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Expert Review of Hematology 2016Iron chelating agents - deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) - are used to treat chronic iron overload in patients with β-thalassemia in an... (Review)
Review
Iron chelating agents - deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) - are used to treat chronic iron overload in patients with β-thalassemia in an attempt to reduce morbidity and mortality related to siderosis. Each of the approved iron chelating agents has its own advantages over the others and also has its own risks, whether related to over-chelation or not. In this review, we briefly discuss the methods to monitor the efficacy of iron chelation therapy (ICT) and the evidence behind the use of each iron chelating agent. We also portray the risks and complications associated with each iron chelating agent and recommend strategies to manage adverse events.
Topics: Benzoates; Chelation Therapy; Deferasirox; Deferiprone; Deferoxamine; Disease Management; Drug-Related Side Effects and Adverse Reactions; Female; Ferritins; Humans; Iron; Iron Chelating Agents; Iron Overload; Liver; Magnetic Resonance Imaging; Male; Myocardium; Pregnancy; Pyridones; Triazoles; beta-Thalassemia
PubMed: 26613264
DOI: 10.1586/17474086.2016.1126176 -
Pediatrics International : Official... Apr 2021Iron overload is a major complication of transfusion-dependent thalassemia (TDT) and requires iron chelation (IC) therapy. However, a combination therapy may be required...
BACKGROUND
Iron overload is a major complication of transfusion-dependent thalassemia (TDT) and requires iron chelation (IC) therapy. However, a combination therapy may be required for patients responding poorly to monotherapy.
METHODS
Nine TDT patients previously treated with IC were enrolled; five patients were previously treated with deferasirox (DFX) twice daily. The dose of DFX was 20-40 mg/kg/day, while the dose of deferoxamine (DFO) was 18-40 mg/kg/day for 3-6 days/week.
RESULTS
At the 6- and 12-month time points, six and eight patients demonstrated decreased serum ferritin levels, with median reductions of 707 ng/mL (range, 1,653-5,444 ng/mL) and 1,129 ng/mL (range, 1,781-7,725 ng/mL) compared to the baseline, respectively. Eight patients also had a reduced liver iron concentration (LIC), with a median reduction of 3.9 mg/g dry wt (range, 8.3-11.1 mg/g dry wt). Of the five patients treated with DFX twice daily, four responded to combination therapy. All responsive patients could finally stop DFO after the decline in LIC. Moreover, there were no treatment-related complications.
CONCLUSION
The combination of DFX and DFO proved to be effective and without significant toxicities for TDT patients who had been unresponsive to standard IC therapy. Further studies with a larger cohort size and long-term follow-up are warranted to elucidate the efficacy of the combination.
Topics: Benzoates; Deferasirox; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Thalassemia; Triazoles; beta-Thalassemia
PubMed: 32856363
DOI: 10.1111/ped.14444 -
Clinical Anatomy (New York, N.Y.) Jul 2021Dyshomeostasis of trace elements have been implicated in the progression of Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) plaques. Trace elements... (Review)
Review
Dyshomeostasis of trace elements have been implicated in the progression of Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) plaques. Trace elements are particularly associated with the Aβ plaques. Metal-protein attenuating compounds have been developed to inhibit metals from binding to Aβ proteins, which result in Aβ termination, in the hope of improving cognitive functioning. However, there are still some contradicting reports. This review aims to first establish which trace elements are increased or decreased in the brains of Alzheimer's patients, and secondly, to review the effectiveness of clinical trials with metal-protein attenuating compounds for AD. Studies have consistently reported unchanged or increased iron, contradicting reports for zinc, decreased copper, unchanged or decreased manganese, inconsistent results for calcium, and magnesium seems to be unaffected. However, varied results have been reported for all trace elements. Clinical trials using metal-protein attenuating compounds to treat AD have also reported varied results. Copper chelators have repeatedly been used in clinical trials, even though few studies report increased brain copper levels in AD patients. Homeostasis of copper levels is important since copper has a vital role in several enzymes, such as cytochrome c, Cu/Zn superoxide dismutase and ceruloplasmin. Dyshomeostasis of copper levels can lead to increased oxidative stress and neuronal loss. Future studies should assess a variety of trace element levels in moderately and severely affected AD patients since there are contradicting reports. This review thus provides some insight into trace element alterations in the brains of individuals with AD.
Topics: Alzheimer Disease; Clioquinol; Copper; Deferoxamine; Humans; Metals; Penicillamine; Siderophores; Trace Elements
PubMed: 33580904
DOI: 10.1002/ca.23727 -
International Journal of Nanomedicine 2022Bone delay union is mostly caused by lack of blood supply. Although autografts, allografts and artificial bone have been widely used to treat bone delay union, the bone...
INTRODUCTION
Bone delay union is mostly caused by lack of blood supply. Although autografts, allografts and artificial bone have been widely used to treat bone delay union, the bone regeneration fails in the ischemic site accompanied by the bone donor site complications and disease transmission. Recently, there is a growing recognition of the importance of hydrogel scaffolds which are regarded as an eligible engineer tissue for bone repair. However, hydrogel is still limited in improving neovascularization.
METHODS
In this work, black phosphorus nanosheet and deferoxamine (BPN-DFO) were loaded in the gelatin hydrogel to overcome the high risk of bone delay union and systemically investigated the regeneration capability of BPN-DFO hydrogel in vitro and vivo.
RESULTS
The resulting BPN-DFO hydrogel scaffold showed superior swollen, degradation and release rate, as well as satisfied biocompatibility. BPN-DFO hydrogel shown the significant up-expression of mRNA related to bone regeneration and cell proliferation. In vivo, the proposed BPN-DFO hydrogel significantly improved osteogenesis and neovascularization in the ischemic tibial bone site of SD rats with acute femoral artery occlusion. Both macroscopic and histological evaluation of new regenerated bone showed newly formed blood vessel and collagen using BPN-DFO hydrogel. The immunohistochemistry and RT-PCR revealed that the bone regeneration could be improved via BMP/Runx2 pathway.
CONCLUSION
The BPN-DFO hydrogel possesses potential tissue engineer material for ischemic bone defect treatment. However, furthermore studies are needed to testify the safety and efficacy of BPN-DFO hydrogel.
Topics: Animals; Bone Regeneration; Deferoxamine; Fracture Healing; Gelatin; Hydrogels; Ischemia; Nanostructures; Phosphorus; Rats; Rats, Sprague-Dawley; Tibia; Tissue Engineering; Tissue Scaffolds
PubMed: 35299865
DOI: 10.2147/IJN.S351814 -
American Journal of Physiology. Heart... Feb 2023Diabetes increases the risk of poststroke cognitive impairment (PSCI). Greater hemorrhagic transformation (HT) after stroke is associated with vasoregression and...
Diabetes increases the risk of poststroke cognitive impairment (PSCI). Greater hemorrhagic transformation (HT) after stroke is associated with vasoregression and cognitive decline in male diabetic rats. Iron chelator deferoxamine (DFX) prevents vasoregression and improves outcomes. Although diabetic female rats develop greater HT, its impact on poststroke cerebrovascularization and cognitive outcomes remained unknown. We hypothesized that diabetes mediates pathological neovascularization, and DFX attenuates poststroke cerebrovascular remodeling and improves neurological outcomes in female diabetic rats. Female control and diabetic animals were treated with DFX or vehicle for 7 days after stroke. Vascular indices, microglial activation, and blood-brain barrier (BBB) integrity were evaluated on . Results from diabetic female rats were partially compared with our previously published findings in male counterparts. Hemin-induced programmed cell death was studied in male and female brain microvascular endothelial cell lines (BMVEC). There was no vasoregression after stroke in either control or diabetic female animals. DFX prevented diabetes-mediated gliovascular remodeling and compromised BBB integrity while improving memory function in diabetes. Comparisons of female and male rats indicated sex differences in cognitive and vascular outcomes. Hemin mediated ferroptosis in both male and female BMVECs. DFX improved survival but had differential effects on ferroptosis signaling in female and male cells. These results suggest that stroke and associated HT do not affect cerebrovascularization in diabetic female rats, but iron chelation may provide a novel therapeutic strategy in the prevention of poststroke memory impairment in females with diabetes via the preservation of gliovascular integrity and improvement of endothelial cell survival. The current study shows for the first time that diabetes does not promote aberrant cerebrovascularization in female rats. This contrasts with what we reported in male animals in various diabetes models. Deferoxamine preserved recognition memory function in diabetic female animals after stroke. The effect(s) of stroke and deferoxamine on cerebrovascular density and microglial activation also appear(s) to be different in female diabetic rats. Lastly, deferoxamine exerts detrimental effects on animals and BMVECs under control conditions.
Topics: Rats; Female; Male; Animals; Deferoxamine; Diabetes Mellitus, Experimental; Ferroptosis; Hemin; Stroke
PubMed: 36563009
DOI: 10.1152/ajpheart.00490.2022 -
Molecules (Basel, Switzerland) Oct 2022Positron emission tomography (PET) imaging is a powerful non-invasive method to determine the in vivo behavior of biomolecules. Determining biodistribution and...
Positron emission tomography (PET) imaging is a powerful non-invasive method to determine the in vivo behavior of biomolecules. Determining biodistribution and pharmacokinetic (PK) properties of targeted therapeutics can enable a better understanding of in vivo drug mechanisms such as tumor uptake, off target accumulation and clearance. Zirconium-89 (Zr) is a readily available tetravalent PET-enabling radiometal that has been used to evaluate the biodistribution and PK of monoclonal antibodies. In the current study, we performed in vitro and in vivo characterization of Zr-lintuzumab, a radiolabeled anti-CD33 antibody, as a model to evaluate the in vivo binding properties in preclinical models of AML. Lintuzumab was conjugated to p-SCN-Bn-deferoxamine (DFO) and labeled with Zr using a 5:1 µCi:µg specific activity at 37 °C for 1h. The biological activity of Zr-lintuzumab was evaluated in a panel of CD33 positive cells using flow cytometry. Fox Chase SCID mice were injected with 2 × 10 OCI-AML3 cells into the right flank. After 12 days, a cohort of mice ( = 4) were injected with Zr-lintuzumab via tail vein. PET/CT scans of mice were acquired on days 1, 2, 3 and 7 post Zr-lintuzumab injection. To demonstrate Zr-lintuzumab specific binding to CD33 expressing tumors in vivo, a blocking study was performed. This cohort of mice ( = 4) was injected with native lintuzumab and 24 h later Zr-lintuzumab was administered. This group was imaged 3 and 7 days after injection of Zr-lintuzumab. A full ex vivo biodistribution study on both cohorts was performed on day 7. The results from the PET image and ex vivo biodistribution studies were compared. Lintuzumab was successfully radiolabeled with Zr resulting in a 99% radiochemical yield. The Zr-lintuzumab radioconjugate specifically binds CD33 positive cells in a similar manner to native lintuzumab as observed by flow cytometry. PET imaging revealed high accumulation of Zr-lintuzumab in OCI-AML3 tumors within 24h post-injection of the radioconjugate. The Zr-lintuzumab high tumor uptake remains for up to 7 days. Tumor analysis of the PET data using volume of interest (VOI) showed significant blocking of Zr-lintuzumab in the group pre-treated with native lintuzumab (pre-blocked group), thus indicating specific targeting of CD33 on OCI-AML3 cells in vivo. The tumor uptake findings from the PET imaging study are in agreement with those from the ex vivo biodistribution results. PET imaging of Zr-lintuzumab shows high specific uptake in CD33 positive human OCI-AML3 tumors. The results from the image study agree with the observations from the ex vivo biodistribution study. Our findings collectively suggest that PET imaging using Zr-lintuzumab could be a powerful drug development tool to evaluate binding properties of anti-CD33 monoclonal antibodies in preclinical cancer models.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Deferoxamine; Humans; Mice; Mice, SCID; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Tissue Distribution; Zirconium
PubMed: 36235126
DOI: 10.3390/molecules27196589 -
Stroke Jul 2022There are limited data on the trajectory of recovery and long-term functional outcomes after intracerebral hemorrhage (ICH). Most ICH trials have conventionally assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
There are limited data on the trajectory of recovery and long-term functional outcomes after intracerebral hemorrhage (ICH). Most ICH trials have conventionally assessed outcomes at 3 months following the footsteps of ischemic stroke. The i-DEF trial (Intracerebral Hemorrhage Deferoxamine Trial) assessed modified Rankin Scale (mRS) longitudinally at prespecified time points from day 7 through the end of the 6-month follow-up period. We evaluated the trajectory of mRS among trial participants and examined the effect of deferoxamine on this trajectory.
METHODS
We performed a post hoc analysis of the i-DEF trial, a multicenter, randomized, placebo-controlled, double-blind, futility-design, phase 2 clinical trial, based on the actual treatment received. Favorable outcome was defined as mRS score of 0-2. A generalized linear mixed model was used to evaluate the outcome trajectory over time, as well as whether the trajectory was altered by deferoxamine, after adjustments for randomization variables, presence of intraventricular hemorrhage, and ICH location.
RESULTS
A total of 291 subjects were included in analysis (145 placebo and 146 deferoxamine). The proportion of patients with mRS score of 0-2 continually increased from day 7 to 180 in both groups (interaction <0.0001 for time in main effects model), but treatment with deferoxamine favorably altered the trajectory (interaction =0.0010). Between day 90 and 180, the deferoxamine group improved (=0.0001), whereas there was not significant improvement in the placebo arm (=0.3005).
CONCLUSIONS
A large proportion of patients continue to improve up to 6 months after ICH. Future ICH trials should assess outcomes past 90 days for a minimum of 6 months. In i-DEF, treatment with deferoxamine seemed to accelerate and alter the trajectory of recovery as assessed by mRS.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT02175225.
Topics: Humans; Cerebral Hemorrhage; Deferoxamine; Double-Blind Method; Medical Futility; Treatment Outcome
PubMed: 35306827
DOI: 10.1161/STROKEAHA.121.037298 -
The British Journal of Dermatology Apr 2017
Review
Topics: Administration, Cutaneous; Chronic Disease; Deferoxamine; Humans; Iron; Siderophores; Skin Ulcer; Wound Healing; Wounds and Injuries
PubMed: 28418133
DOI: 10.1111/bjd.14956 -
Dalton Transactions (Cambridge, England... Nov 2021Diversifying our ability to guard against emerging pathogenic threats is essential for keeping pace with global health challenges, including those presented by...
Diversifying our ability to guard against emerging pathogenic threats is essential for keeping pace with global health challenges, including those presented by drug-resistant bacteria. Some modern diagnostic and therapeutic innovations to address this challenge focus on targeting methods that exploit bacterial nutrient sequestration pathways, such as the desferrioxamine (DFO) siderophore used by () to sequester Fe. Building on recent studies that have shown DFO to be a versatile vehicle for chemical delivery, we show proof-of-principle that the Fe sequestration pathway can be used to deliver a potential radiotherapeutic. Our approach replaces the Fe nutrient sequestered by HDFO with Th and made use of a common fluorophore, FITC, which we covalently bonded to DFO to provide a combinatorial probe for simultaneous chelation paired with imaging and spectroscopy, HDFO_FITC. Combining insight provided from FITC-based imaging with characterization by NMR spectroscopy, we demonstrated that the fluorescent DFO_FITC conjugate retained the Th chelation properties of native HDFO. Fluorescence microscopy with both [Th(DFO_FITC)] and [Fe(DFO_FITC)] complexes showed similar uptake by and increased intercellular accumulation as compared to the FITC and unchelated HDFO_FITC controls. Collectively, these results demonstrate the potential for the newly developed HDFO_FITC conjugate to be used as a targeting vector and bacterial imaging probe for . The results presented within provide a framework to expand HDFO and HDFO_FITC to relevant radiotherapeutics (like Th).
Topics: Deferoxamine
PubMed: 34636377
DOI: 10.1039/d1dt02177j -
Journal of Controlled Release :... Jun 2020Intracellular bacteria (ICBs) are among the most life-threatening causes of drug resistance. Challenges remains in the intracellular drug release specific to...
Intracellular bacteria (ICBs) are among the most life-threatening causes of drug resistance. Challenges remains in the intracellular drug release specific to ICB-infected cells and efficient uptake into ICBs. In this study, mannose-grafted polymers containing enzymes-responsive and tetraphenylethylene segments (mPET) are assembled into nanoparticles with loading complexes of deferoxamine-ciprofloxacin conjugates with Fe (DC). The aggregation-induced emission (AIE) of tetraphenylethylene segments is overlapped with DC absorptions, leading to fluorescence resonance energy transfer (FRET)-caused quenching of mPET@DC nanoparticles. Nanoparticles are efficiently acquired by infected macrophages via mannose mediation, and the DC release is triggered by intracellular lipase and alkaline phosphatase specific to ICB-engulfed macrophages, followed by deferoxamine-mediated ingestion of ciprofloxacin into ICBs. The gradual alleviation of FRET effect and the concurrent restoration of AIE activity demonstrate capabilities of dynamically tracking the drug release and ICB treatment outcome. The mPET@DC treatment inhibits the hematological, hepatic and nephric toxicities caused by ICB infections, and all the infected mice survive with dramatic reductions of bacterial levels in livers (over 430 folds), spleens (over 240 folds) and kidneys (5.6 × 10 folds). Thus, this study has provided a feasible strategy to achieve intracellular enzymes-responsive and traceable release of antibiotics and then deferoxamine-mediated bacterial ingestion for ICB destruction.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Deferoxamine; Drug Liberation; Eating; Mice; Nanoparticles
PubMed: 32243975
DOI: 10.1016/j.jconrel.2020.03.037