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BMJ Open Feb 2024Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per...
Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial.
INTRODUCTION
Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload.
METHODS AND ANALYSIS
This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures.
ETHICS AND DISSEMINATION
Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals.
TRIAL REGISTRATION NUMBER
The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).
Topics: Adult; Adolescent; Humans; Deferasirox; Deferiprone; Deferoxamine; beta-Thalassemia; Benzoates; Triazoles; Pyridones; Iron Overload; Iron Chelating Agents; Iron; Randomized Controlled Trials as Topic
PubMed: 38331857
DOI: 10.1136/bmjopen-2023-077342 -
Scientific Reports Nov 2023Retinal ischemia‒reperfusion (I/R) injury can cause significant damage to human retinal neurons, greatly compromising their functions. Existing interventions have been...
Retinal ischemia‒reperfusion (I/R) injury can cause significant damage to human retinal neurons, greatly compromising their functions. Existing interventions have been proven to have little effect. Ferroptosis is a newly discovered type of programmed cell death that has been found to be involved in the process of ischemia‒reperfusion in multiple organs throughout the body. Studies have shown that it is also present in retinal ischemia‒reperfusion injury. A rat model of retinal ischemia‒reperfusion injury was constructed and treated with deferoxamine. In this study, we found the accumulation of Fe, reactive oxygen species (ROS), malondialdehyde (MDA), and the consumption of glutathione (GSH) via ELISA testing; increased expression of transferrin; and decreased expression of ferritin, SLC7A11, and GPX4 via Western blotting (WB) and real-time PCR testing. Structural signs of ferroptosis (mitochondrial shrinkage) were observed across multiple cell types, including retinal ganglion cells (RGCs), photoreceptor cells, and pigment epithelial cells. Changes in visual function were detected by F-VEP and ERG. The results showed that iron and oxidative stress were increased in the retinal ischemia‒reperfusion injury model, resulting in ferroptosis and tissue damage. Deferoxamine protects the structural and functional soundness of the retina by inhibiting ferroptosis through the simultaneous inhibition of hemochromatosis, the initiation of transferrin, and the degradation of ferritin and activating the antioxidant capacity of the System Xc-GSH-GPX4 pathway.
Topics: Humans; Animals; Rats; Ferroptosis; Deferoxamine; Reperfusion; Vision, Low; Reperfusion Injury; Ferritins; Glutathione; Transferrins; Reactive Oxygen Species
PubMed: 37978208
DOI: 10.1038/s41598-023-46104-0 -
Free Radical Biology & Medicine Nov 2023Recent studies have highlighted the positive effects of Kaempferol (KP), including its anti-inflammatory and antioxidant properties. However, its impact on oxidative...
Recent studies have highlighted the positive effects of Kaempferol (KP), including its anti-inflammatory and antioxidant properties. However, its impact on oxidative damage induced by heavy metals and pro-inflammatory mediators, such as arachidonic acid (AA), has not yet been identified. Our objective was to specifically evaluate liver damage due to AA + iron-induced oxidative stress, both in vitro and in vivo. In HepG2 cells, KP activated the AMP-activated protein kinase (AMPK), suggesting a hepatoprotective effect through AMPK inhibition, as assessed by immunoblot and FACS analysis (EC = 10 μM). KP also stimulated autophagy, a degradation process that eliminates aged, damaged, and unnecessary components, via mTOR inhibition and ULK1 phosphorylation. This activation was further validated by the upregulation of autophagy-related genes (ATG5) and Beclin-1, along with the conversion of LC3BI to LC3BII. Ferroptosis, a non-apoptotic type of cell death characterized by oxidative stress from the production of reactive oxygen species (ROS) and excessive iron accumulation, was linked to the activation of autophagy, as confirmed through the protein expression of deferoxamine (DFO) and ferrostatin-1 (Fer-1), the representative ferroptosis inhibitors (positive controls). In mice, oral administration of KP demonstrated protective effects against CCl-induced hepatotoxicity. In conclusion, KP provides hepatoprotective effects against oxidative stress induced by AA + iron treatment in vitro and CCl treatment in vivo.
Topics: Mice; Animals; AMP-Activated Protein Kinases; Ferroptosis; Kaempferols; Oxidative Stress; Reactive Oxygen Species; Arachidonic Acid; Autophagy; Iron
PubMed: 37703935
DOI: 10.1016/j.freeradbiomed.2023.09.008 -
Brain Research Aug 2023Traumatic brain injury (TBI) is an important reason of neurological damage and has high morbidity and mortality rates. The secondary damage caused by TBI leads to a poor...
Traumatic brain injury (TBI) is an important reason of neurological damage and has high morbidity and mortality rates. The secondary damage caused by TBI leads to a poor clinical prognosis. According to the literature, TBI leads to ferrous iron aggregation at the site of trauma and may be a key factor in secondary injury. Deferoxamine (DFO), which is an iron chelator, has been shown to inhibit neuron degeneration; however, the role of DFO in TBI is unclear. The purpose of this study was to explore whether DFO can ameliorate TBI by inhibiting ferroptosis and neuroinflammation. Here, our findings suggest that DFO can reduce the accumulation of iron, lipid peroxides, and reactive oxygen species (ROS) and modulate the expression of ferroptosis-related indicators. Moreover, DFO may reduce NLRP3 activation via the ROS/NF-κB pathway, modulate microglial polarization, reduce neutrophil and macrophage infiltration, and inhibit the release of inflammatory factors after TBI. Additionally, DFO may reduce the activation of neurotoxic responsive astrocytes. Finally, we demonstrated that DFO can protect motor memory function, reduce edema and improve peripheral blood perfusion at the site of trauma in mice with TBI, as shown by behavioral experiments such as the Morris water maze test, cortical blood perfusion assessment and animal MRI. In conclusion, DFO ameliorates TBI by reducing iron accumulation to alleviate ferroptosis and neuroinflammation, and these findings provide a new therapeutic perspective for TBI.
Topics: Mice; Animals; Deferoxamine; Neuroinflammatory Diseases; Reactive Oxygen Species; Ferroptosis; Brain Injuries, Traumatic; Iron
PubMed: 37149247
DOI: 10.1016/j.brainres.2023.148383 -
Molecular Oncology Nov 2023During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix...
During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3β signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target.
Topics: Humans; Lipocalin-2; Matrix Metalloproteinase 9; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Signal Transduction; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Proteoglycans; Amino Acid Oxidoreductases
PubMed: 37753805
DOI: 10.1002/1878-0261.13529 -
Journal of Neuroinflammation Jul 2023Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have...
BACKGROUND
Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI.
METHODS
A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20-Bax-caspase-gasdermin E (GSDME) pathway were analyzed.
RESULTS
SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20-Bax-caspase-GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20-Bax-caspase-GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20-Bax-caspase-GSDME-induced B cell pyroptosis.
CONCLUSIONS
Iron overload activates the Tom20-Bax-caspase-GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI.
Topics: Animals; Humans; Mice; B-Lymphocytes; bcl-2-Associated X Protein; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Caspases; Gasdermins; Inflammation; Iron; Pseudolymphoma; Pyroptosis; Spinal Cord Injuries
PubMed: 37480037
DOI: 10.1186/s12974-023-02848-0 -
Acta Pharmaceutica Sinica. B Oct 2023Delayed diabetic wound healing has placed an enormous burden on society. The key factors limiting wound healing include unresolved inflammation and impaired...
Delayed diabetic wound healing has placed an enormous burden on society. The key factors limiting wound healing include unresolved inflammation and impaired angiogenesis. Platelet-rich plasma (PRP) gel, a popular biomaterial in the field of regeneration, has limited applications due to its non-injectable properties and rapid release and degradation of growth factors. Here, we prepared an injectable hydrogel (DPLG) based on PRP and laponite by a simple one-step mixing method. Taking advantages of the non-covalent interactions, DPLG could overcome the limitations of PRP gels, which is injectable to fill irregular injures and could serve as a local drug reservoir to achieve the sustained release of growth factors in PRP and deferoxamine (an angiogenesis promoter). DPLG has an excellent ability in accelerating wound healing by promoting macrophage polarization and angiogenesis in a full-thickness skin defect model in type I diabetic rats and normal rats. Taken together, this study may provide the ingenious and simple bioactive wound dressing with a superior ability to promote wound healing.
PubMed: 37799395
DOI: 10.1016/j.apsb.2022.11.006 -
Molecules (Basel, Switzerland) Apr 2024Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of... (Review)
Review
Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies.
Topics: Deferoxamine; Humans; Animals; Neovascularization, Physiologic; Regeneration; Wound Healing; Neovascularization, Pathologic; Angiogenesis
PubMed: 38731540
DOI: 10.3390/molecules29092050 -
International Journal of Molecular... Nov 2023The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols... (Review)
Review
The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.
Topics: Humans; Deferiprone; Deferoxamine; Pyridones; Iron Chelating Agents; Iron Overload; Chelation Therapy; Iron; beta-Thalassemia; Drug Therapy, Combination
PubMed: 38069073
DOI: 10.3390/ijms242316749 -
European Journal of Ophthalmology Apr 2024Deferasirox is the only iron chelator available in oral formulation and a rare cause of pigmentary retinopathy. We report the first case of multimodal imaging in an...
INTRODUCTION
Deferasirox is the only iron chelator available in oral formulation and a rare cause of pigmentary retinopathy. We report the first case of multimodal imaging in an adult with deferasirox retinopathy.
METHODS
Case report and literature review, with search terms including deferasirox retinopathy and deferasirox toxicity.
RESULTS
A 63-year-old man with end stage renal disease and transfusion-dependent anemia on deferasirox for one year presented with asymptomatic pigment epitheliopathy. Optical coherence tomography featured outer retinal and retinal pigment epithelial discontinuity corresponding to hypoautofluorescence on fundus autofluorescence and blocking on fluorescein angiography. Multifocal electroretinography revealed subtle reduction in all amplitudes.
CONCLUSIONS
Retinal examinations should be considered for patients requiring chronic administration of deferasirox.
PubMed: 38562036
DOI: 10.1177/11206721241245740