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Expert Review of Clinical Pharmacology Jun 2018To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis.
METHODS
Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy.
RESULTS
Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons.
CONCLUSION
Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.
Topics: Anemia, Sickle Cell; Benzoates; Deferasirox; Deferiprone; Deferoxamine; Drug Therapy, Combination; Humans; Iron Chelating Agents; Iron Overload; Network Meta-Analysis; Pyridones; Randomized Controlled Trials as Topic; Silymarin; Thalassemia; Triazoles
PubMed: 29727586
DOI: 10.1080/17512433.2018.1473760 -
PloS One 2015Intracerebral hemorrhage (ICH) is a subtype of stroke associated with high morbidity and mortality rates. No proven treatments are available for this condition.... (Review)
Review
Intracerebral hemorrhage (ICH) is a subtype of stroke associated with high morbidity and mortality rates. No proven treatments are available for this condition. Iron-mediated free radical injury is associated with secondary damage following ICH. Deferoxamine (DFX), a ferric-iron chelator, is a candidate drug for the treatment of ICH. We performed a systematic review of studies involving the administration of DFX following ICH. In total, 20 studies were identified that described the efficacy of DFX in animal models of ICH and assessed changes in the brain water content, neurobehavioral score, or both. DFX reduced the brain water content by 85.7% in animal models of ICH (-0.86, 95% CI: -.48- -0.23; P < 0.01; 23 comparisons), and improved the neurobehavioral score by -1.08 (95% CI: -1.23- -0.92; P < 0.01; 62 comparisons). DFX was most efficacious when administered 2-4 h after ICH at a dose of 10-50 mg/kg depending on species, and this beneficial effect remained for up to 24 h postinjury. The efficacy was higher with phenobarbital anesthesia, intramuscular injection, and lysed erythrocyte infusion, and in Fischer 344 rats or aged animals. Overall, although DFX was found to be effective in experimental ICH, additional confirmation is needed due to possible publication bias, poor study quality, and the limited number of studies conducting clinical trials.
Topics: Animals; Cerebral Hemorrhage; Deferoxamine; Disease Models, Animal; Mice; Rats; Siderophores; Swine; Treatment Outcome
PubMed: 26000830
DOI: 10.1371/journal.pone.0127256 -
Journal of Controlled Release :... Apr 2023Iron-overload diseases are characterized by a variety of symptoms resulting from excessive iron stores, oxidative stress and consequent end-organ damage. Deferoxamine...
Iron-overload diseases are characterized by a variety of symptoms resulting from excessive iron stores, oxidative stress and consequent end-organ damage. Deferoxamine (DFO) is an iron-chelator that can protect tissues from iron-induced damage. However, its application is limited due to its low stability and weak free radical scavenging ability. Herein, natural polyphenols have been employed to enhance the protective efficacy of DFO through the construction of supramolecular dynamic amphiphiles, which self-assemble into spherical nanoparticles with excellent scavenging capacity against both iron (III) and reactive oxygen species (ROS). This class of natural polyphenols-assisted nanoparticles was found to exhibit enhanced protective efficacy both in vitro in an iron-overload cell model and in vivo in an intracerebral hemorrhage model. This strategy of constructing natural polyphenols- assisted nanoparticles could benefit the treatment of iron-overload related diseases with excessive accumulation of toxic or harmful substances.
Topics: Humans; Deferoxamine; Iron Chelating Agents; Polyphenols; Iron; Iron Overload; Nanoparticles
PubMed: 36813037
DOI: 10.1016/j.jconrel.2023.02.027 -
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 -
Technology in Cancer Research &... Jan 2018Mounting evidence suggest that iron overload enhances cancer growth and metastasis; hence, iron chelation is being increasingly used as part of the treatment regimen in...
Mounting evidence suggest that iron overload enhances cancer growth and metastasis; hence, iron chelation is being increasingly used as part of the treatment regimen in patients with cancer. Now whether iron chelation depletes intracellular iron and/or disrupts intracellular iron homeostasis is yet to be fully addressed. MCF-7 and MDA-MB-231 breast cancer cells treated with increasing concentrations of the iron chelator deferoxamine were assessed for intracellular iron status, the expression of key proteins involved in iron metabolism, cell viability, growth potential, and apoptosis at different time points following treatment. Treatment with deferoxamine at 1, 5, or 10 μM for 24 or 48 hours, while not leading to significant changes in intracellular labile iron content, upregulated the expression of hepcidin, ferroportin, and transferrin receptors 1 and 2. In contrast, deferoxamine at 30, 100, or 300 μM for 24 hours induced a significant decrease in intracellular labile iron, which was associated with increased expression of hepcidin, ferritin, and transferrin receptors 1 and 2. At 48 hours, there was an increase in intracellular labile iron, which was associated with a significant reduction in hepcidin and ferritin expression and a significant increase in ferroportin expression. Although low-dose deferoxamine treatment resulted in a low to moderate decrease in MCF-7 cell growth, high-dose treatment resulted in a significant and precipitous decrease in cell viability and growth, which was associated with increased expression of phosphorylated Histone 2A family member X and near absence of survivin. High-dose deferoxamine treatment also resulted in a very pronounced reduction in wound healing and growth in MDA-MB-231 cells. These findings suggest that high-dose deferoxamine treatment disrupts intracellular iron homeostasis, reduces cell viability and growth, and enhances apoptosis in breast cancer cells. This is further evidence to the potential utility of iron chelation as an adjunctive therapy in iron-overloaded cancers.
Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Deferoxamine; Female; Homeostasis; Humans; Iron; Iron Chelating Agents
PubMed: 29562821
DOI: 10.1177/1533033818764470 -
International Journal of Biological... Mar 2022Chronic non-healing diabetic wounds and ulcers can be fatal, lead to amputations, and remain a major challenge to medical, and health care sectors. Susceptibility to...
Chronic non-healing diabetic wounds and ulcers can be fatal, lead to amputations, and remain a major challenge to medical, and health care sectors. Susceptibility to infection and impaired angiogenesis are two central reasons for the clinical consequences associated with chronic non-healing diabetic wounds. Herein, we successfully developed calcium ion (Ca) cross-linked sodium alginate (SA) hydrogels with both pro-angiogenesis and antibacterial properties. Our results demonstrated that deferoxamine (DFO) and copper nanoparticles (Cu-NPs) worked synergistically to enhance the proliferation, migration, and angiogenesis of human umbilical venous endothelial cells in vitro. Results of colony formation assay indicated Cu-NPs were effective against E. coli and S. aureus in a dose-dependent manner in vitro. An SA hydrogel containing both DFO and Cu-NPs (SA-DFO/Cu) was prepared using a Ca cross-linking method. Cytotoxicity assay and colony formation assay indicated that the hydrogel exhibited beneficial biocompatible and antibacterial properties in vitro. Furthermore, SA-DFO/Cu significantly accelerated diabetic wound healing, improved angiogenesis and reduced long-lasting inflammation in a mouse model of diabetic wound. Mechanistically, DFO and Cu-NPs synergistically stimulated the levels of hypoxia-inducible factor 1α and vascular endothelial growth factor in vivo. Given the pro-angiogenesis, antibacterial and healing properties, the hydrogel possesses high potential for clinical application in refractory wounds.
Topics: Alginates; Animals; Calcium; Copper; Deferoxamine; Diabetes Mellitus; Escherichia coli; Human Umbilical Vein Endothelial Cells; Humans; Hydrogels; Mice; Nanoparticles; Staphylococcus aureus; Vascular Endothelial Growth Factor A; Wound Healing
PubMed: 35066024
DOI: 10.1016/j.ijbiomac.2022.01.080 -
Journal of Biomaterials Applications May 2017Prolyl hydroxylase inhibitors induce a proangiogenic response and are therefore proposed to optimize regenerative approaches in periodontics and oral surgery. Here the...
Prolyl hydroxylase inhibitors induce a proangiogenic response and are therefore proposed to optimize regenerative approaches in periodontics and oral surgery. Here the effect of the prolyl hydroxylase inhibitors dimethyloxalylglycine and deferoxamine, released from collagen barrier membranes, on osteoclastogenesis and osteoblastogenesis was evaluated. Collagen barrier membranes were loaded with dimethyloxalylglycine and deferoxamine. Release studies were performed and supernatants were taken after 1, 3, 6, 24, and 48 h. The effect of these supernatants on osteoblast- and osteoclast-precursor cells was evaluated. Furthermore, dose response studies for dimethyloxalylglycine and deferoxamine were performed. Osteoclastogenesis was evaluated with RAW 264.7 cells based on the number of multinuclear tartrate-resistant acid phosphatase positive cells. Osteoblastogenesis was evaluated with MC3T3-E1 cells based on alkaline phosphatase. Metabolic activity and cell proliferation were assessed based on MTT and BrdU assays. Vascular endothelial growth factor production was evaluated using an immunoassay. We found that supernatants taken in the first hour from collagen barrier membranes loaded with dimethyloxalylglycine or deferoxamine reduced osteoclastogenesis. Osteoblastogenesis was not reduced significantly. Cell proliferation and metabolic activity of RAW 264.7 and MC3T3-E1 cells were inhibited by supernatants of collagen barrier membranes loaded with deferoxamine but not dimethyloxalylglycine. In RAW 264.7 cell culture, vascular endothelial growth factor production was increased only by supernatants of collagen barrier membranes loaded with dimethyloxalylglycine, but not deferoxamine. In MC3T3-E1 cell culture, supernatants of collagen barrier membranes loaded with dimethyloxalylglycine and deferoxamine both increased vascular endothelial growth factor production. Direct measurements showed that the majority of dimethyloxalylglycine and deferoxamine is released in the first hours. Dose-response studies supported the divergent effects of deferoxamine and dimethyloxalylglycine in RAW 264.7 and MC3T3-E1 cultures. Our findings show diverse effects of dimethyloxalylglycine- and deferoxamine-loaded collagen barrier membranes during osteoclastogenesis and osteoblastogenesis. Preclinical studies will reveal if the increase in vascular endothelial growth factor together with the inhibitory effect on osteoclasts can stimulate oral tissue regeneration.
Topics: Alkaline Phosphatase; Amino Acids, Dicarboxylic; Animals; Biological Transport; Bone Resorption; Cell Line; Cell Proliferation; Cell Survival; Collagen; Deferoxamine; Guided Tissue Regeneration; Mice; Osteoblasts; Osteoclasts; Osteogenesis; Permeability; Prolyl-Hydroxylase Inhibitors; Tartrate-Resistant Acid Phosphatase; Tissue Engineering; Vascular Endothelial Growth Factor A
PubMed: 28376673
DOI: 10.1177/0885328217702563 -
Plastic and Reconstructive Surgery Jan 2015Radiation therapy results in permanent damage to the microvasculature, leading to dermal damage and inelasticity in normal tissues. Deferoxamine is a U.S. Food and Drug...
BACKGROUND
Radiation therapy results in permanent damage to the microvasculature, leading to dermal damage and inelasticity in normal tissues. Deferoxamine is a U.S. Food and Drug Administration-approved iron-chelating medication that has also been shown to increase angiogenesis. The authors hypothesize that the application of deferoxamine will result in increased vascularity and improved tissue elasticity in a rat irradiated transverse rectus abdominis musculocutaneous flap model.
METHODS
Fifteen rats underwent a transverse rectus abdominis myocutaneous flap and were randomized to three groups: control, radiation therapy, and radiation therapy plus deferoxamine. The flaps in the radiation therapy and radiation therapy plus deferoxamine groups were irradiated with 35 Gy in a single dose. Four weeks after irradiation, rats in the radiation therapy plus deferoxamine group were treated with deferoxamine. Flaps were imaged with micro-computed tomographic angiography. Flap creep and stress relaxation were assessed using a tensiometer. Hematoxylin and eosin, picrosirius red, and Verhoeff-van Gieson staining was performed.
RESULTS
Irradiated flaps demonstrated gross stigmata of cutaneous radiation injury within 4 weeks. Histologically, the epidermis in the radiation therapy flaps was found to be thicker than in the radiation therapy plus deferoxamine and control flaps (p < 0.001). Micro-computed tomographic angiography demonstrated a statistically significant (p < 0.05) increase in vascularity in the radiation therapy plus deferoxamine flaps compared with radiation therapy alone. The creep curve was indicative of increased elasticity in the radiation therapy plus deferoxamine flaps compared with radiation therapy flaps.
CONCLUSION
Deferoxamine appears to mitigate radiation-induced hypovascularity and improve tissue elasticity in a rat model of soft-tissue reconstruction.
Topics: Animals; Deferoxamine; Disease Models, Animal; Male; Radiation Injuries; Rats; Rats, Sprague-Dawley; Rectus Abdominis; Surgical Flaps
PubMed: 25539319
DOI: 10.1097/PRS.0000000000000844 -
Anaerobe Jun 2022Desulfovibrio spp. is a commensal sulfate reducing bacterium that is present in small numbers in the gastrointestinal tract. Increased concentrations of Desulfovibrio...
UNLABELLED
Desulfovibrio spp. is a commensal sulfate reducing bacterium that is present in small numbers in the gastrointestinal tract. Increased concentrations of Desulfovibrio spp. (blooms) have been reported in patients with inflammatory bowel disease and irritable bowel syndrome. Since stress has been reported to exacerbate symptoms of these chronic diseases, this study examined whether the stress catecholamine norepinephrine (NE) promotes Desulfovibrio growth. Norepinephrine-stimulated growth has been reported in other bacterial taxa, and this effect may depend on the availability of the micronutrient iron.
OBJECTIVES
This study tested whether norepinephrine exposure affects the in vitro growth of Desulfovibrio vulgaris in an iron dependent manner.
METHODS
DSV was incubated in a growth medium with and without 1 μm of norepinephrine. An additional growth assay added the iron chelator deferoxamine in NE exposed DSV. Iron regulatory genes were assessed with and without the treatment of NE and Deferoxamine.
RESULTS
We found that norepinephrine significantly increased growth of D. vulgaris. Norepinephrine also increased bacterial production of hydrogen sulfide. Additionally, norepinephrine significantly increased bacterial expression in three of the four tested iron regulatory genes. The iron chelator deferoxamine inhibited growth of D. vulgaris in a dose-dependent manner and reversed the effect of norepinephrine on proliferation of D. vulgaris and on bacterial expression of iron regulatory genes.
CONCLUSION
The data presented in this work suggests that promotion of D. vulgaris growth by norepinephrine is iron dependent.
Topics: Deferoxamine; Desulfovibrio; Desulfovibrio vulgaris; Humans; Iron; Iron Chelating Agents; Norepinephrine
PubMed: 35533828
DOI: 10.1016/j.anaerobe.2022.102582 -
Toxicology and Applied Pharmacology Nov 2023Iron overload cardiomyopathy (IOC) is the leading cause of death in cases of iron overload in patients. Previous studies demonstrated that iron overload led to...
Ferroptosis inhibitor improves cardiac function more effectively than inhibitors of apoptosis and necroptosis through cardiac mitochondrial protection in rats with iron-overloaded cardiomyopathy.
Iron overload cardiomyopathy (IOC) is the leading cause of death in cases of iron overload in patients. Previous studies demonstrated that iron overload led to cardiomyocyte dysfunction and death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart needs clarification. We tested the hypothesis that ferroptosis, an iron-dependent cell death, plays a dominant role in IOC, and ferroptosis inhibitor exerts greater efficacy than inhibitors of apoptosis and necroptosis on improving cardiac function in iron-overloaded rats. Iron dextran was injected intraperitoneally into male Wistar rats for four weeks to induce iron overload. Then, the rats were divided into 5 groups: treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (Necrostatin-1), ferroptosis inhibitor (Ferrostatin-1) or iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, apoptosis, necroptosis and ferroptosis were determined. The increased expression of apoptosis-, necroptosis- and ferroptosis-related proteins, were associated with impaired cardiac and mitochondrial function in iron-overloaded rats. All cell death inhibitors attenuated cardiac apoptosis, necroptosis and ferroptosis in iron-overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial dysfunction and Bax/Bcl-2 ratio. Moreover, both Ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by restored left ventricular ejection fraction and E/A ratio, whereas z-VAD-FMK and Necrostatin-1 only partially improved this parameter. These results indicated that ferroptosis could be the predominant form of cardiomyocyte death in IOC, and that inhibiting ferroptosis might be a potential novel treatment for IOC.
Topics: Rats; Humans; Male; Animals; Ferroptosis; Deferoxamine; Necroptosis; Stroke Volume; Rats, Wistar; Ventricular Function, Left; Apoptosis; Iron Overload; Iron; Cardiomyopathies; Mitochondria; Myocytes, Cardiac
PubMed: 37863361
DOI: 10.1016/j.taap.2023.116727