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Current Drug Metabolism Dec 2022Iron-chelation therapy is life-saving in patients on a chronic transfusion regimen as it reduces organ damage related to iron deposition in the tissues. Deferasirox, an...
BACKGROUND
Iron-chelation therapy is life-saving in patients on a chronic transfusion regimen as it reduces organ damage related to iron deposition in the tissues. Deferasirox, an iron-chelator, is characterized by pharmacokinetics variability, and some patients may discontinue the treatment due to toxicities.
OBJECTIVE
Understanding whether deferasirox plasma levels are related to patients' specific characteristics could help optimize DFX dosage.
METHODS
We analyzed deferasirox plasma concentration in 57 transfusion-dependent anemic patients using the HPLC method in this prospective-retrospective cohort study. All outpatients (3 to 98 years) were treated with deferasirox (film-coated tablet) for at least one year (median dose, 16.5 mg/Kg once a day). Deferasirox plasma concentration was normalized for dose/Kg (C/dose) and corrected with a linear regression model that relates C/dose and the time of blood sampling (Cref/dose).
RESULTS
No significant differences in Cref/dose were found between males and females, either between different types of hemoglobinopathies or depending on the presence of the UGT1A1*28 polymorphism. Cref/dose has a positive and significant correlation with age, creatinine, and direct bilirubin. Cref/dose, instead, has a negative and significant correlation with Liver Iron Concentration (LIC), ferritin, and eGFR. Cref/dose was significantly different between three age categories <18yrs, 18-50yrs, and >50yrs, with Cref/dose median values of 1.0, 1.2, and 1.5, respectively.
CONCLUSION
The study evidenced that to ensure the efficacy of deferasirox in terms of control over LIC and, at the same time, a lesser influence on renal function, the dose of the drug to be administered to an elderly patient could be reduced.
PubMed: 36503397
DOI: 10.2174/1389200224666221209144420 -
Hemoglobin Sep 2021Deferiprone (DFP) and deferasirox (DFX) are the most well-known, efficacious and safe chelators to reduce the serum ferritin (SF) level in multi transfused thalassemic...
Comparative Efficacy and Safety Between Deferiprone and Deferasirox with Special Reference to Serum Ferritin Level and Cardiac Function in Bengali β-Thalassemia Major Children.
Deferiprone (DFP) and deferasirox (DFX) are the most well-known, efficacious and safe chelators to reduce the serum ferritin (SF) level in multi transfused thalassemic children, although there are few reports available for assessing the efficacy between DFP and DFX. We compared the efficacy of DFP DFX as iron chelating drugs in β-thalassemia major (β-TM) patients. Pediatric patients diagnosed to carry β-TM, aged between 2 and 10 years, were recruited. A suitable data collection form and questionnaire were used. Paired and unpaired -tests were used to compare the safety and efficacy of the chelating drugs DFP and DFX. The mean SF level at the 12th month was found to be 3016.73 ± 670.04 ng/mL ( = 0.002) in the DFX-treated group, which was quite significant in contrast to DFP response, where the value was 3204.06 ± 690.15 ng/mL ( = 0.14). There is no statistically significant ( = 0.15) difference on relative changes of the left ventricular ejection fraction (LVEF), between these two groups. The adverse effects were transient and none of them required stoppage of therapy. Deferasirox is more effective when compared to DFP in reducing chelating drug-related complications and iron overload specially in multiple transfusion dependent β-TM patients.
Topics: Child; Child, Preschool; Deferasirox; Deferiprone; Ferritins; Humans; Iron Chelating Agents; Iron Overload; Stroke Volume; Ventricular Function, Left; beta-Thalassemia
PubMed: 34758688
DOI: 10.1080/03630269.2021.1999258 -
Circulation. Cardiovascular Imaging Feb 2022
Topics: Aged; Biopsy; Deferasirox; Drug Hypersensitivity; Echocardiography; Electrocardiography; Female; Humans; Iron Chelating Agents; Magnetic Resonance Imaging, Cine; Myelodysplastic Syndromes; Myocarditis; Myocardium
PubMed: 35094520
DOI: 10.1161/CIRCIMAGING.121.013702 -
Biomolecules Nov 2022The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead... (Review)
Review
The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox-DFOA and the tetrathiomolybdate-DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations.
Topics: Humans; Manganese; Copper; Iron; Chelating Agents; Ions; Metals; Neurotoxicity Syndromes; Succimer; Water
PubMed: 36421727
DOI: 10.3390/biom12111713 -
Biomedicine & Pharmacotherapy =... Sep 2022The improvements of antitumor effects and tolerability on chemotherapy for advanced hepatocellular carcinoma (HCC) are warranted. Here, we aimed to elucidate the...
OBJECTIVE
The improvements of antitumor effects and tolerability on chemotherapy for advanced hepatocellular carcinoma (HCC) are warranted. Here, we aimed to elucidate the mechanism of the combining effect of tyrosine kinase inhibitor sorafenib (SOR) and iron chelator deferasirox (DFX) in human hepatoma cell lines, HepG2 and Huh-7.
METHODS
The types of programmed cell deaths (PCDs); necrosis/necroptosis and apoptosis, were evaluated by flow cytometry and fluorescent microscopy. Human cleaved caspase-3 was analyzed by ELISA for apoptosis. GSH assay was used for ferroptosis. PCDs inhibition was analyzed by adding apoptosis inhibitor Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1, necroptosis inhibitor necrosulfonamide, respectively. The expression of NF-κB was quantified by Western blotting.
RESULTS
In SOR monotherapy, cleaved caspase-3 expression was increased in all concentrations, confirming the result that SOR induces apoptosis. In SOR monotherapy, GSH/GSSG ratio was decreased on concentration-dependent, showing that SOR also induced ferroptosis. Lipid Peroxidation caused by SOR, corresponding to ferroptosis, was suppressed by DFX. In fluorescence microscopy of SOR monotherapy, apoptosis was observed at a constant rate on all concentrations, while necroptosis and ferroptosis were increased on high concentration. In sorafenib and deferasirox combinations, sub G1 phase increased additively. In SOR and DFX combinations, the cytotoxic effects were not suppressed by ferrostatin-1, but suppressed by Z-VAD-FMK and necrosulfonamide. In each monotherapy, and SOR + DFX combinations, the expression of NF-κB in nucleus was suppressed. Regarding PCD by SOR and DFX combination, ferroptosis was suppressed and both apoptosis and necroptosis became dominant.
CONCLUSION
Suppression of NF-κB is possibly involved in the effect of DFX. As a result, SOR and DFX combination showed additive antitumor effects for HCC through the mechanism of programed cell deaths and NF-kB signal modification.
Topics: Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Line; Cell Line, Tumor; Deferasirox; Humans; Iron Chelating Agents; Liver Neoplasms; NF-kappa B; Sorafenib
PubMed: 35834989
DOI: 10.1016/j.biopha.2022.113363 -
Leukemia & Lymphoma Jan 2020
Review
Topics: Anemia, Aplastic; Benzoates; Deferasirox; Humans; Hydrazines; Pyrazoles
PubMed: 31502895
DOI: 10.1080/10428194.2019.1660969 -
The Cochrane Database of Systematic... Mar 2023Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in... (Review)
Review
BACKGROUND
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence.
OBJECTIVES
To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia.
SEARCH METHODS
We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022).
SELECTION CRITERIA
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion. For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
DATA COLLECTION AND ANALYSIS
For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox. We rated the certainty of evidence as very low to low across all outcomes identified in this review. Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL. We identified nine comparisons of interest. 1. Deferiprone versus deferoxamine We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence). Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only. 2. Deferasirox versus deferoxamine We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials. We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia). 3. Deferiprone versus deferasirox We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality. 4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT) One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs. We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence. 5. Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled). We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality. 6. Deferiprone and deferoxamine combined versus deferoxamine alone We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials. 7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups. We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT). 8. Medication management versus standard care We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group. 9. Education versus standard care One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding.
AUTHORS' CONCLUSIONS
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Topics: Child; Humans; Anemia, Sickle Cell; Chelating Agents; Chelation Therapy; Deferoxamine; Drug-Related Side Effects and Adverse Reactions; Iron; Thalassemia
PubMed: 36877640
DOI: 10.1002/14651858.CD012349.pub3 -
Bulletin Du Cancer Nov 2023Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult... (Review)
Review
Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult to demonstrate because of associated comorbidities. Cardiovascular disease increases vulnerability to the toxic effects of IO. In recent years, registry studies have shown a survival benefit of Iron Chelation Therapy (ICT) in these patients. These findings are now corroborated by an improvement in event-free survival in a single randomized study: the Telesto study. The EFS curves separate after two years of follow-up. This indicates inertia in the occurrence of complications. The benefits of ICT are also very slowly being revealed. It is possible to offer ICT to patients with transfusion-dependent MDS with a life expectancy of at least two years. In Telesto, patients had a serum ferritin (F) level of at least 1000ng/mL, recommendations using this F threshold as a trigger for chelation seem to be reinforced. It remains an open question whether chelation should be started earlier for effective suppression of IO-related oxidative stress. ICTs could be used in transfusion-dependent MDS patients with life expectancy greater than two years. including possibly higher risk patients responding to hypomethylating agents.
Topics: Humans; Aged; Iron Chelating Agents; Myelodysplastic Syndromes; Blood Transfusion; Iron Overload; Progression-Free Survival
PubMed: 37543453
DOI: 10.1016/j.bulcan.2023.06.004 -
ChemMedChem Aug 2019Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this...
Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann-Pick type C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6 -amino-6 -deoxy-β-cyclodextrin and 3 -amino-3 -deoxy-2 (S),3 (S)-β-cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of β-cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.
Topics: Animals; Antioxidants; CHO Cells; Cricetulus; Cyclodextrins; Deferasirox; Hep G2 Cells; Humans; Iron Chelating Agents; Protein Multimerization; alpha-Synuclein
PubMed: 31162826
DOI: 10.1002/cmdc.201900334 -
The Korean Journal of Internal Medicine Nov 2023Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a...
BACKGROUND/AIMS
Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a challenge.
METHODS
We developed a rituximab-resistant cell line (RRCL) by sequential exposure to gradually increasing concentrations of rituximab in a rituximab-sensitive cell line (RSCL). When the same dose of rituximab was administered, RRCL showed a smaller decrease in cell viability and apoptosis than RSCL. To determine the differences in gene expression between RSCL and RRCL, we performed next-generation sequencing.
RESULTS
In total, 1,879 differentially expressed genes were identified, and in the over-representation analysis of Consensus-PathDB, mitogen-activated protein kinase (MAPK) signaling pathway showed statistical significance. MAPK13, which encodes the p38δ protein, was expressed more than four-fold in RRCL. Western blot analysis revealed that phosphop38 expression mainwas increased in RRCL, and when p38 inhibitor was administered, phosphop38 expression was significantly decreased. Therefore, we hypothesized that p38 MAPK activation was associated with rituximab resistance. Previous studies have suggested that p38 is associated with NF-κB activation. Deferasirox has been reported to inhibit NF-κB activity and suppress phosphorylation of the MAPK pathway. Furthermore, it also has cytotoxic effects on various cancers and synergistic effects in overcoming drug resistance. In this study, we confirmed that deferasirox induced dose-dependent cytotoxicity in both RSCL and RRCL, and the combination of deferasirox and rituximab showed a synergistic effect in RRCL at all combination concentrations.
CONCLUSION
We suggest that p38 MAPK, especially p38δ, activation is associated with rituximab resistance, and deferasirox may be a candidate to overcome rituximab resistance.
Topics: Humans; Rituximab; Deferasirox; Mitogen-Activated Protein Kinase 13; NF-kappa B; Antibodies, Monoclonal, Murine-Derived; Drug Resistance, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Apoptosis; High-Throughput Nucleotide Sequencing; Cell Line, Tumor; p38 Mitogen-Activated Protein Kinases
PubMed: 37599392
DOI: 10.3904/kjim.2023.134