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Translational Stroke Research Oct 2023Posthemorrhagic hydrocephalus occurs in up to 30% of infants with high-grade intraventricular hemorrhage and is associated with the worst neurocognitive outcomes in...
Posthemorrhagic hydrocephalus occurs in up to 30% of infants with high-grade intraventricular hemorrhage and is associated with the worst neurocognitive outcomes in preterm infants. The mechanisms of posthemorrhagic hydrocephalus after intraventricular hemorrhage are unknown; however, CSF levels of iron metabolic pathway proteins including hemoglobin have been implicated in its pathogenesis. Here, we develop an animal model of intraventricular hemorrhage using intraventricular injection of hemoglobin at post-natal day 4 that results in acute and chronic hydrocephalus, pathologic choroid plexus iron accumulation, and subsequent choroid plexus injury at post-natal days 5, 7, and 15. This model also results in increased expression of aquaporin-1, Na/K/Cl cotransporter 1, and Na/K/ATPase on the apical surface of the choroid plexus 24 h post-intraventricular hemorrhage. We use this model to evaluate a clinically relevant treatment strategy for the prevention of neurological sequelae after intraventricular hemorrhage using intraventricular administration of the iron chelator deferoxamine at the time of hemorrhage. Deferoxamine treatment prevented posthemorrhagic hydrocephalus for up to 11 days after intraventricular hemorrhage and prevented the development of sensorimotor gating deficits. In addition, deferoxamine treatment facilitated acute iron clearance through the choroid plexus and subsequently reduced choroid plexus iron levels at 24 h with reversal of hemoglobin-induced aquaporin-1 upregulation on the apical surface of the choroid plexus. Intraventricular administration of deferoxamine at the time of intraventricular hemorrhage may be a clinically relevant treatment strategy for preventing posthemorrhagic hydrocephalus and likely acts through promoting iron clearance through the choroid plexus to prevent hemoglobin-induced injury.
Topics: Infant, Newborn; Humans; Animals; Choroid Plexus; Iron; Deferoxamine; Infant, Premature; Hydrocephalus; Cerebral Hemorrhage; Hemoglobins; Aquaporins
PubMed: 36308676
DOI: 10.1007/s12975-022-01092-7 -
The Lancet. Neurology May 2019Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in...
BACKGROUND
Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.
METHODS
We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.
FINDINGS
We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.
INTERPRETATION
Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile.
FUNDING
US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.
Topics: Aged; Cerebral Hemorrhage; Deferoxamine; Double-Blind Method; Female; Humans; Infusions, Intravenous; Iron Chelating Agents; Male; Medical Futility; Middle Aged; Negative Results; Prospective Studies; Risk Assessment; Treatment Outcome
PubMed: 30898550
DOI: 10.1016/S1474-4422(19)30069-9 -
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 -
Journal of Oral and Maxillofacial... Dec 2018Despite the relative surgical ease and reduced donor-site morbidity of distraction osteogenesis (DO) in comparison with free tissue transfer, DO is currently precluded...
PURPOSE
Despite the relative surgical ease and reduced donor-site morbidity of distraction osteogenesis (DO) in comparison with free tissue transfer, DO is currently precluded as a reconstructive option for head and neck cancer (HNC) patients because of the destructive effects of radiotherapy (XRT). This study investigates the ability of a novel combined therapy (CT) of radioprotective amifostine (AMF) and angiogenic deferoxamine (DFO) to mitigate XRT-induced bone injury in a murine model of DO.
MATERIALS AND METHODS
Thirty male Sprague-Dawley rats were divided into 5 groups: DO (primary control), XRT (secondary control), AMF, DFO, and CT. With the exclusion of the DO group, all rats were administered a fractionated, human-equivalent XRT dose of 35 Gy, comparable with 70 Gy administered to HNC patients clinically. All groups underwent mandibular osteotomy and distraction to 5.1 mm. After euthanasia administration on postoperative day 40, the mandibles were sectioned and stained with Gomori trichrome. Osteocyte number, bone volume, and osteoid volume were compared between all groups by analysis of variance (P < .05).
RESULTS
All rats survived and were included in the final analysis. The XRT group exhibited substantial bone injury, evidenced by a decreased osteocyte number and bone volume, as well as an increase in immature osteoid volume, compared with DO controls. The AMF, DFO, and CT groups showed significant increases in osteocyte proliferation compared with the XRT group and were not statistically different from the DO group. Notably, the CT group showed remediation of XRT-induced impairment of bone maturation and exhibited significantly greater bone volume and reduced osteoid volume in comparison with all groups.
CONCLUSIONS
Combined AMF and DFO treatment showed the capacity to remediate the deleterious effects of XRT, restore cellularity to nonirradiated levels, and surpass all groups in mature bone formation. Although further investigations of AMF and DFO are warranted, this study provides preliminary support for the potential use of DO in HNC patients through pharmaceutical facilitation of irradiated bone healing.
Topics: Amifostine; Animals; Deferoxamine; Drug Therapy, Combination; Male; Mandible; Osteogenesis, Distraction; Radiation Injuries; Radiation-Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome
PubMed: 29883588
DOI: 10.1016/j.joms.2018.05.013 -
Journal of Neurotrauma Oct 2017Deferoxamine mesylate can cross the blood-brain barrier and reduce iron accumulation in nervous tissue; moreover, it has a variety of neuroprotective functions in... (Clinical Trial)
Clinical Trial
Deferoxamine mesylate can cross the blood-brain barrier and reduce iron accumulation in nervous tissue; moreover, it has a variety of neuroprotective functions in addition to complexing with iron ions. Such iron chelators are expected to become a new treatment option for intracerebral hemorrhage. This study evaluated the effects of deferoxamine mesylate on hematoma and edema absorption after traumatic intracerebral hemorrhage (TICH), and it provides clinical evidence for TICH treatment with deferoxamine mesylate. Patients with isolated TICH, confirmed by head computed tomography, were enrolled prospectively from January 2013 to December 2016. Patients were divided non-randomly into an experimental or control group as decided by the attending neurosurgeon. Patients in the experimental group received intravenous deferoxamine mesylate (20 mg/kg daily) from the day of admission for 5 consecutive days. We evaluated the impact of deferoxamine mesylate on the change in edema volume and the absorption of hematoma volume using a propensity score-matched analysis. In total, 190 patients were included. After matching, 94 patients were included in the final analysis (47 per group); no variable differed significantly between the two groups. The hematoma volume on the 7th day in the control group was higher than that at the same time-point in the experimental group (9.4 ± 7.2 vs. 5.2 ± 4.8 mL; p = 0.001). There was no difference in hematoma volume on Day 1 (12.6 ± 7.8 vs. 12.8 ± 6.4 mL; p = 0.896), Day 3 (12.4 ± 7.4 vs. 11.4 ± 4.9 mL; p = 0.442), and Day 14 (3.2 ± 3.0 vs. 2.5 ± 2.6 mL; p = 0.215) between the groups. The absorption of hematoma volume between the 1st and 3rd days and the 1st and 7th days in the experimental group was higher than that during the same periods in the control group. The edema volumes on the 3rd, 7th, and 14th days in the control group were higher than those at the same time-points in the experimental group. There was no difference in edema volume on the 1st day. The changes in edema volume between the 1st and 3rd days, the 1st and 7th days, and the 1st and 14th days in the control group were higher than those during the same periods in the experimental group. Deferoxamine mesylate may accelerate hematoma absorption and inhibit edema after TICH; however, further investigation is required to reach definitive conclusions.
Topics: Adult; Aged; Brain Edema; Cerebral Hemorrhage, Traumatic; Deferoxamine; Female; Humans; Male; Middle Aged; Siderophores; Treatment Outcome
PubMed: 28462672
DOI: 10.1089/neu.2017.5033 -
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 -
Artificial Organs Feb 2021Studies from China on COVID-19 revealed that nonsurvivors had cytokine storm with high IL-6 and hyperferritinemia. Iron liberated from necrotic cells may catalyze free...
Studies from China on COVID-19 revealed that nonsurvivors had cytokine storm with high IL-6 and hyperferritinemia. Iron liberated from necrotic cells may catalyze free radical production and amplify lipid peroxidation causing membrane dysfunction and multiorgan failure. Consequently, iron chelators have been successfully utilized in various experimental and clinical models of cytokine storm and multiorgan damage, such as in ischemia-reperfusion injury, sepsis, and infections. Since viral replication may be influenced by iron accumulation, iron chelation has been proven beneficial in a variety of viral infections, such as HIV-1, hepatitis B virus, Mengovirus, Marburg hemorrhagic fever, Enterovirus 71, and West Nile virus. In this commentary, we elaborate on the idea of considering iron chelation as a therapeutic modality in patients with severe COVID-19 infection. For critically ill patients in the ICU, intravenous deferoxamine would provide sufficient and rapid iron chelation to ameliorate cytokine storm, whereas in less severe cases an oral chelator could prevent the development of excessive inflammatory response.
Topics: Administration, Oral; COVID-19; Cytokine Release Syndrome; Deferoxamine; Humans; Hyperferritinemia; Infusions, Intravenous; Iron Chelating Agents; COVID-19 Drug Treatment
PubMed: 32882061
DOI: 10.1111/aor.13812 -
Biometals : An International Journal on... Oct 2017Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment...
Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment of iron overload-related neurodegenerative diseases. Triphenylphosphonium (TPP) is a delocalized lipophilic cation used to ferry molecules to mitochondria. Here we report the synthesis and characterization of the conjugate TPP-DFO as a mitochondrial iron chelator. TPP-DFO maintained both a high affinity for iron and the antioxidant activity when compared to parent DFO. TPP-DFO was less toxic than TPP alone to A2780 cells (IC = 135.60 ± 1.08 and 4.34 ± 1.06 μmol L, respectively) and its native fluorescence was used to assess its mitochondrial localization (Rr = +0.56). These results suggest that TPP-DFO could be an interesting alternative for the treatment of mitochondrial iron overload e.g. in Friedreich's ataxia.
Topics: Binding, Competitive; Cell Line, Tumor; Cell Survival; Deferoxamine; Epithelial Cells; Fluoresceins; Humans; Iron Chelating Agents; Kinetics; Mitochondria; Optical Imaging; Organophosphorus Compounds
PubMed: 28770399
DOI: 10.1007/s10534-017-0039-5 -
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