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Pathology International Feb 2022Asbestos fibers have been used as an industrial and construction material worldwide due to their high durability and low production cost. Commercial usage of asbestos is... (Review)
Review
Asbestos fibers have been used as an industrial and construction material worldwide due to their high durability and low production cost. Commercial usage of asbestos is currently prohibited in Japan; however, the risk of asbestos-induced malignant mesothelioma (MM) remains. According to epidemiological data, the onset of MM is estimated to occur after a latent period of 30-40 years from initial exposure to asbestos fibers; thus, the continuous increase in MM is a concern. To explore the molecular mechanisms of MM using animal models, iron saccharate with iron chelator-induced sarcomatoid mesothelioma (SM) revealed hallmarks of homozygous deletion of Cdkn2a/2b by aCGH and microRNA-199/214 by expression microarray. Oral treatment of iron chelation by deferasirox decreased the rate of high-grade SM. Moreover, phlebotomy delayed MM development in crocidolite-induced MM in rats. In Divalent metal transporter 1 (Dmt1) transgenic mice, MM development was delayed because of low reactive oxygen species (ROS) production. These results indicate the importance of iron and ROS in mesothelial carcinogenesis. The aims of this review focus on the pathogenesis of elongated mineral particles (EMPs), including asbestos fibers and multiwalled carbon nanotubes (MWCNTs) that share similar rod-like shapes in addition to the molecular mechanisms of MM development.
Topics: Animals; Asbestos; Asbestos, Crocidolite; Carcinogenesis; Cation Transport Proteins; Deferasirox; Humans; Iron; Iron Chelating Agents; Mesothelioma, Malignant; Mice; Mice, Transgenic; Mineral Fibers; Nanotubes, Carbon; Oxidative Stress; Reactive Oxygen Species
PubMed: 34965001
DOI: 10.1111/pin.13196 -
Haematologica May 2024CALYPSO (clinicaltrials gov. Identifier: NCT02435212), a randomized, open-label, multicenter, phase II study evaluated the compliance, clinical benefits, and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.
CALYPSO (clinicaltrials gov. Identifier: NCT02435212), a randomized, open-label, multicenter, phase II study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets (DT) in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pretreated patients aged 2 to <18 years with transfusion- dependent anemias were enrolled. Patients were randomized 1:1 to deferasirox granules or DT for 48 weeks, stratified by age group and prior iron chelation therapy. In this study, the co-primary objectives are to evaluate compliance and change from baseline in serum ferritin after 24 weeks for both formulations in iron chelation therapy-naive patients. In total, 224 patients, mostly with β-thalassemia major (63.4%), were randomized to granules (N=112) or DT (N=112). Primary analysis was conducted when 96 iron chelation therapy-naive patients had completed 24 weeks of treatment/discontinued early; least squares mean (LSM) compliance in the deferasirox granules and DT groups, was 86.8% and 84.3% (difference 2.6%; P=0.360) respectively, while least squares mean change from baseline in serum ferritin was +4.8 and -171.5 ng/mL (difference: 176.4 ng/mL; P=0.255). Slight differences were observed in the observer/patient-reported outcome scores between the granule and dispersible-tablet groups and the overall scores indicate good adherence, satisfaction/preference, fewer concerns and good palatability with both deferasirox formulations. Safety analyses (N=221) found that the most frequently observed adverse events (granules and DT) were increased urine protein/creatinine ratio (>0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and DT formulations, and was consistent with the general safety profile of deferasirox.
Topics: Humans; Deferasirox; Child; Iron Overload; Male; Female; Child, Preschool; Adolescent; Tablets; Iron Chelating Agents; Treatment Outcome; Medication Adherence; Ferritins; Drug Compounding
PubMed: 37855069
DOI: 10.3324/haematol.2023.283133 -
Medical Molecular Morphology Sep 2023Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be...
Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be further subdivided into types 4A (loss-of-function mutations) and 4B (gain-of-function mutations). To date, only a few cases of type 4B cases have been reported, and the treatment has not been clearly mentioned. Here, we report a genotype of hereditary hemochromatosis type 4B involving the heterozygous mutation c.997 T > C (p. Tyr333His) in SLC40A1. The patient was treated with red blood cell apheresis every month for 1 year, followed by oral deferasirox, and the combined therapy was found to be effective.
Topics: Humans; Genotype; Hemochromatosis; Iron Overload; Mutation
PubMed: 37382698
DOI: 10.1007/s00795-023-00359-8 -
Molecules (Basel, Switzerland) Aug 2021Deferasirox is an orally active, lipophilic iron chelating drug used on thousands of patients worldwide for the treatment of transfusional iron overload. The essential... (Comparative Study)
Comparative Study
Deferasirox is an orally active, lipophilic iron chelating drug used on thousands of patients worldwide for the treatment of transfusional iron overload. The essential transition metals iron and copper are the primary catalysts of reactive oxygen species and oxidative damage in biological systems. The redox effects of deferasirox and its metal complexes with iron, copper and other metals are of pharmacological, toxicological, biological and physiological importance. Several molecular model systems of oxidative damage caused by iron and copper catalysis including the oxidation of ascorbic acid, the peroxidation of linoleic acid micelles and the oxidation of dihydropyridine have been investigated in the presence of deferasirox using UV-visible and NMR spectroscopy. Deferasirox has shown antioxidant activity in all three model systems, causing substantial reduction in the rate of oxidation and oxidative damage. Deferasirox showed the greatest antioxidant activity in the oxidation of ascorbic acid with the participation of iron ions and reduced the reaction rate by about a 100 times. Overall, deferasirox appears to have lower affinity for copper in comparison to iron. Comparative studies of the antioxidant activity of deferasirox and the hydrophilic oral iron chelating drug deferiprone in the peroxidation of linoleic acid micelles showed lower efficiency of deferasirox in comparison to deferiprone.
Topics: Antioxidants; Ascorbic Acid; Coordination Complexes; Deferasirox; Deferiprone; Humans; Iron; Iron Chelating Agents; Iron Overload; Linoleic Acid; Metals; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 34443652
DOI: 10.3390/molecules26165064 -
Journal of the American Chemical Society Oct 2023Deferasirox is an FDA-approved iron chelator used in the treatment of iron toxicity. In this work, we report the use of several deferasirox derivatives as lanthanide...
Deferasirox is an FDA-approved iron chelator used in the treatment of iron toxicity. In this work, we report the use of several deferasirox derivatives as lanthanide chelators. Solid-state structural studies of three representative trivalent lanthanide cations, La(III), Eu(III), and Lu(III), revealed the formation of 2:2 complexes in the solid state. A 1:1 stoichiometry dominates in DMSO solution, with values of 472 ± 14, 477 ± 11, and 496 ± 15 M being obtained in the case of these three cations, respectively. Under the conditions of competitive precipitation in the presence of triethylamine, high selectivity (up to 80%) for lutetium(III) was observed in competition with La(III), Ce(III), and Eu(III). Theoretical calculations provided support for the observed selective crystallization.
PubMed: 37751361
DOI: 10.1021/jacs.3c08375 -
Clinical Ophthalmology (Auckland, N.Z.) 2021The aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the...
BACKGROUND
The aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the onset of ocular alterations and the intake of iron chelating drugs.
METHODS
A prospective cohort study was performed. Eighty-eight patients, composed of children and adults with thalassemia major (TM) who are taking or had taken iron chelating drugs (deferoxamine, deferiprone or deferasirox), have been initially enrolled in the study. The final sample featured 80 patients, including 18 children and 62 adults. These subjects received an eye examination to evaluate intraocular pressure (IOP), best corrected visual acuity (BCVA), the presence of refractive defects, cornea, anterior chamber, lens, fundus oculi, visual field and mean retinal nerve fiber layer (RNFL) thickness. Logistic regression model analysis was performed in order to assess any correlation. In addition, a literature search regarding the relation between iron chelating drugs and ocular adverse events was carried out to compare the results obtained with the evidence in the literature.
RESULTS
Logistic regression did not report a significant correlation between the intake of iron chelating drugs and the onset of anterior ocular segment alterations, lens opacities, retinal diseases, optical neuropathies, astigmatism, visual field and RNFL thickness defects. Logistic regression returned a statistically significant correlation between myopia and iron chelation therapy (p-value 0.04; OR 1.05) and also between presbyopia and total duration of therapy with deferoxamine (p-value 0.03; OR 1.21). Although intraocular pressure levels remained within the normal range, a significant correlation with the length of deferoxamine therapy has been found (p-value 0.002; association coefficient -0.12). A negative correlation between deferiprone and presbyopia has also been observed.
CONCLUSION
Iron chelation therapy is not associated with severe visual function alterations. Limitation of deferoxamine treatment can help prevent ocular complications. Deferiprone and/or deferasirox may be preferable, especially in patients over age 40 years.
PubMed: 34045846
DOI: 10.2147/OPTH.S300974 -
Oxidative Medicine and Cellular... 2022Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders.... (Review)
Review
Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.
Topics: Aging; Bone Remodeling; Eye Diseases; Humans; Iron Chelating Agents; Iron Overload; Neoplasms; Neurodegenerative Diseases; Oxidative Stress; Wnt Signaling Pathway
PubMed: 35116092
DOI: 10.1155/2022/7163326 -
Journal of Environmental Science and... 2021The aim of this paper is to study the clinical features of severe intoxications with thallium salts and developing effective care schemes for the application of...
The aim of this paper is to study the clinical features of severe intoxications with thallium salts and developing effective care schemes for the application of potassium hexacyanoferrate (II) and deferasirox for correction of detected disorders. A total of 39 patients diagnosed with severe thallium salt poisoning were examined in two groups. Group I comprised 20 patients with severe thallium salt poisoning, who were prescribed with potassium-iron hexacyanoferrate in a dose of 250 mg/kg/day per os, intravenous potassium infusions, furosemide intravenously in amount of 40 mg three times per, and hemodialysis until the thallium level in the blood dropped below 10 mg/L, lactulose 30 mL two times per day per os. Group II consisted of 19 people with severe thallium salt poisoning, which in addition to the above treatment, received Deferasirox in a dosage of 500 mg two times per day per os. The clinical picture of severe poisoning with thallium salts is characterized by lesions of the gastrointestinal tract, nervous system (central and peripheral), alopecia, heart rhythm disorders, and myocardial ischemia zones. Extension of standard therapy with potassium-iron by adding hexacyanoferrate deferasirox showed better effect on thallium elimination rate and improved functional state of liver and kidneys in patients with severe thallium salt poisoning.
Topics: Deferasirox; Drug Therapy, Combination; Ferrocyanides; Heavy Metal Poisoning; Humans; Infusions, Intravenous; Potassium; Renal Dialysis; Salts; Thallium
PubMed: 33573452
DOI: 10.1080/10934529.2021.1885905 -
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 -
Chemical Research in Toxicology Aug 2023Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver...
Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS and to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or -acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.
Topics: Rats; Animals; Activation, Metabolic; Deferasirox; Liver; Hepatocytes; Microsomes, Liver; Acetylcysteine; Glutathione
PubMed: 37435843
DOI: 10.1021/acs.chemrestox.2c00416