, Focal Segmental; Iron; Kidney Tubules, Distal; Male; Mice; Receptors, Cell Surface; Siderophores
PubMed: 35075227
DOI: 10.1038/s41598-022-05261-4 -
Beyoglu Eye Journal 2022This study aims to analyze the posterior segment of the eye in children with thalassemia major (TM) treated with chelation therapy.
OBJECTIVES
This study aims to analyze the posterior segment of the eye in children with thalassemia major (TM) treated with chelation therapy.
METHODS
Forty-four patients diagnosed with TM and 44 age- and gender-matched participants without systemic diseases were included in this cross-sectional comparative study. A complete ophthalmologic examination, including visual acuity and fundus examination, was performed on all participants. The study and control groups' optic coherence tomography (OCT) evaluation was performed with a spectral domain featured OCT device. Central macular thickness (CMT), macular volume, ganglion cell complex (GCC) thickness, retinal nerve fiber layer (RNFL) thickness, subfoveal choroidal thickness (CT), CT at 1 mm temporal to the fovea, CT at 1 mm nasal to the fovea, CT at the 1 mm temporal to the optic nerve head, and CT at the 1 mm nasal to the optic nerve head were compared between the study and control groups.
RESULTS
The mean ages for the study group and for the control group were 15.2±6.2 and 14.2±4.9 years, respectively. The mean subfoveal CT was 287.73±47.04 µm in the TM group and 312.66±39.95 µm in the control group (p=0.014). CT at the nasal to the fovea and temporal to the optic nerve head was thinner in the TM group than in the healthy group. The mean CMT, macular volume, GCC thickness, and RNFL thickness of the study and the control groups were similar. No significant difference was found between the patients with and without deferoxamine therapy concerning macular thickness, GCC thickness, and macular and peripapillary CT.
CONCLUSION
Our results suggested that subfoveal, perifoveal, and peripapillary CTs were significantly thinner in children with TM than the control group. The use of deferoxamine did not cause a further reduction in CT.
PubMed: 36628077
DOI: 10.14744/bej.2022.62534 -
Stroke Aug 2014This study investigated if acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage (GMH).
BACKGROUND AND PURPOSE
This study investigated if acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage (GMH).
METHODS
Bacterial collagenase (0.3 U) was infused intraparenchymally into the right hemispheric ganglionic eminence in P7 rat pups to induce GMH. GMH animals received either deferoxamine or vehicle twice a day for 7 consecutive days. Deferoxamine administration was initiated at either 1 hour or 72 hours post-GMH. Long-term neurocognitive deficits and motor coordination were assessed using Morris water maze, rotarod, and foot fault tests between day 21 to 28 post-GMH. At 28 days post-GMH, brain morphology was assessed and extracellular matrix protein (fibronectin and vitronectin) expression was determined.
RESULTS
Acute and delayed deferoxamine treatment improved long-term motor and cognitive function at 21 to 28 days post-GMH. Attenuated neurofunction was paralleled with improved overall brain morphology at 28 days post-GMH, reducing white matter loss, basal ganglia loss, posthemorrhagic ventricular dilation, and cortical loss. GMH resulted in significantly increased expression of fibronectin and vitronectin, which was reversed by acute and delayed deferoxamine treatment.
CONCLUSIONS
Acute and delayed deferoxamine administration ameliorated long-term sequelae after GMH.
Topics: Animals; Animals, Newborn; Brain; Deferoxamine; Disease Models, Animal; Intracranial Hemorrhages; Maze Learning; Motor Activity; Rats; Time Factors
PubMed: 24947291
DOI: 10.1161/STROKEAHA.114.005079 -
Wound Repair and Regeneration :... May 2018Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound...
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.
Topics: Administration, Cutaneous; Animals; Deferoxamine; Disease Models, Animal; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Pressure Ulcer; Siderophores; Wound Healing
PubMed: 30152571
DOI: 10.1111/wrr.12667 -
Stroke Sep 2015Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes.
METHODS
We assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform.
RESULTS
Deferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04).
CONCLUSIONS
Deferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Cerebrovascular Circulation; Chelation Therapy; Cross-Over Studies; Deferoxamine; Erythropoietin; Female; Hemodynamics; Humans; Hypoxia-Inducible Factor 1; Male; Middle Aged; Siderophores; Signal Transduction; Treatment Outcome; Ultrasonography, Doppler, Transcranial; Vascular Endothelial Growth Factors; Young Adult
PubMed: 26304864
DOI: 10.1161/STROKEAHA.115.009906 -
Proceedings of the National Academy of... Jan 2015There 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...
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.
Topics: Administration, Cutaneous; Animals; Apoptosis; Deferoxamine; Dermis; Diabetes Complications; Diabetes Mellitus, Experimental; Drug Delivery Systems; Mice, Inbred C57BL; Necrosis; Neovascularization, Physiologic; Pressure; Reactive Oxygen Species; Stress, Physiological; Ulcer; Vascular Endothelial Growth Factor A; Wound Healing
PubMed: 25535360
DOI: 10.1073/pnas.1413445112 -
Biomedicine & Pharmacotherapy =... Dec 2023The aim of this study was to design a novel tracer targeting programmed cell death-ligand 2 (PD-L2) to dynamically monitor PD-L2 expression and perform preclinical...
OBJECTIVES
The aim of this study was to design a novel tracer targeting programmed cell death-ligand 2 (PD-L2) to dynamically monitor PD-L2 expression and perform preclinical screening to identify patients who may benefit from immune checkpoint inhibitor therapy (ICI) therapy.
METHODS
Zr labelling of DFO-conjugated PD-L2 antibody (ATL2) was carried out in NaCO buffer at pH 7 (37 °C, 1 h). In vitro stability was analysed using radio-thin layer chromatography (radio-TLC). The affinity of [Zr]Zr-DFO-ATL2 was evaluated by radio-ELISA. Cell uptake, pharmacokinetic, and biodistribution experiments were used to evaluate the biological properties. Micro-PET/CT imaging with [Zr]Zr-DFO-ATL2 was conducted at different time points. Immunohistochemical and HE staining studies were carried out using tumour tissues from tumour-bearing mice.
RESULTS
The radiochemical yield of [Zr]Zr-DFO-ATL2 was 65.6 ± 3.9%, and the radiochemical purity (RCP) of the tracer was greater than 99%. The tracer maintained relatively high stability and had a high affinity for the PD-L2 protein (Kd = 31.85 nM, R = 0.94). The uptake of [Zr]Zr-DFO-ATL2 in A549-PD-L2 cells was higher than that in A549 cells at each time point. Micro-PET/CT showed significant uptake in the tumour region of mice bearing tumours derived from A549-PD-L2 (SUVmax = 3.53 ± 0.09 at 96 h) and H2228 (SUVmax = 2.30 ± 0.12 at 48 h) cells.
CONCLUSION
The high tumour uptake at early imaging time points demonstrates the feasibility of applying [Zr]Zr-DFO-ATL2 to image PD-L2 expression in tumours and is encouraging for further clinical application in the screening of patients who may benefit from ICI therapy.
Topics: Humans; Animals; Mice; Antibodies, Monoclonal; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Lung Neoplasms; Tissue Distribution; Deferoxamine; Cell Line, Tumor
PubMed: 37852097
DOI: 10.1016/j.biopha.2023.115602 -
Journal of Neurochemistry Jun 2018Hemopexin (Hpx) binds heme with extraordinary affinity, and after haptoglobin may provide a second line of defense against the toxicity of extracellular hemoglobin (Hb)....
Hemopexin (Hpx) binds heme with extraordinary affinity, and after haptoglobin may provide a second line of defense against the toxicity of extracellular hemoglobin (Hb). In this series of experiments, the hypothesis that Hpx protects neurons from Hb neurotoxicity was evaluated in murine primary cultures containing neurons and glial cells. Contrary to hypothesis, Hpx increased neuronal loss due to micromolar concentrations of Hb by 4- to 12-fold, as measured by LDH release assay; conversely, the neurotoxicity of hemin was completely prevented. The endogenous fluorescence of Hpx was quenched by Hb, consistent with transfer of Hb-bound heme to Hpx. This was associated with precipitation of globin chains, as detected by immunostaining and fluorescent Hb labeling. A portion of this precipitate attached firmly to cells and could not be removed by multiple washes. Concomitant treatment with haptoglobin (Hp) prevented globin precipitation and most of the increase in neuronal loss. Hpx weakly attenuated the increase in culture non-heme iron produced by Hb treatment, quantified by ferrozine assay. However, Hb-Hpx toxicity was iron-dependent, and was blocked by deferoxamine and ferrostatin-1. Up-regulation of cell ferritin expression, a primary cell defense against Hb toxicity, was not observed on western blots of culture lysates that had been concomitantly treated with Hpx. These results suggest that Hpx destabilizes Hb in the absence of haptoglobin, leading to globin precipitation and exacerbation of iron-dependent oxidative cell injury. Combined therapy with hemopexin plus haptoglobin may be preferable to hemopexin alone after CNS hemorrhage.
Topics: Animals; Antidotes; Cyclohexylamines; Deferoxamine; Female; Ferritins; Globins; Haptoglobins; Heme Oxygenase-1; Hemin; Hemoglobins; Hemopexin; Iron; Male; Mice; Neuroglia; Neurons; Neurotoxicity Syndromes; Nonheme Iron Proteins; Phenylenediamines; Pregnancy; Primary Cell Culture
PubMed: 29500821
DOI: 10.1111/jnc.14328 -
Pharmaceutical Research Feb 2016Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload....
PURPOSE
Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients.
METHODS
Serum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by β-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0).
RESULTS
A turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if >60% of the doses are missed.
CONCLUSIONS
Modelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents.
Topics: Adolescent; Adult; Chelation Therapy; Child; Computer Simulation; Deferoxamine; Dose-Response Relationship, Drug; Erythrocyte Transfusion; Ferritins; Humans; Iron Overload; Models, Biological; Siderophores; Young Adult; beta-Thalassemia
PubMed: 26555666
DOI: 10.1007/s11095-015-1805-0