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British Journal of Clinical Pharmacology Aug 2022To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and...
AIMS
To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox.
METHODS
Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations.
RESULTS
An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079-0.0131] vs. 0.0013 [90% CI: 0.0008-0.0018] L/mg mo). In addition to drug-specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline.
CONCLUSION
Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug-induced changes in iron elimination rate and ferritin production. The use of a semi-mechanistic parameterisation allowed us to disentangle disease-specific factors from drug-specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.
Topics: Benzoates; Chelation Therapy; Deferasirox; Deferiprone; Deferoxamine; Ferritins; Hemoglobinopathies; Humans; Iron; Iron Chelating Agents; Pyridones; Triazoles
PubMed: 35199367
DOI: 10.1111/bcp.15290 -
Caspian Journal of Internal Medicine 2022Beta-thalassemia major patients typically require chronic transfusion and iron-chelating agents to reduce serum iron overload. Osveral is an available Iranian brand name...
Two trade names of deferasirox (Osveral® and Exjade®) in reduction of iron overload parameters in major beta-thalassemia patients: A randomized open labeled clinical trial.
BACKGROUND
Beta-thalassemia major patients typically require chronic transfusion and iron-chelating agents to reduce serum iron overload. Osveral is an available Iranian brand name of deferasirox used by majority of thalassemic patients. The aim of this study was to compare the efficacy of Osveral vs. Exjade in major beta- thalassemia patients.
METHODS
In this randomized clinical trial, all patients received a single daily dose of 30 mg/kg either of Osveral or Exjade for 6 months. Primary outcome was the mean of bimonthly changes in serum ferritin concentration and secondary outcomes included mean changes of heart and liver MRI T2* after a year.
RESULTS
Finally, 80 patients completed the study. The mean serum ferritin level at the end of sixth month significantly decreased in Osveral and Exjade groups (p<0.01). After a year, means cardiac MRI T2* in Osveral group were changed from 25.9±9.6 ms to 25.4±9.7 ms and in Exjade group from 24.8±9.2 ms to 26.9±5.9 ms, with no significant difference (P=0.43). Mean liver MRI T2* for Osveral and Exjade groups were 8.6±6.4 ms (baseline 6.3±4.7) and 6.3±4 ms (baseline 4.9±3.5), respectively and there was no significant difference between two study arms (P=0.1).
CONCLUSION
Osveral decreased significantly the serum ferritin level and improved heart and liver iron overload as efficient as Exjade. It can be a suitable cost-effective alternative agent in beta-thalassemia major patients.
PubMed: 35178209
DOI: 10.22088/cjim.13.1.61 -
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 -
British Journal of Haematology Apr 2022Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively...
Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.
Topics: Benzoates; Deferasirox; Humans; Iron Chelating Agents; Iron Overload; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Retrospective Studies
PubMed: 35137397
DOI: 10.1111/bjh.18057 -
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 -
Scientific Reports Jan 2022Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may...
Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p < 0.001). Inguinal fat from HFD + deferasirox mice showed increased beige fat quantity with greater Ucp1 and Prdm16 expression. Inguinal adipose tissue explants were studied in a Seahorse bioanalyser and energy expenditure was significantly increased. Deferasirox was also effective in established obesity and in ob/ob mice, indicating that intact leptin signalling is not needed for efficacy. These studies identify iron chelation as a strategy to preferentially activate beige fat. Whether activating brown/beige fat is effective in humans is unproven. However, depleting iron to low-normal levels is a potential therapeutic strategy to improve obesity and related metabolic disorders, and human studies may be warranted.
Topics: Adipose Tissue, Beige; Animals; Cell Differentiation; Deferasirox; Diet, High-Fat; Glucose; Humans; Iron Chelating Agents; Lipid Metabolism; Mice; Obesity; Thermogenesis; Uncoupling Protein 1
PubMed: 35031684
DOI: 10.1038/s41598-022-04809-8 -
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 -
Frontiers in Medicine 2021Management of β-thalassemia in developing countries is demanding in the absence of available therapies rather than recurrent transfusions. This study describes the...
Management of β-thalassemia in developing countries is demanding in the absence of available therapies rather than recurrent transfusions. This study describes the characteristics and evaluates the hematological, biochemical, and hormonal findings of patients with β-thalassemia in the West Bank. We conducted a retrospective cohort study between January 2017 and December 2018. Data were collected through medical files of the patients with β-thalassemia from eight primary healthcare clinics, nine emergency departments, and 11 governmental hospitals across the West Bank. Results of the hematological, biochemical, and hormonal evaluations, in addition to demographic data and the use of iron chelation were included in the study and analyzed. A total of 309 patients with β-thalassemia were included with a male-to-female ratio of 1:1 and an average age of 23.4 ± 10.4 years. The anemic presentation was reported in 78.6% of the patients as indicated by hemoglobin level (mean ± SD = 8.4 ± 1.4 g/dl), and 73.1% had iron overload with serum ferritin (SF) levels ≥ 1,000 μg/L (mean ± SD = 317.8 ± 3,378.8 μg/L). Evaluation of the liver function tests showed that alanine transaminase (ALT) and aspartate transaminase (AST) levels were high among 38.1 and 61.2% of the patients, respectively. ALT and AST showed significant positive correlations with SF levels, while the kidney tests did not. As for iron chelation medications, patients receiving deferoxamine (26.5%) showed significantly higher SF levels compared with patients receiving deferasirox (73.5%). This study highlights the importance of establishing patient-tailored comprehensive assessment and follow-up protocols for the management of β-thalassemia with an emphasis on blood transfusion and iron chelation practices.
PubMed: 34988098
DOI: 10.3389/fmed.2021.788758 -
Pharmaceuticals (Basel, Switzerland) Dec 2021Highly stable and facile one-pot copper nanoclusters (Cu NCs) coated with poly(allylamine hydrochloride) (PAH) have been synthesized for selectively sensing deferasirox...
Highly stable and facile one-pot copper nanoclusters (Cu NCs) coated with poly(allylamine hydrochloride) (PAH) have been synthesized for selectively sensing deferasirox (DFX) in β-thalassemia plasma. DFX is an important drug used for treating iron overloading in β-thalassemia, but needs to be monitored due to certain toxicity. In this study, the PAH-Cu NCs showed highly stable fluorescence with emission wavelengths at 450 nm. The DFX specifically interacted with the copper nanocluster to turn off the fluorescence of the PAH-Cu NCs, and could be selectively quantified through the fluorescence quenching effect. The linear range of DFX in plasma analyzed by PAH-Cu NCs was 1.0-100.0 µg/mL (r = 0.985). The relative standard deviation (RSD) and relative error (RE) were lower than 6.51% and 7.57%, respectively, showing excellent reproducibility of PAH-Cu NCs for sensing DFX in plasma. This method was also successfully applied for an analysis of three clinical plasma samples from β-thalassemia patients taking DFX. The data presented high similarity with that obtained through a capillary electrophoresis method. According to the results, the PAH-Cu NCs could be used as a tool for clinically sensing DFX in human plasma for clinical surveys.
PubMed: 34959714
DOI: 10.3390/ph14121314 -
Drug Design, Development and Therapy 2021With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers,...
INTRODUCTION
With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1.
RESULTS
A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234.
CONCLUSION
Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.
Topics: Apoptosis Regulatory Proteins; Deferasirox; Drug Repositioning; Lenalidomide; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein; Oxcarbazepine; Risperidone; Torsemide
PubMed: 34949914
DOI: 10.2147/DDDT.S323077