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American Journal of Hematology Aug 2022
Topics: Benzoates; Child; Deferasirox; Hemosiderosis; Humans; Iron Chelating Agents; Iron Overload; Tablets
PubMed: 35570412
DOI: 10.1002/ajh.26598 -
American Journal of Hematology Aug 2022
Topics: Benzoates; Deferasirox; Humans; Iron; Iron Chelating Agents; Iron Overload; Thalassemia; beta-Thalassemia
PubMed: 35560253
DOI: 10.1002/ajh.26592 -
RSC Advances May 2022This work implements a combined experimental approach of analytical quality-by-design (AQbD) and green analytical chemistry (GAC) to develop an HPLC method for...
This work implements a combined experimental approach of analytical quality-by-design (AQbD) and green analytical chemistry (GAC) to develop an HPLC method for simultaneous determination of the two thalassemia drugs, deferasirox (DFX) and deferiprone (DFP), in biological fluid for the first time. This integration was designed to maximize efficiency and minimize environmental impacts, as well as energy and solvent consumption. To accomplish this goal, an analytical quality-by-design approach was performed, beginning with quality risk assessment and scouting analysis, followed by Placket-Burman design screening for five chromatographic parameters. Critical method parameters were thoroughly recognized and then optimized by using a two levels-three factors custom experimental design to evaluate the optimum conditions that achieved the highest resolution with acceptable peak symmetry within the shortest run time. The desirability function was used to define the optimal chromatographic conditions, and the optimal separation was achieved using an XBridge® HPLC RP-C18 (4.6 × 250 mm, 5 μm) column with ethanol : acidic water at pH 3.0 adjusted by phosphoric acid in the ratio of (70 : 30, v/v) as the mobile phase at a flow rate of 1 mL min with UV detection at 225 nm at a temperature of 25 °C. Linearity was obtained over the concentration range of 0.30-20.00 μg mL and 0.20-20.00 μg mL for DFX and DFP, respectively, using 20.00 μg mL ibuprofen (IBF) as an internal standard. The established method's greenness profile was evaluated and measured using various assessment tools, and the developed method was green. For the validation of the developed method, FDA recommendations were followed, and all the results obtained met the acceptance criteria. The suggested method was successfully used to study the pharmacokinetic parameters of DFX and DFP in rat plasma. Due to the substantial increase in bioavailability of the two iron chelating drugs, the results from this study strongly recommend their co-administration.
PubMed: 35548387
DOI: 10.1039/d2ra00966h -
RSC Advances Oct 2021The monitoring of deferasirox (DEF) has important clinical roles in patients who need iron excretion. However, analytical methods with practicability and simplicity are...
The monitoring of deferasirox (DEF) has important clinical roles in patients who need iron excretion. However, analytical methods with practicability and simplicity are limited. Moreover, ratiometric fluorescence strategies based on Förster resonance energy transfer (FRET) from carbon dots (CDs) as a donor are rarely reported as a drug monitor. In this work, CDs with an appropriate emitting wavelength at 480 nm and excitation around 370 nm were prepared by hydrothermal approach and HCl post-treatment. O-Phenylenediamine (OPD) can be oxidized by Cu to produce yellow fluorescent 2,3-diaminophenazine (oxOPD) in the system of Cu and OPD (Cu-OPD). Correspondingly, a remarkable FRET from CDs to oxOPD in the system of CDs, Cu and OPD (CDs-Cu-OPD) was fabricated with the quenching illustration of CDs, but emitting property of oxOPD. Attributed to the chelation ability of DEF on Cu, the inhibitory effects of DEF on the Cu-triggered oxidative capability reduced the FRET system by the decreased oxOPD. Thus, the recovered CDs at and decreased oxOPD at were found through a ratiometric mode by the addition of DEF in CDs-Cu-OPD for the DEF assay. The FRET behavior of CDs and oxOPD in CDs-Cu-OPD was proved clearly through the calculation of the association constant, binding constant, number of binding sites, and the distance between the donor and acceptor. Furthermore, this ratiometric method exhibited promising analytical performance for DEF with the application in real samples. The implementation of this work expands the application field of CDs and OPD oxidation in drug monitoring, and even other biological analyses through ratiometric strategy.
PubMed: 35494749
DOI: 10.1039/d1ra07078a -
Journal of Clinical Medicine Apr 2022The aim of this study is the evaluation of the safety and the efficacy of long-term combination therapy deferasirox plus desferrioxamine and deferasirox plus deferiprone...
The aim of this study is the evaluation of the safety and the efficacy of long-term combination therapy deferasirox plus desferrioxamine and deferasirox plus deferiprone in a large group of transfusion-dependent thalassemia patients with high values of serum ferritin and/or magnetic resonance, indicative of severe liver and cardiac iron accumulation. Sixteen adults with transfusion-dependent thalassemia were treated simultaneously with deferasirox plus desferrioxamine, while another 42 patients (seven children) were treated with deferasirox plus deferiprone. The hepatic and cardiac iron overload was assessed prior to treatment and then annually with magnetic resonance imaging, and the serum ferritin was measured monthly. Adverse events were checked at each transfusion visit. The safety of both the combinations was consistent with established monotherapies. Both treatments were able to decrease the serum ferritin and liver iron concentration over time, depending on the level of compliance with therapy. Cardiac iron measured as R2* did not significantly change in patients treated with deferasirox plus desferrioxamine. Most patients with MRI indicative of myocardial siderosis at the beginning of treatment reached normal values of cardiac iron at the last determination if treated with deferasirox plus desferrioxamine. The greatest limitation of these therapies was low patient adherence to the two drugs, which is not surprising considering that the need for an intensive chelation is generally linked to previous issues of compliance.
PubMed: 35407617
DOI: 10.3390/jcm11072010 -
Biomolecules Feb 2022The accumulation of iron may contribute to Alzheimer's disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients....
The accumulation of iron may contribute to Alzheimer's disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients. However, desferrioxamine requires injection, which is inconvenient and may hinder compliance. We therefore tested an oral iron chelator, desferasirox (Exjade), in transgenic animal models. Tg2576 mice overexpress the mutant human APP protein and produce the Aβ peptide. JNPL3 mice (Tau/Tau) overexpress the mutant human tau protein. Crossing these produced APP/Tau mice, overexpressing both APP and tau. Treating the three models with 1.6 mg deferasirox thrice weekly from age 8 to 14 months did not affect memory as measured by contextual fear conditioning or motor function as measured by rotarod, but tended to decrease hyperphosphorylated tau as measured by AT8 immunohistochemistry and immunoblotting. Deferasirox might act by decreasing iron, which aggregates tau, or directly binding tau to inhibit aggregation.
Topics: Alzheimer Disease; Animals; Deferasirox; Deferoxamine; Disease Models, Animal; Humans; Iron; Iron Chelating Agents; Mice; Mice, Transgenic; Tauopathies; tau Proteins
PubMed: 35327557
DOI: 10.3390/biom12030365 -
Blood Advances Jun 2022
Topics: ATP-Binding Cassette Transporters; Anemia; Calcium-Calmodulin-Dependent Protein Kinases; Deferasirox; Humans; Iron Chelating Agents
PubMed: 35320338
DOI: 10.1182/bloodadvances.2021006277 -
Bioactive Materials Aug 2022An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron...
An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug, , that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading onto ultrathin 2D TiC MXene nanosheets produces a construct, , that allows the iron chelation and chemotherapeutic functions of to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation, serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both and . The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.
PubMed: 35310350
DOI: 10.1016/j.bioactmat.2021.12.011 -
Biology Feb 2022Thalassemic syndromes are characterized by clinical heterogenicity. For severe disease forms, lifelong blood transfusions remain the mainstay of therapy, while iron...
Thalassemic syndromes are characterized by clinical heterogenicity. For severe disease forms, lifelong blood transfusions remain the mainstay of therapy, while iron overload monitoring and adequate chelation treatment are required in order to ensure effective disease management. Compared to previous chelators, the new deferasirox film-coated tablet (DFX FCT) is considered to offer a more convenient and well-tolerated treatment scheme, aiming at better treatment-related and patient-related outcomes. The present study's objective was to prospectively evaluate the safety and efficacy of DFX FCT in children and adolescents with transfusion-dependent thalassemia. Data collected included patient demographics, hematology and biochemistry laboratory work up, magnetic resonance imaging of heart and liver for iron load, as well as ophthalmological and audiological examination prior to and a year following drug administration. Study results confirmed DFX FCT safety in older children in a manner similar to adults, but demonstrated increased frequency of adverse events in younger patients, mainly, involving liver function. With regards to efficacy, study results confirmed the preventive role of DFX FCT in iron loading of liver and heart, however, higher doses than generally recommended were required in order to ensure adequate chelation.
PubMed: 35205113
DOI: 10.3390/biology11020247 -
Antibiotics (Basel, Switzerland) Jan 2022Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other...
Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other germs, making them untreatable. The search for more combative antibiotic compounds has led researchers to explore metal-based strategies centered on perturbing the bioavailability of essential metals in microbes and examining the therapeutic potential of metal complexes. Given the limited knowledge on the application of titanium(IV), in this work, eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. The compounds were selected for evaluation because of their low cytotoxic/antiproliferative behavior against a human non-cancer cell line. At pH 7.4, these compounds vary in terms of their solution stability and ligand exchange lability; therefore, an assessment of their solution behavior provides some insight regarding the importance of the identity of the metal compound to the antimicrobial therapeutic potential. Only one compound, Ti(deferasirox), exhibited promising inhibitory activity against the Gram-positive bacteria methicillin-resistant and minimal toxicity against human cells. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and ribonucleotide reductase is evaluated as a possible mechanism for its antibiotic effect.
PubMed: 35203761
DOI: 10.3390/antibiotics11020158