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Frontiers in Pharmacology 2023Deferasirox is an iron-chelating agent prescribed to patients with iron overload. Due to the interindividual variability of deferasirox responses reported in various...
Deferasirox is an iron-chelating agent prescribed to patients with iron overload. Due to the interindividual variability of deferasirox responses reported in various populations, this study aims to determine the genetic polymorphisms that influence drug responses. A systematic search was performed from inception to March 2022 on electronic databases. All studies investigating genetic associations of deferasirox in humans were included, and the outcomes of interest included pharmacokinetics, efficacy, and adverse drug reactions. Fixed- and random-effects model meta-analyses using the ratio of means (ROM) were performed. Seven studies involving 367 participants were included in a meta-analysis. The results showed that subjects carrying the A allele (AG/AA) of rs2273697 had a 1.23-fold increase in deferasirox C (ROM = 1.23; 95% confidence interval [CI]:1.06-1.43; = 0.007) and a lower Vd (ROM = 0.48; 95% CI: 0.36-0.63; < 0.00001), compared to those with GG. A significant attenuated area under the curve of deferasirox was observed in the subjects with rs3806596 AG/GG by 1.28-fold (ROM = 0.78; 95% CI: 0.60-0.99; = 0.04). In addition, two SNPs of were also associated with the decreased C: rs2248359 CC (ROM = 0.50; 95% CI: 0.29-0.87; = 0.01) and rs2585428 GG (ROM = 0.47; 95% CI: 0.35-0.63; < 0.00001). Only rs2248359 CC was associated with decreased C (ROM = 0.26; 95% CI: 0.08-0.93; = 0.04), while rs2585428 GG was associated with a shorter half-life (ROM = 0.44; 95% CI: 0.23-0.83; = 0.01). This research summarizes the current evidence supporting the influence of variations in genes involved with drug transporters, drug-metabolizing enzymes, and vitamin D metabolism on deferasirox responses.
PubMed: 37261288
DOI: 10.3389/fphar.2023.1069854 -
Journal of the American Heart... Jan 2024Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial...
BACKGROUND
Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury.
METHODS AND RESULTS
The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R.
CONCLUSIONS
Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.
Topics: Mice; Animals; Cyclosporine; Myocardial Reperfusion Injury; Deferasirox; Ferroptosis; Ventricular Remodeling; Myocytes, Cardiac; Myocardial Infarction; Reperfusion Injury; Iron; Hypoxia; Iron Overload; Myocardial Ischemia
PubMed: 38158218
DOI: 10.1161/JAHA.123.031219 -
Saudi Journal of Biological Sciences Apr 2022Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron... (Review)
Review
Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron metabolism. Its normal value is between 10 and 200 ngmL in men and between 30 and 300 ngmL in women. Iron is delivered to the tissue via them, and they act as immunomodulators, signaling molecules, and inflammatory markers. When ferritin level exceeds 1000 µgL, the patient is categorized as having hyperferritinemia. Iron chelators such as deferiprone, deferirox, and deferoxamine are currently FDA approved to treat iron overload. The inflammation cascade and poor prognosis of COVID-19 may be attributed to high ferritin levels. Critically ill patients can benefit from deferasirox, an iron chelator administered orally at 20-40 mgkg once daily, as well as intravenous deferoxamine at 1000 mg initially followed by 500 mg every 4 to 12 h. It can be combined with monoclonal antibodies, antioxidants, corticosteroids, and lactoferrin to make iron chelation therapy effective for COVID-19 victims. In this article, we analyze the antiviral and antifibrotic activity of iron chelators, thereby promoting iron depletion therapy as a potentially innovative treatment strategy for COVID-19.
PubMed: 34924800
DOI: 10.1016/j.sjbs.2021.11.061 -
Frontiers in Bioscience (Elite Edition) Jul 2022Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of... (Review)
Review
Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.
Topics: Benzoates; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Pyridones; Risk Assessment; Thalassemia; Triazoles
PubMed: 36137990
DOI: 10.31083/j.fbe1403018 -
Cureus Feb 2024This network meta-analysis was conducted with the aim of comparing the efficacy and safety of deferiprone (DFP), deferasirox (DFX), and deferoxamine (DFO) in individuals... (Review)
Review
Compare the Efficacy and Safety of Deferoxamine, Deferasirox, and Deferiprone in Patients With Sickle Cell Disease or Transfusion-Dependent Anemia: A Network Meta-Analysis of Randomized Control Trials.
This network meta-analysis was conducted with the aim of comparing the efficacy and safety of deferiprone (DFP), deferasirox (DFX), and deferoxamine (DFO) in individuals with sickle cell disease (SCD) or transfusion-dependent anemia. This systematic review and meta-analysis adhered to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines. The search was conducted on electronic databases, including PubMed, CINAHIL, and EMBASE, from the inception of databases to January 10, 2024. Outcomes assessed in this study included a change in liver iron concentration (LIC) and a change in ferritin from baseline. For safety analysis, adverse events were compared among three treatment groups. A total of five studies were included in this meta-analysis. The pooled analysis showed that the change in LIC and serum ferritin from baseline was not significantly different in patients with SCD or other anemias. In terms of adverse events, deferiprone was the safest among all. In conclusion, deferiprone demonstrated noninferiority to deferoxamine and deferasirox in measures of iron load, presenting a viable treatment option. Safety outcomes revealed deferasirox carried a higher risk of adverse events compared to deferiprone, supporting its favorable safety profile.
PubMed: 38455804
DOI: 10.7759/cureus.53644 -
Cells Feb 2022Moving from indication to transplantation is a critical process in myelofibrosis. Most of guidelines specifically focus on either myelofibrosis disease or transplant... (Review)
Review
Moving from indication to transplantation is a critical process in myelofibrosis. Most of guidelines specifically focus on either myelofibrosis disease or transplant procedure, and, currently, no distinct indication for the management of MF candidates to transplant is available. Nevertheless, this period of time is crucial for the transplant outcome because engraftment, non-relapse mortality, and relapse incidence are greatly dependent upon the pre-transplant management. Based on these premises, in this review, we will go through the path of identification of the MF patients suitable for a transplant, by using disease-specific prognostic scores, and the evaluation of eligibility for a transplant, based on performance, comorbidity, and other combined tools. Then, we will focus on the process of donor and conditioning regimens' choice. The pre-transplant management of splenomegaly and constitutional symptoms, cytopenias, iron overload and transplant timing will be comprehensively discussed. The principal aim of this review is, therefore, to give a practical guidance for managing MF patients who are potential candidates for allo-HCT.
Topics: Aged; Aged, 80 and over; Hematopoietic Stem Cell Transplantation; Humans; Primary Myelofibrosis; Transplantation Conditioning; Transplantation, Homologous
PubMed: 35159362
DOI: 10.3390/cells11030553 -
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 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 -
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