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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 -
Human & Experimental Toxicology 2023Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a...
Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.
Topics: Humans; Iron; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Reactive Oxygen Species; Superoxides; Hydrogen Peroxide; Pyridones; Benzoates; Triazoles; DNA
PubMed: 37526177
DOI: 10.1177/09603271231192361 -
Caspian Journal of Internal Medicine 2023Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The...
BACKGROUND
Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The cause of this condition was chronic hypoxia, iron overload, endocrinopathy, inadequate transfusion, and iron chelation. We analyze the relationship between ferritin level and growth status of pediatric TDTs.
METHODS
This was a cross-sectional study on pediatric TDTs aged 2-18 years old at Dr. Soetomo General Academic Hospital Surabaya, Indonesia conducted in 2020. They required blood transfusion every 2-4 weeks. We evaluated the ratio of upper/lower body segments, weight for age Z-score (WAZ), height for age Z-score (HAZ), and body mass index (BMI) Z-score, based on CDC growth chart as growth status parameters. Serum ferritin was checked every three months to determine iron overload and iron chelation (deferiprone, deferasirox and deferoxamine). We used Spearman correlation and Mann-Whitney U test to analyze between variables (α=0.05).
RESULTS
We enrolled 15/29 males with median age 10.5 years. Serum Ferritin had negative correlation with the ratio of upper/lower body segments (rho=-0.552; P=0.002), but not for HAZ (rho=-0.078; P=0.694), WAZ (rho=-0.186; P=0.342), BMI Z-score (rho=-0.089; P=0.653) especially if serum ferritin was above 2500 µ/L. In deferiprone group (n=8), the WAZ (P=0.034) and BMI Z-score (P=0.031) were lower; but the ratio of upper/lower body segments was greater (P=0.039) than the deferasirox group.
CONCLUSION
Growth retardation was more visible in pediatric TDTs with high ferritin and in deferiprone group. The height and the ratio of upper/lower body segments of the body were more affected.
PubMed: 37520873
DOI: 10.22088/cjim.14.3.425 -
European Review For Medical and... Jul 2023β-thalassemia major is an inherited hematological disorder with significant oxidative stress and iron overload. Oxidative stress results in several pathological... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparative effectiveness of adding omega-3 and Manuka honey combination to conventional therapy in preventing and treating oxidative stress in pediatric β-thalassemia major - a randomized clinical trial.
OBJECTIVE
β-thalassemia major is an inherited hematological disorder with significant oxidative stress and iron overload. Oxidative stress results in several pathological complications, including cell death, tissue injury, organ dysfunction, and thyroid dysfunction. The present study examined the effectiveness of omega-3 and Manuka honey combination or Manuka honey alone to the conventional therapy (deferasirox, blood transfusion, and L-carnitine) used for preventing and managing oxidative stress or iron overload-induced oxidative stress conditions in pediatric β-thalassemic patients (type major).
PATIENTS AND METHODS
165 patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 1,000 mg omega-3 fish oil [350 mg eicosapentaenoic acid (EPA) and 250 mg docosahexaenoic acid (DHA)] combined with Manuka honey lozenge (344 mg) daily or Manuka honey alone plus the conventional therapy for ten months. Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), Lactate dehydrogenase (LDH), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), CRP (C-reactive protein), ferritin level, and serum iron were determined at baseline and month 10.
RESULTS
Omega-3 and Manuka honey combination were a significant add-on to conventional therapy of β-thalassemia in reducing the oxidative stress condition. The combination of Omega-3 and Manuka honey reduced the level of F2-isoprostane(8-iso-PGF2α) significantly compared to the Manuka alone and the control groups. Additionally, they showed an antihemolytic action measured by reduced LDH level. The combination restored the patient's lipid profile (LDL-C and HDL-C) significantly compared to the control group. Manuka honey enhanced the action of omega-3 in reducing oxidative stress by reducing serum iron significantly compared to the control group.
CONCLUSIONS
Results showed that omega-3 + Manuka honey was more effective than Manuka alone or the conventional treatment alone in managing oxidative stress of β-thalassemic patients.
Topics: Humans; beta-Thalassemia; Cholesterol, LDL; Honey; Fatty Acids, Omega-3; Oxidative Stress; Iron Overload; Iron
PubMed: 37458648
DOI: 10.26355/eurrev_202307_32960 -
BMC Cancer Jun 2023
PubMed: 37353751
DOI: 10.1186/s12885-023-11091-y -
Cureus May 2023Context Deferasirox, an iron chelator, can potentially reduce intraoperative right-to-left shunt and improve oxygenation in patients undergoing thoracic surgery...
Context Deferasirox, an iron chelator, can potentially reduce intraoperative right-to-left shunt and improve oxygenation in patients undergoing thoracic surgery requiring one-lung ventilation (OLV) by potentiating hypoxic pulmonary vasoconstriction (HPV). Aim The aim was to determine the effect of deferasirox on the intraoperative shunt fraction (SF) of patients undergoing thoracic surgery using OLV. Study design and settings This was a prospective, single-blind, randomized, controlled study. The study was conducted at a tertiary-care hospital. Methods Before surgery, 64 patients were allocated to two groups comprising 32 patients each. Group D patients were administered deferasirox, while those in group C were given a placebo. We included patients with the American Society of Anesthesiologists physical status III or IV, aged 18-60 years, undergoing elective thoracic surgery needing OLV. SF was the primary outcome variable. Secondary outcome variables were arterial oxygen tension (PaO), peripheral oxygen saturation (SpO), the ratio of PaO and inspired oxygen concentration (P/F), and complications such as desaturation episodes, hypotension, and tachycardia. Results Baseline and postoperative values of outcome variables were statistically similar in both groups. Intraoperative values of SF were lower and PaO, SpO, and P/F were higher in group D. The incidence of intraoperative desaturation was lower in group D. Conclusion We conclude that pre-treatment with deferasirox reduces intraoperative SF and improves oxygenation during thoracic surgery using OLV.
PubMed: 37323343
DOI: 10.7759/cureus.39071 -
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 -
Annals of Hematology Aug 2023Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient...
Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.
Topics: Humans; Deferasirox; Iron Overload; Patient Preference; Thalassemia; Tablets; Iron; Iron Chelating Agents; Benzoates
PubMed: 37227493
DOI: 10.1007/s00277-023-05240-3 -
Blood Transfusion = Trasfusione Del... Jan 2024In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on...
Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.
BACKGROUND
In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months.
MATERIALS AND METHODS
We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique.
RESULTS
At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups.
DISCUSSION
In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.
Topics: Humans; Child, Preschool; Iron; Deferasirox; Deferiprone; Deferoxamine; Iron Chelating Agents; Pyridones; beta-Thalassemia; Benzoates; Triazoles; Drug Therapy, Combination; Thalassemia; Iron Overload; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pancreas
PubMed: 37146300
DOI: 10.2450/BloodTransfus.485 -
PeerJ 2023Recent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death-ferroptosis. This form of cell death is associated...
BACKGROUND
Recent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death-ferroptosis. This form of cell death is associated with a variety of diseases, including type 2 diabetes. We hypothesize that iron overload may play a role in driving glucose metabolism abnormalities by inducing endoplasmic reticulum stress that mediates ferroptosis in islet β cells. In this study, we tested this conjecture from and experiments.
METHODS
We established a mouse iron overload model by intraperitoneal injection of iron dextrose (50 mg/kg) and an iron overload cell model by treating MIN6 cells with ferric ammonium citrate (640 μmol/L, 48 h) . The iron deposition in pancreatic tissue was observed by Prussian blue staining, and the pathological changes in pancreatic tissues by HE staining and the protein expression level by pancreatic immunohistochemistry. In the cellular experiments, we detected the cell viability by CCK8 and observed the cellular ultrastructure by transmission electron microscopy. We also used MDA and ROS kits to detect the level of oxidative stress and lipid peroxidation in cells. Western blotting was performed to detect the expression levels of target proteins.
RESULTS
Iron overload induces MIN6 cell dysfunction, leading to increased fasting blood glucose, impaired glucose tolerance, and significantly decreased insulin sensitivity in mice. This process may be related to the ferroptosis of islet β cells and the activation of ASK1/P-P38/CHOP signaling pathway.
Topics: Mice; Animals; Ferroptosis; Diabetes Mellitus, Type 2; Iron Overload; Iron; Signal Transduction
PubMed: 37090106
DOI: 10.7717/peerj.15206