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European Journal of Pharmacology Oct 2019Alterations in iron homeostasis are well described in obese patients. The effects of iron chelators on adipose tissue and other organs affected by obesity have been the... (Review)
Review
Alterations in iron homeostasis are well described in obese patients. The effects of iron chelators on adipose tissue and other organs affected by obesity have been the interest of experimental studies, both in vivo and in vitro. The aim of this review was to update the available information indicating the potential of iron chelators as adjuvant drugs in the management of obesity and its comorbidities. The pharmacological actions of iron chelators, mainly deferoxamine, deferasirox, and deferiprone, on adipose tissue and liver alterations associated with obesity, were reviewed. Renal and other organ modifications observed in experimental obesity models (endotoxemia, β-cell function, and systemic inflammation) were included, as well as data from clinical studies that were relevant to this review. The experimental results obtained with iron chelators showed their potential in the control of obesity-induced alterations in the adipose tissue and liver. However, knowledge about the possible systemic effects on endotoxemia and low-grade inflammation in obesity models is still lacking. In endotoxemia in humans, data obtained did not corroborate the anti-inflammatory effect described in experimental models. Clinical and experimental data reveal renal, β-cell protection and inhibition of advanced glycation end products, which have long-term benefits in obesity. Experimental models of obesity demonstrated the beneficial effects of iron chelators on the adipose tissue, liver, kidneys, and β-cells. Hence, clinical studies could be designed to evaluate the potential of iron chelators as a therapeutic option in the management of obesity.
Topics: Animals; Homeostasis; Humans; Iron; Iron Chelating Agents; Obesity
PubMed: 31421090
DOI: 10.1016/j.ejphar.2019.172614 -
Indian Journal of Pharmacology 2020Chronic iron overload in beta-thalassemia patients after continuous blood transfusions has caused notable morbidity and mortality in these patients. The once-a-day oral... (Review)
Review
Chronic iron overload in beta-thalassemia patients after continuous blood transfusions has caused notable morbidity and mortality in these patients. The once-a-day oral iron chelator, deferasirox has established efficacy and bearable safety in adults and pediatric thalassemia patients. It is now extensively used for the management of transfusional hemosiderosis. However, a number of studies have revealed a few patients continued to be none respondent or intolerant toward the once-a-day regimen of deferasirox even after the administration of maximum dose recommended by the World Health Organization. In the literature, there were three studies showing the boon of twice in a day dosing of deferasirox among transfusional-dependent beta thalassemia patients. Therefore, a nonsystematic review was conducted on above three studies to ascertain the enhanced effectiveness and tolerability of twice per day regimen of deferasirox with the same total dose as that of once daily regimen of deferasirox in unresponsive or intolerant transfusion-dependent beta-thalassemia (TDT) patients. All the above studies concluded that the twice per day regimen of deferasirox was more efficacious and tolerable among TDT patients when compared to the once-a-day regimen with the same total daily dose. Although there was a significant good results from these studies, there is a need to conduct either muticenter study or randomized control study in a larger number of patients for the better confirmation of the results as all the above studies were conducted in the small number of TDT patients.
Topics: Administration, Oral; Deferasirox; Humans; Iron Chelating Agents; Patient Education as Topic; beta-Thalassemia
PubMed: 33666193
DOI: 10.4103/ijp.IJP_333_19 -
Children (Basel, Switzerland) Dec 2021Deferasirox is a first-line therapy for iron overload that can sometimes cause kidney damage. To better define the pattern of tubular damage, a systematic literature... (Review)
Review
Deferasirox is a first-line therapy for iron overload that can sometimes cause kidney damage. To better define the pattern of tubular damage, a systematic literature review was conducted on the United States National Library of Medicine, Excerpta Medica, and Web of Science databases. Twenty-three reports describing 57 individual cases could be included. The majority ( = 35) of the 57 patients were ≤18 years of age and affected by thalassemia ( = 46). Abnormal urinary findings were noted in 54, electrolyte or acid-base abnormalities in 46, and acute kidney injury in 9 patients. Latent tubular damage was diagnosed in 11 (19%), overt kidney tubular damage in 37 (65%), and an acute kidney injury in the remaining nine (16%) patients. Out of the 117 acid-base and electrolyte disorders reported in 48 patients, normal-gap metabolic acidosis and hypophosphatemia were the most frequent. Further abnormalities were, in decreasing order of frequency, hypokalemia, hypouricemia, hypocalcemia, and hyponatremia. Out of the 81 abnormal urinary findings, renal glucosuria was the most frequent, followed by tubular proteinuria, total proteinuria, and aminoaciduria. In conclusion, a proximal tubulopathy pattern may be observed on treatment with deferasirox. Since deferasirox-associated kidney damage is dose-dependent, physicians should prescribe the lowest efficacious dose.
PubMed: 34943300
DOI: 10.3390/children8121104 -
Indian Journal of Pediatrics Apr 2021To assess the efficacy and safety of dual oral iron chelation therapy (deferiprone and deferasirox) in decreasing iron overload status, using serum ferritin and liver... (Observational Study)
Observational Study
Efficacy and Safety of Combined Oral Chelation with Deferiprone and Deferasirox on Iron Overload in Transfusion Dependent Children with Thalassemia - A Prospective Observational Study.
OBJECTIVES
To assess the efficacy and safety of dual oral iron chelation therapy (deferiprone and deferasirox) in decreasing iron overload status, using serum ferritin and liver and cardiac MRI as indicators, in transfusion dependent thalassemic children.
METHODS
This was a prospective observational study conducted in a tertiary care hospital for a period of one year. Children with thalassemia between 2 and 18 y of age with serum ferritin above 1500 ng/ml were started on oral deferiprone and deferasirox. They were followed up for one year. Serum ferritin and MRI quantification of liver and cardiac iron concentration was done at enrolment and end of 12 mo. They were also monitored monthly for any adverse effects.
RESULTS
Twenty one thalassemic children with mean age of 7.8 y (range 4-12 y) and a mean ferritin value of 3129 + 1231.5 ng/ml were enrolled. Mean serum ferritin decreased by 1226.3 ng/ml (p = 0.047, 95% CI =10.2, 1504.3) with 16.8% fall from baseline. The reduction in ferritin correlated significantly with the initial ferritin level (spearman's rho = 0.742, p = 0.001). Mean liver iron concentration and myocardial iron concentration did not change significantly. Red color urine, transient rise in creatinine and liver enzymes were noted during the study period.
CONCLUSIONS
Combined oral chelation with deferiprone and deferasirox significantly decreases the serum ferritin level in children with severe iron overload. The drugs were tolerated well without any serious adverse effects.
Topics: Benzoates; Child; Deferasirox; Deferiprone; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Thalassemia; beta-Thalassemia
PubMed: 32661609
DOI: 10.1007/s12098-020-03442-5 -
Pediatric Hematology and Oncology Sep 2020Endocrine system dysfunctions are the significant complications of excessive iron overload in beta thalassemia patients. The aim of this study was to evaluate the...
Endocrine system dysfunctions are the significant complications of excessive iron overload in beta thalassemia patients. The aim of this study was to evaluate the long-term effect of chelation with deferasirox on endocrine complications. The study group consisted of children with beta thalassemia who had been evaluated for the growth and pubertal development, bone metabolism, thyroid/parathyroid functions, glucose metabolism dysfunctions in the department of pediatric hematology of Ankara Dışkapı Child Health and Diseases Hematology Oncology Training And Research Hospital between 2009-2011 and reevaluated after deferasirox chelation therapy in 2018. Thirty-one transfusion dependent beta-thalassemia patients were enrolled for the study. Seventeen (54.8%) patients were male and the mean age was 16.9 ± 3.8 (9-23) years. Splenectomy was performed in 11 patients (35.5%). In the initial evaluation, 26 patients (84%) received deferoxamine and/or deferiprone and five (17%) patients received deferasirox as a chelator; in the final evaluation all patients were receiving deferasirox. The mean duration of deferasirox treatment was 5.9 ± 2.02 years (1-10 years). Of the 26 patients who had endocrine complications between 2009-2011, 18 were recovered. In the final evaluation, eight patients (25%) developed new endocrinopathies. The frequency of endocrine complications seen before the deferasirox treatment (83%) was higher than the frequency of complications while receiving deferasirox treatment (25.8%) (p < 0,05). In this study, it was determined that both existing endocrine abnormalities were reduced and recent developed problems were less likely with long-term deferasirox treatment in thalassemia patients.
Topics: Adolescent; Adult; Child; Deferasirox; Endocrine System Diseases; Female; Follow-Up Studies; Humans; Male; Splenectomy; beta-Thalassemia
PubMed: 32131650
DOI: 10.1080/08880018.2020.1734124 -
Pharmaceutics Aug 2021Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic...
BACKGROUND
Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2-17 years, who underwent an allogeneic hematopoietic stem cell transplantation.
METHODS
IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling.
RESULTS
The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (C) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (-value < 0.0001, T-test and Fisher's exact tests) when C threshold values of 7.0 and 11.5 mg/L were chosen, respectively.
CONCLUSIONS
The population pharmacokinetic model described the interindividual variability and identified C threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.
PubMed: 34452199
DOI: 10.3390/pharmaceutics13081238 -
Health Science Reports Sep 2021When patients with sickle cell disease have appropriate indications, they can be prescribed hydroxyurea (HU) and deferasirox (DFX) concurrently despite little knowledge...
BACKGROUND AND AIMS
When patients with sickle cell disease have appropriate indications, they can be prescribed hydroxyurea (HU) and deferasirox (DFX) concurrently despite little knowledge about how the two medications interact. We wished to analyze whether there was evidence of adverse interaction between HU and DFX when taken simultaneously and hypothesized that those who took both drugs together had similar clinical complications when compared to those who took only one or neither drug.
METHODS
We conducted this retrospective cohort investigation between 2009 and 2016 of persons with SCD in the California Sickle Cell Data Collection Program, a validated database of Californians with SCD a statewide. People in the database who took HU and DFX simultaneously for at least 3 months as compared to those who took either HU or DFX alone or to matched persons who took neither drug were eligible.
RESULTS
We identified 104 people who were prescribed both HU and DFX concurrently, 877 who were prescribed HU only, and 314 who were prescribed DFX only during the study period. We identified 416 matched controls who took neither HU nor DFX. People who took both HU and DFX concurrently had similar rates of ED and inpatient encounters and had similar rates and distribution of adverse effects compared to those who took either HU or DFX alone or took neither drug.
CONCLUSION
Three months of concurrent use of DFX and HU appears safe, but further studies are required to better understand the safety and effectiveness of this medication combination. (Funded by CDC, CDC Foundation, and others).
PubMed: 34277954
DOI: 10.1002/hsr2.323 -
International Journal of Molecular... Dec 2021Neoplastic diseases are still a major medical challenge, requiring a constant search for new therapeutic options. A serious problem of many cancers is resistance to... (Review)
Review
Neoplastic diseases are still a major medical challenge, requiring a constant search for new therapeutic options. A serious problem of many cancers is resistance to anticancer drugs and disease progression in metastases or local recurrence. These characteristics of cancer cells may be related to the specific properties of cancer stem cells (CSC). CSCs are involved in inhibiting cells' maturation, which is essential for maintaining their self-renewal capacity and pluripotency. They show increased expression of transcription factor proteins, which were defined as stemness-related markers. This group of proteins includes OCT4, SOX2, KLF4, Nanog, and SALL4. It has been noticed that the metabolism of cancer cells is changed, and the demand for iron is significantly increased. Iron chelators have been proven to have antitumor activity and influence the expression of stemness-related markers, thus reducing chemoresistance and the risk of tumor cell progression. This prompts further investigation of these agents as promising anticancer novel drugs. The article presents the characteristics of stemness markers and their influence on the development and course of neoplastic disease. Available iron chelators were also described, and their effects on cancer cells and expression of stemness-related markers were analyzed.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Iron Chelating Agents; Neoplastic Stem Cells; Transcription Factors
PubMed: 35008527
DOI: 10.3390/ijms23010089 -
Journal of the American Chemical Society Apr 2022Deferasirox, an FDA-approved iron chelator, has gained increasing attention for use in anticancer and antimicrobial applications. Recent efforts by our group led to the...
Deferasirox, an FDA-approved iron chelator, has gained increasing attention for use in anticancer and antimicrobial applications. Recent efforts by our group led to the identification of this core as an easy-to-visualize aggregation-induced emission platform, or AIEgen, that provides a therapeutic effect equivalent to deferasirox ( , , 3, 1278-1283). However, the emission wavelength of the first-generation system overlapped with that of Syto9, a green emissive dye used to indicate live cells. Here, we report a library of deferasirox derivatives with various fluorescence emission profiles designed to overcome this limitation. We propose referring to systems that show promise as both therapeutic and optical imaging agents as "illuminoceuticals". The color differences between the derivatives were observable to the unaided eye (solid- and solution-state) and were in accord with the Commission Internationale de L'Eclairage (CIE) chromaticity diagram 1913. Each fluorescent derivative successfully imaged the respective spherical and rod shapes of methicillin-resistant (MRSA) and . They also displayed iron-dependent antibiotic activity. Three derivatives, (), (), and (), display emission features that are sufficiently distinct so as to permit the multiplex (triplex) imaging of both MRSA and stimulated emission depletion microscopy. The present deferasirox derivatives allowed for the construction of a multi-fluorophore sensor array. This array enabled the successful discrimination between Gram-positive/Gram-negative and drug-sensitive/drug-resistant bacteria. Antibiotic sensitivity and drug-resistant mutants from clinically isolated strains could also be identified and differentiated.
Topics: Anti-Bacterial Agents; Deferasirox; Fluorescence; Iron Chelating Agents; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 35421310
DOI: 10.1021/jacs.2c01155 -
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