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European Journal of Haematology May 2023Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow... (Review)
Review
Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow erythroid hyperplasia, or a chronic transfusional regimen. In normal conditions, intracellular and systemic mechanisms contribute to maintaining iron balance. When this complex homeostatic mechanism fails, an iron overload could be present. Detecting an iron overload is not easy. The gold standard remains the liver biopsy, even if it is invasive and dangerous. Identifying iron using noninvasive techniques allowed a better understanding of the rate of iron overload in different organs, with a low risk for the patient. Estimating serum ferritin (mg/L) is the easiest and, consequently, the most employed diagnostic tool for assessing body iron stores, even if it could be a not specific method. The most common hematological causes of iron overload are myelodysplastic syndromes, sickle cell disease, and thalassemia. In all of these conditions, three drugs have been approved for the treatment of iron overload: deferiprone, deferoxamine, and deferasirox. These chelators have been demonstrated to help lower tissue iron levels and prevent iron overload complications, improving event-free survival (EFS). Nowadays, the decision to start chelation and which chelator to choose remains the joint decision of the clinician and patient.
Topics: Humans; Chelation Therapy; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Pyridones; Benzoates; Triazoles; Iron Overload; Iron
PubMed: 36708354
DOI: 10.1111/ejh.13935 -
Life Sciences Feb 2023Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) caused by multiple factors. Studies have shown that epithelial cell damage was associated with...
AIMS
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) caused by multiple factors. Studies have shown that epithelial cell damage was associated with ferroptosis in UC. Therefore, our research focused on the effects and mechanism of iron chelator deferasirox in UC.
MAIN METHODS
The UC model was induced by 2.5 % dextran sulfate sodium salt (DSS) and administered with deferasirox (10 mg/kg) for 7 days. Histological pathologies, inflammatory response, ferrous iron contents, oxidative stress and ferroptosis regulators were determined. Intestinal microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA gene sequencing and targeted metabolomics.
KEY FINDINGS
Deferasirox significantly relieved the DSS-induced UC in mice, as evidenced by weight loss, survival rate, colon length shortening disease activity index (DAI) score and histology score. Deferasirox treatment reduced the level of pro inflammatory cytokines (IL-1β, IL-6, TNF-α and INF-γ). Ferroptosis was induced in mice with UC, as evidenced by ferrous iron accumulation, increased ROS production, SOD and GSH depletion, decreased the expression of GPX-4 and FTH, accompanied by increased expression of TF. Deferasirox treatment strongly reversed the alterations caused by ferroptotic characteristics in DSS-induced mice. Moreover, deferasirox treatment reshaped the composition of intestinal microbiota. The results revealed the genera of norank_f__Muribaculaceae, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, Odoribacter and Blautia were increased distinctly, while Escherichia-Shigella and Streptococcus were significantly decreased by deferasirox treatment. Targeted metabolomics analysis indicated the SCFAs production enhanced in deferasirox-treated mice.
SIGNIFICANCE
Our results suggested that deferasirox could treat DSS-induced UC in mice by inhibiting ferroptosis and improving intestinal microbiota.
Topics: Mice; Animals; Colitis, Ulcerative; Deferasirox; Gastrointestinal Microbiome; Ferroptosis; RNA, Ribosomal, 16S; Colon; Sodium Chloride; Sodium Chloride, Dietary; Iron; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal; Colitis
PubMed: 36563842
DOI: 10.1016/j.lfs.2022.121312 -
Revista Alergia Mexico (Tecamachalco,... Sep 2023Deferasirox is an active iron chelator, used in the treatment of iron overload such as hemochromatosis. Up to 28% may present adverse reactions to said drug. A...
BACKGROUND
Deferasirox is an active iron chelator, used in the treatment of iron overload such as hemochromatosis. Up to 28% may present adverse reactions to said drug. A desensitization protocol for this drug may be useful when there are no other therapeutic options.
CASE REPORT
A 52-year-old female with a diagnosis of hemochromatosis who began treatment with phlebotomy, poor response and tolerance, so it was decided to treat with deferasirox 500 mg daily, presenting symptoms of urticaria and angioedema on the third dose. Hospitalization was decided for a desensitization protocol with an initial dose of 0.6mg with a gradual increase in the dose, reaching a maintenance dose of 500 mg per day on the third day.
CONCLUSIONS
The rapid desensitization protocol for Deferasirox is useful when there is no response or therapeutic alternative.
Topics: Female; Humans; Middle Aged; Deferasirox; Hemochromatosis; Iron Chelating Agents
PubMed: 37933925
DOI: 10.29262/ram.v70i3.1256 -
Naunyn-Schmiedeberg's Archives of... Nov 2022Renal I/R injury is a severe medical condition contributing to acute kidney injury (AKI), leading to rapid kidney dysfunction and high mortality rates. It is generally... (Review)
Review
Renal I/R injury is a severe medical condition contributing to acute kidney injury (AKI), leading to rapid kidney dysfunction and high mortality rates. It is generally observed during renal transplantation, shock, trauma, and urologic and cardiovascular surgery, for which there is no effective treatment. Cell death and damage are commonly linked to I/R. Cell death triggered by iron-dependent lipid peroxidation, such as ferroptosis, has been demonstrated to have a significant detrimental effect in renal IRI models, making it a new type of cell death currently being researched. Ferroptosis is a nonapoptotic type of cell death that occurs when free iron enters the cell and is a critical component of many biological processes. In ferroptosis-induced renal I/R injury, iron chelators such as Deferasirox, Deferiprone, and lipophilic antioxidants are currently suppressed lipid peroxidation Liproxstatin-1 (Lip-1), Ferrostatin-1 along with antioxidants like vitamin and quercetin. Ferroptosis has been considered a potential target for pharmaceutical intervention to alleviate renal IRI-associated cell damage. Thus, this review emphasized the role of ferroptosis and its inhibition in renal IRI. Also, Pharmacological modulation of ferroptosis mechanism in renal I/R injury has been conferred. Graphical abstract.
Topics: Deferasirox; Deferiprone; Ferroptosis; Humans; Iron; Iron Chelating Agents; Ischemia; Kidney; Pharmaceutical Preparations; Quercetin; Reperfusion; Reperfusion Injury; Vitamins
PubMed: 35920897
DOI: 10.1007/s00210-022-02277-5 -
Annals of the New York Academy of... Nov 2023Combination chelation therapies are considered in transfusion-dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or... (Review)
Review
Combination chelation therapies are considered in transfusion-dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or intensification of iron chelation therapy is required for the rapid reduction of excess iron to avoid permanent organ damage. Combination chelation may provide a more flexible approach for individualizing chelation therapy, thereby improving tolerability, adherence, and quality of life. In principle, iron chelators can be combined with an infinite number of dosing regimens; these involve simultaneous or sequential exposure to the chelators on the same day or alternating the drugs on different days. Clinical studies have established the safety and efficacy of chelation combinations. However, real-life data with combination therapies indicate the significance of compliance for a meaningful reduction in iron overload compared to monotherapies.
Topics: Humans; Chelation Therapy; Deferasirox; Deferoxamine; Deferiprone; Quality of Life; Benzoates; Triazoles; Pyridones; Iron Chelating Agents; Iron Overload; Iron; Drug Therapy, Combination
PubMed: 37594980
DOI: 10.1111/nyas.15052 -
Clinical Pharmacokinetics Aug 2014Iron accumulation is a consequence of regular red cell transfusions, and can occur as a result of ineffective erythropoiesis secondary to increased intestinal iron... (Review)
Review
Iron accumulation is a consequence of regular red cell transfusions, and can occur as a result of ineffective erythropoiesis secondary to increased intestinal iron absorption, in patients with various anemias. Without appropriate treatment, iron overload can lead to increased morbidity and mortality. Deferasirox is an oral iron chelator effective for reduction of body iron in iron-overloaded patients with transfusion-dependent anemias and non-transfusion-dependent thalassemia, with a well-established safety profile. This review summarizes the clinical pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of deferasirox, and the claims supporting once-daily dosing for effective chelation. Sustained labile plasma iron suppression is observed with no rebound between doses, protecting organs from potential tissue damage. Increased iron excretion positively correlates with increased deferasirox exposure; to optimize iron removal transfusional iron intake, body iron burden and safety parameters should also be considered. Deferasirox dispersible tablets should be taken ≥30 min before food due to an effect of food on bioavailability. Dosing is consistent across pediatric and adult patients and there is no ethnic sensitivity. Dose adjustment is required for patients with hepatic impairment and may be considered upon coadministration with strong uridine diphosphate glucuronosyltransferase inducers or bile acid sequestrants (coadministration should be avoided where possible), and patients should be monitored upon coadministration with cytochrome P450 (CYP) 3A4/5, CYP2C8, or CYP1A2 substrates. Coadministration with hydroxyurea, a fetal hemoglobin modulator, does not appear to impact deferasirox pharmacokinetics. In summary, a substantial body of clinical and pharmacokinetic data are available for deferasirox to guide its optimal use in multiple patient populations and clinical circumstances.
Topics: Absorption, Physicochemical; Benzoates; Biological Availability; Deferasirox; Drug Interactions; Humans; Iron Chelating Agents; Metabolic Clearance Rate; Molecular Structure; Protein Binding; Tissue Distribution; Triazoles
PubMed: 24996374
DOI: 10.1007/s40262-014-0151-4 -
Current Cancer Drug Targets 2021Osteosarcoma is an aggressive bone tumor. It represents the principal cause of cancer-associated death in children. Considering the recent findings on the role of iron...
BACKGROUND
Osteosarcoma is an aggressive bone tumor. It represents the principal cause of cancer-associated death in children. Considering the recent findings on the role of iron in cancer, iron chelation has been investigated for its antineoplastic properties in many tumors. Deferasirox is the most used iron chelator compound and in previous studies showed an anticancer effect in hematologic and solid malignancies. Eltrombopag is a Thrombopoietin receptor used in thrombocytopenia that also binds and mobilize iron. It demonstrated an effect on iron overload conditions and also in contrasting cancer cell proliferation.
OBJECTIVE
We analyzed the effects of deferasirox and eltrombopag in human osteosarcoma cells in an attempt to identify other therapeutic approaches for this tumor.
METHODS
We cultured and treated with deferasirox and Eltrombopag, alone and in combination, two human osteosarcoma cell lines, MG63 and 143B. After 72h exposure, we performed RTqPCR, Western Blotting, Iron Assay and cytofluorimetric assays to evaluate the effect on viability, apoptosis, cell cycle progression and ROS production.
RESULTS
The iron-chelating properties of the two compounds are also confirmed in osteosarcoma, but we did not observe any direct effect on tumor progression.
DISCUSSION
We tested deferasirox and eltrombopag, alone and in combination, in human osteosarcoma cells for the first time and demonstrated that their iron-chelating activity does not influence biochemical pathways related to cancer progression and maintenance.
CONCLUSION
Although further investigations on possible effects mediated by cells of the tumor microenvironment could be of great interest, in vitro iron chelation in osteosarcoma does not impair tumor progression.
Topics: Apoptosis; Benzoates; Bone Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deferasirox; Drug Therapy, Combination; Humans; Hydrazines; Iron Chelating Agents; Osteosarcoma; Pyrazoles; Treatment Outcome
PubMed: 33380300
DOI: 10.2174/1568009620666201230090531 -
Blood Oct 2020
Topics: Aged, 80 and over; Anemia, Sideroblastic; Arteriosclerosis; Biopsy; Blood Transfusion; Blood Vessels; Bone Marrow; Deferasirox; Female; Humans; Iron; Iron Overload; Metals, Heavy; Myelodysplastic-Myeloproliferative Diseases; Thrombocytosis; Transfusion Reaction; Treatment Failure
PubMed: 33091139
DOI: 10.1182/blood.2020007779 -
Environmental Toxicology and... Mar 2015Deferasirox (commercially formulated as Exjade(®)) is one of the effective iron chelators used in treatment of iron overload diseases. In this study the effect of this...
Deferasirox (commercially formulated as Exjade(®)) is one of the effective iron chelators used in treatment of iron overload diseases. In this study the effect of this substance for chromosome aberration, sister chromatid exchange and mitotic index was studied by in vitro (by using human peripheral lymphocytes) and in vivo (by using rat) analysis. Deferasirox increased the sister chromatid exchange frequency in all tested concentrations and periods in vitro. Also, in the presence of metabolic activator, the substance led to a statistically significant increase in the sister chromatid exchange frequencies only at high concentration. While in in vitro analysis the substance significantly increased abnormal cell percentages in all concentrations, in in vivo study the substance increased chromosome aberrations only in two concentrations at 12h treatment. In the cultured lymphocytes, deferasirox showed cytotoxicity by significantly reducing proliferation index and mitotic index values. While in the presence of metabolic activation it did not affect the proliferation index frequency, it had a stimulant effect on the mitotic index frequency. Deferasirox reduced significantly the mitotic index value in the bone marrow cells especially in high concentration and short treatment period (12h).
Topics: Adult; Animals; Benzoates; Bone Marrow Cells; Cells, Cultured; Chromosome Aberrations; Deferasirox; Female; Humans; Iron Chelating Agents; Lymphocytes; Male; Mutagens; Rats; Sister Chromatid Exchange; Triazoles; Young Adult
PubMed: 25733130
DOI: 10.1016/j.etap.2015.02.001