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Background and aims: A number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients—some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (ABCC2 , ABCG2 , and UGT1A1) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient's genotype and the development of toxicity. Methods: Sanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: ABCC2 rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); ABCG2 rs2231142 (c.421C>A); UGT1A1 *6 rs4148323 (c.211G>A), *28 rs3064744 (g.233760235TA[8]), *36 rs3064744 (g.233760235TA[6]) and *37 rs3064744 (g.233760235TA[9]). Results: The patient is heterozygous for two ABCC2 variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity. Discussion: The precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene ABCC2 played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene ABCC2. [ABSTRACT FROM AUTHOR]

Background: Patients with β-thalassemia major (TM) require lifelong blood transfusions, leading to iron overload, where active intervention is required. Aims and Objectives: The aim of the study was to evaluate real-world efficacy and safety of deferasirox (DFX) in TM patients at a tertiary care teaching hospital. Materials and Methods: A prospective observational study was conducted at thalassemia ward in a tertiary care teaching hospital in Gujarat for a period of 15 months from April 2021 to July 2022. A total of 100 patients were analyzed during the study period. Patient's demographic profile, laboratory investigation, and treatment details were analyzed using descriptive statistics. Statistical analysis was done through the statistical software GraphPad Prism 9.4.1 (681). Results: A total of 100 patients were included in the study. A serial significant decrease in median serum ferritin levels was observed in >13 years age group after initiation of DFX. A significant increase in the median dose of DFX was observed at 12 months in the age group of 2-≤13 years as compared to baseline (P < 0.05). Adverse reactions observed during the study were increased bilirubin level, increased alanine aminotransferase, and increased serum creatinine, rashes with itching, and arthralgia. Conclusion: A greater reduction in median serum ferritin levels was observed in the adult age group compared to pediatric patients. [ABSTRACT FROM AUTHOR]

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal's body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action's molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect. [ABSTRACT FROM AUTHOR]

A rapid, simple and highly sensitive stability-indicating reverse-phase high-performance liquid chromatographic technique, coupled with a photodiode array detector, was developed and validated for the estimation of Deferasirox (DFS). The chromatographic separation was achieved using a C-18 (250 × 4.6 mm, 5 μm) stationary phase and a mobile phase composed of 0.1% orthophosphoric acid and acetonitrile at a flow rate of 1 mL/min. The detection was carried out at a wavelength of 245 nm with a constant injection volume of 10 μL throughout the analysis. With an R2 value of 0.9996, the calibration curve was determined to be linear over an appropriate concentration range of 50–500 ng/mL. According to the International Conference on Harmonization (ICH) Q1 (R2) guideline, DFS was evaluated under stress conditions that included hydrolytic (acid, alkali and neutral), oxidative and thermal degradation. The findings demonstrated that significant degradation was observed in acidic degradation conditions, whereas drug substance was found to be stable when exposed to neutral, basic, oxidative and thermal degradation. The developed method was validated as per ICH guidelines. The developed method was employed successfully to estimate the amount of DFS in bulk and pharmaceutical formulation. [ABSTRACT FROM AUTHOR]

Background: B-thalassemia is the most common single-gene disorder in India with nearly 36 million people carrying the responsible gene. Thalassemia major is the severe form of β thalassemia characterized by severe anemia, hepatosplenomegaly, facial and skeletal changes due to increased hemolysis of defective red blood cells (RBCs). Blood transfusion (BT) remains the first‑line treatment in these patients. One unit of blood contains approximately 200–250 mg of elemental iron, and it can cause iron overload when transfused repeatedly. Transfusion‑related iron overload has been associated with various complications, for example, growth retardation, endocrinal abnormalities, and cardiac failure. To prevent complications iron chelators are used which remove excess of iron from the body by forming non-toxic stable, and water-soluble complexes. Deferasirox is a new iron chelator, that requires once-a-day oral administration. However, there is limited data regarding long-term efficacy and safety of this drug in the Indian population Objectives: The present study will evaluate the long-term efficacy, safety, and tolerability of deferasirox in pediatric patients with transfusion-dependent β thalassemia major. The information obtained from the study could prove useful to recommend modifications, if any, in the management of iron overload in cases of thalassemia on long- term chelation therapy. Material & methods: 64 B-thalassemia major regularly transfused children on deferasirox for a minimum of 5 years were enrolled and observed prospectively for reduction of serum Ferritin levels at the dose range of 20-30 mg/kg. Adverse drug reactions were recorded from monthly follow-ups. Reactions were classified by the Edwards and Aronsons system and severity by modified Hartwig and Siegel’s method for judging the long-term safety. Results: The mean age was 8.75(±2.6) years with 38 (59.4%) males and 26 (40.6%) Female. The mean duration and dose of deferasirox treatment received by children was 6.3 (2.24) years and 21.56 (7.5) mg/kg respectively. Mean ferritin levels at o month was 1956 ng/ml, at 6 months was1554ng/ml and at 1 year of study was 1232ng/ml. deferasirox was found to be efficacious at dose ranges between 20-30 mg/kg for various serum ferritin levels at 6 months and it was statistically significant (p-value 0.00). most of the adverse drug reactions were gastrointestinal like abdominal pain, diarrhea, and vomiting. They were mild. Some other reactions like transaminitis and raised creatinine were moderate in severity and responded to temporarily withholding the drug for 3 weeks. Two patients had macular pigmentation and mild raised curve for sensory neural hearing. [ABSTRACT FROM AUTHOR]

Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload. [ABSTRACT FROM AUTHOR]

Introduction. Deferasirox is a complexing drug and belongs to class II according to the biopharmaceutical classification system (BCS), has acidic properties and belongs to subclass “a” (acid). This class is characterized by high permeability and low solubility, which limits the absorption of the active substance into the blood. As a result, the development of drugs with an active substance that can be assigning BCS to this class is a difficult task, and for generic drugs it is also associated with a high risk of obtaining unproven equivalence during clinical trials. To minimize the above risks, a physiologically relevant test was carried out with further data processing and construction of putative pharmacokinetic profiles.Aim. The aim of the study is to conduct a physiologically relevant test (PRT) to predict in vitro pharmacokinetic profiles and compare them with in vivo data as part of a bioequivalence study of deferasirox.Materials and methods. The objects of the study are "Deferasirox, film-coated tablets, 360 mg" of a domestic manufacturer and "Jadenu®, film-coated tablets, 360 mg" (WTN22 series, expiration date until 10.2023, Novartis Pharma Stein AG, Switzerland). A physiologically relevant test was performed on the device SC PRT-6, Compliance. Quantitative analysis was carried out by HPLC-UV method.Pharmacokinetic profiles were modeled using PK-Sim® (Systems Biology Software Suite 11.2, Bayer Technology Services GmbH, Germany) based on data obtained from physiologically relevant test.Results and discussion. A physiologically relevant drug test for deferasirox was performed and release profiles were obtained, which formed the basis of a physiologically based pharmacokinetic model together with data on the physicochemical properties of the studied compound and literature data on the pharmacokinetics of deferasirox. The pharmacokinetic profiles obtained as part of the simulation on a virtual population were compared with data obtained during clinical trials.Conclusion. A physiologically relevant test for the drug deferasirox was carried out, quantitative determination in the samples was carried out by HPLC-UV. The test resulted in data that allowed prediction of pharmacokinetic profiles that reflected the same differences observed in the profiles of the test and reference drug in the comparative pharmacokinetics and bioequivalence study of deferasirox drugs.

A hereditary condition called beta thalassemia is defined by a decreased or nonexistent synthesis of beta-globin chains, which are a part of hemoglobin. The protein in red blood cells called hemoglobin is responsible for transporting oxygen to all of the body's tissues. Deficiencies in selenium and copper can cause a variety of health concerns, such as impaired immune system performance, heart difficulties, and anomalies in the nervous system. Objective: Assess the selenium and copper levels in patients with thalassemia to look for imbalances or deficits relative to normal limits. This can reveal information about the nutritional condition of those with thalassemia. Methods: In the research, 40 female and 40 male patients were compared to 20 female and male healthy controls who were matched for ages. Samples were collected between (July 1 - September)2023. the patients were questioned to gather information on sociodemographic factors. Graphite furnace atomic absorption spectroscopy (GFAAS) was used to determine level of selenium and copper Results: For (β-Th) female patients, selenium level was higher than that of the female control group; however, for (β-Th) male patients, selenium level was similar in the male control group. The mean serum copper level was lower in male beta thalassemia patients with β-Th than in the male control group.. The association between the individuals who were infected within and outside the city was also discovered, and the outcome comprised 63 patients from the city center and 19 patients with beta thalassemia from beyond the city. Compared to patients from the city center, patients from outside the city had higher average levels of copper and selenium. Conclusions: Serum Se and Cu might play a role in the patients with β-Th. Cu is related to many diseases, such as Wilson's disease, mineral deficiency related for (Se) to the body's muscles, and iron deficiency, so it can be considered. [ABSTRACT FROM AUTHOR]

Tumor metastasis presents a formidable challenge in cancer treatment, necessitating effective tools for anti-cancer drug development. Conventional 2D cell culture methods, while considered the “gold standard” for invasive studies, exhibit limitations in representing cancer hallmarks and phenotypes. This study proposes an innovative approach that combines the advantages of 3D tumor spheroid culture with impedance-based biosensing technologies to establish a high-throughput 3D cell invasion assay for anti-metastasis drug screening through multicellular tumor spheroids. In addition, the xCELLigence device is employed to monitor the time-dependent kinetics of cell behavior, including attachment and invasion out of the 3D matrix. Moreover, an iron chelator (deferoxamine) is employed to monitor the inhibition of epithelial–mesenchymal transition in 3D spheroids across different tumor cell types. The above results indicate that our integrated 3D cell invasion assay with impedance-based sensing could be a promising tool for enhancing the quality of the drug development pipeline by providing a robust platform for predicting the efficacy and safety of anti-metastatic drugs before advancing into preclinical or clinical trials. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of global cancer-related deaths. Platinum-based chemotherapy is the first-line treatment for the most common type of lung cancer, i.e., non-small-cell lung cancer (NSCLC), but its therapeutic efficiency is limited by chemotherapeutic resistance. Therefore, it is vital to develop effective therapeutic modalities that bypass the common molecular mechanisms associated with chemotherapeutic resistance. Ferroptosis is a form of nonapoptotic regulated cell death characterized by iron-dependent lipid peroxidation (LPO). Ferroptosis is crucial for the proper therapeutic efficacy of lung cancer-associated chemotherapies. If targeted as a novel therapeutic mechanism, ferroptosis modulators present new opportunities for increasing the therapeutic efficacy of lung cancer chemotherapy. Emerging studies have revealed that the pharmacological induction of ferroptosis using natural compounds boosts the efficacy of chemotherapy in lung cancer or drugresistant cancer. In this review, we first discuss chemotherapeutic resistance (or chemoresistance) in lung cancer and introduce the core mechanisms behind ferroptosis. Then, we comprehensively summarize the small-molecule compounds sourced from traditional medicines that may boost the antitumor activity of current chemotherapeutic agents and overcome chemotherapeutic resistance in NSCLC. Cumulatively, we suggest that traditional medicines with ferroptosis-related anticancer activity could serve as a starting point to overcome chemotherapeutic resistance in NSCLC by inducing ferroptosis, highlighting new potential therapeutic regimens used to overcome chemoresistance in NSCLC. [ABSTRACT FROM AUTHOR]

Background: The increased iron level aids the formation of many of oxygen-reactive compounds via Haber-Weiss and Fenton reactions. These compounds participate in the metal regulation of the redox reaction and can affect many organs, erythrocytes and endocrine glands causing disturbances in the function of these organs. Iron chelating therapy is required to detoxify iron's toxic effects to avoid oxidative injury. Objective: This research aims to determine the relationship between oxidative status and serum ferritin in major β- thalassemic patients treated by iron chelating agents ( deferasirox and deferoxamine). Methods: It is a cross-sectional study, 55 known cases of β-thalassemic patients receiving chelating agents therapy under follow-up participated in the study, their ages ranged between 3-20 years, divided into two groups, group one consisted of 30 patients, 14 male and 16 female, received oral agent deferasirox, Group two consisted of 25 patients, 11 male and 14 female, on Deferoxamine therapy. Total antioxidant capacity (TAOC), serum Malondialdehyde (MDA), haemoglobin and serum ferritin were measured in the studied groups. Results: the TAOC in the patients group on Deferoxamine, is significantly higher than in the Defrasirox group (34.5±13.2; 29.8±11.8 u/ml) respectively, while MDA is higher in Defrasirox than in patients in the deferoxamine group (8.6±5.4; 5.8 ±4.4 nmol/ml) respectively. A non-significant variation in serum ferritin levels and haemoglobin between the 2 groups was found. A considerable affirmative correlation, between TAOC and serum ferritin, and a non–considerable affirmative correlation between MDA and serum ferritin. Conclusion: A considerable affirmative correlation, between TAOC and serum ferritin, and anon – considerable affirmative correlation between MDA and serum ferritin when comparing the results of all patients as one group, were found. [ABSTRACT FROM AUTHOR]

BackgroundDeferasirox (DFX) is a once-daily oral iron chelator with proven dose-dependent efficacy in patients with thalassemia major (TM). The reason for switching from DFX dispersible tablets (Exjade®) to DFX film-coated tablets (Jadenu®) was intolerance. Many patients also reported that deferasirox® did not taste good. In this study, we compared the effect of Jadenu® and Exjade® on satisfaction, convenience, cardiac/liver MRI T2*, serum ferritin levels, and biochemical profiles in patients with thalassemia major.MethodSixty-two patients with thalassemia over 2 years of age, who had iron overload indicated by chelation therapy, were randomly divided into two groups. The first group (n = 32) is treated with Exjade®, and the second group (n = 30) is treated with Jadenu®. Laboratory investigations included alkaline phosphatase (ALK), alanine transferase (ALT), aspartate transferase (AST), and serum ferritin levels. Cardiac/liver MRI T2* levels and patient satisfaction and convenience, were assessed before and 1 year after starting therapy.ResultsThe study found that 53.3% of Jadenu® patients were satisfied with the taste of the medication compared to only 12.5% of Exjade® patients, which was statistically significant (p = 0.001). Additionally, 40% of Jadenu® patients were satisfied with the ease of taking the medication compared to 28.1% of Exjade® patients, and again, the difference was statistically significant (p = 0.047). A comparison of the cardiac MRI T2* levels between the two studied groups showed no significant difference (p = 0.851).ConclusionJadenu® offers patients an improved formulation that can be taken on an empty stomach, has a better taste, and presents fewer gastrointestinal tolerability concerns. Overall, patient satisfaction is higher with Jadenu®, which may improve adherence and reduce the frequency and severity of complications associated with iron overload. This, in turn, may help mitigate cardiovascular and hepatic complications from iron overload in the long term.Clinical Trial Registrationhttps://irct.behdasht.gov.ir/search/result?query=IRCT20210830052346N1

Background and aimsA number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients—some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (ABCC2, ABCG2, and UGT1A1) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient’s genotype and the development of toxicity.MethodsSanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: ABCC2 rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); ABCG2 rs2231142 (c.421C>A); UGT1A1 *6 rs4148323 (c.211G>A), *28 rs3064744 (g.233760235TA[8]), *36 rs3064744 (g.233760235TA[6]) and *37 rs3064744 (g.233760235TA[9]).ResultsThe patient is heterozygous for two ABCC2 variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity.DiscussionThe precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene ABCC2 played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene ABCC2.

Abstract Background β-Thalassemia major (BTM) is one of the most common hereditary anemias worldwide. Patients suffer from iron overload that results from repeated blood transfusion This in turn leads to multiple organ damage and endocrinopathies. This study aims to assess the prevalence of growth retardation, hypothyroidism, and diabetes mellitus in children and adolescents with BTM treated at Dubai Thalassemia Centre. Methods A total of 105 children and adolescents were included in this retrospective observational study. Results 39 children and 66 adolescents’ data were analyzed. Females composed 51.3% (n = 20) of children and 53.0% (n = 35) of adolescents. Pretransfusion hemoglobin below 9 gm/dl was observed in 10.8% (n = 4) and 10.6% (n = 7) in children and adolescents, respectively. The mean age of menarche was 13.5 years. Among all study participants, 22.6% (n = 14) had normal height velocity whereas 37.1% (n = 23) had reduced height velocity in one year and 40.3% (n = 25) had reduced height velocity in two consecutive years. The proportion of children and adolescents showing reduced height velocity was significantly higher in females compared to the males (90.6% versus 63.3%, respectively, Chi-square = 6.597, p-value = 0.010). Although none of the study participants had diabetes mellitus, 26.1% (n = 12/46) had pre-diabetes. Elevated TSH was observed in 14.7% (n = 5) children and 8.1% (n = 5) adolescents while low FT4 was reported in one child and one adolescent. Conclusion Of all endocrinopathies seen among children and adolescents with BTM, growth delay remains the main concern for this group of patients. Effective treatment is key to further reducing endocrinopathies. Although the sample size is limited, we postulate that the low percentage of endocrinopathies among children with BTM treated at Dubai thalassemia center and the low level of pretransfusion anemia reflect the effective transfusion and chelation at the center.

Summary: Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion‐dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo‐controlled, randomised study to evaluate the iron chelator deferasirox in patients with low‐ or intermediate‐1–risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk. [ABSTRACT FROM AUTHOR]

Hematoma, a risk factor of implant‐associated infections (IAIs), creates a Fe‐rich environment following implantation, which proliferates the growth of pathogenic bacteria. Fe metabolism is a major vulnerability for pathogens and is crucial for several fundamental physiological processes. Herein, a deferiprone (DFP)‐loaded layered double hydroxide (LDH)‐based nanomedicine (DFP@Ga‐LDH) that targets the Fe‐rich environments of IAIs is reported. In response to acidic changes at the infection site, DFP@Ga‐LDH systematically interferes with bacterial Fe metabolism via the substitution of Ga3+ and Fe scavenging by DFP. DFP@Ga‐LDH effectively reverses the Fe/Ga ratio in Pseudomonas aeruginosa, causing comprehensive interference in various Fe‐associated targets, including transcription and substance metabolism. In addition to its favorable antibacterial properties, DFP@Ga‐LDH functions as a nano‐adjuvant capable of delaying the emergence of antibiotic resistance. Accordingly, DFP@Ga‐LDH is loaded with a siderophore antibiotic (cefiderocol, Cefi) to achieve the antibacterial nanodrug DFP@Ga‐LDH‐Cefi. Antimicrobial and biosafety efficacies of DFP@Ga‐LDH‐Cefi are validated using ex vivo human skin and mouse IAI models. The pivotal role of the hematoma‐created Fe‐rich environment of IAIs is highlighted, and a nanoplatform that efficiently interferes with bacterial Fe metabolism is developed. The findings of the study provide promising guidance for future research on the exploration of nano‐adjuvants as antibacterial agents. [ABSTRACT FROM AUTHOR]

Deferasirox, an oral iron-chelating agent, is a poorly soluble drug (Biopharmaceutical Classification System class II) having insufficient solubility in physiological fluids resulting in low bioavailability of the drug. The idea behind the present study was to explore the prospects of solid dispersion as a prolific method to enhance the dissolution rate of drug using a water soluble polymer. The solid dispersion was prepared by the solvent evaporation technique using Polyvinyl pyrrolidone with different drug to carrier and solvent ratio. Formulations were characterized through attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), Powder X-ray diffraction (XRD), and in vitro release studies. A 32 factorial design was implemented to obtain optimum solubility, % yield, and optimization of solid dispersion (SD) also quantitates the influence of PVP on the solubility and dissolution profile. Thedrug-to-carrier and solvent ratio was chosen as independent variable, while %yield, drug content, and saturation solubility were chosen as dependent variables. The results showed that the optimized formulation of SD-DFX was able to significantly enhance its solubility. The SD containing a dispersion of Deferasirox with PVP show an exceptional rise in the solubility. This study describes the development of solid dispersion that significantly improved the solubility and bioavailability of DFX. The FTIR studies indicate the interaction between the drug and polymer. The DSC and XRD analysis indicated that the drug was in an amorphous state when dispersed in the polymer. It is resolved that the SD method significantly improves the solubility and dissolution rate, which could also be exploit for other poorly water soluble drug candidates. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols. [ABSTRACT FROM AUTHOR]

Thalassemia treatment still relies on supportive care, mainly including blood transfusion and iron chelation therapy. Iron chelation is considered the main factor responsible for the marked improvement in survival rates of thalassemic patients. Hemosiderosis may be prevented if appropriate chelation therapy is offered from early childhood, with timely dose adjustments according to changing body weight and close monitoring of organ iron load. With three iron chelators currently available, the choice of appropriate chelation, either as monotherapy or combined therapy, should be individualized depending on the iron overload of target organs, patient's age, presence of adverse events and compliance issues, given known limitations related to each agent's administration. [ABSTRACT FROM AUTHOR]

Background and Objectives Chelation therapy is essential for beta-thalassemia major. This study aims to determine the complications clinical and laboratory symptoms of monotherapy and combined treatment of iron chelators in beta-thalassemia major patients in Yasuj. Materials and Methods In this cross-sectional-descriptive-analytical study, 103 patients with beta-thalassemia major in Yasuj city were evaluated during 2021-2022. After collecting the demographic, clinical and laboratory information of the patients, the results were reported as mean ± standard deviation and percentage. The degree of statistical differences between ratios was calculated using the Kruskal-Wallis test. Results The average age of our patients was reported to be 24.74 ± 8.34 years. 54.4% (n = 56) of the study patients were men and 45.6% (n = 47) were women. The results of the present study showed that there was a statistically significant difference in mean ferritin among different study groups (p = 0.028). Patients treated with deferoxamine showed the highest mean serum ferritin (5925.5 ± 3397ng%) and patients who took deferoxamine together with deferiprone or deferasirox had a lower mean ferritin compared to deferoxamine alone (3348 ± 2560, 4269 ± 3322 ng%), respectively. Also, the present study showed that after taking iron removers, 47.6% of patients (n = 49) had no clinical complications and 52.4% (n = 54) had at least one complication. Conclusions Our results showed that Deferoxamine can have a great effect in reducing iron deposition and serum ferritin levels in combination with oral drugs. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of switching from deferasirox dispersible tablet (DT) to deferasirox film-coated tablet (FCT) on serum ferritin (SF) levels in transfusion-dependent patients. Materials and Methods: Patients who received regular erythrocyte transfusion and whose treatment was switched from DT to FCT were included in the study. FCT start date was taken as the index date. Patients were followed over 2 equal and long periods, both before and after index date. Results: Thirty-two patients were included, and the comparison periods ranged from 4 to 12 months. The SF values increased from a median of 1723 ng/mL (range 717-5369 ng/mL) to 1.853 ng/mL (range 924-5478 ng/mL) after switching from DT to FCT (P = .036). While there was a significant increase in median SF after switching in Turkish patients (1467 ng/mL to 1778 ng/ mL, P = .010) and patients ≥12 years (1598-1848 ng/mL, P = .009), there was an insignificant (P = .859) decrease in SF in immigrant children. Considering only the post-switch period, there was a non-significant increase in median SF in the entire cohort, while SF decreased significantly in immigrant children (P = .026). No serious side effects were observed in any patient that would cause discontinuation of treatment. Conclusion: Overall, higher SF value was observed with FCT compared to DT in short term. There were different results between patient groups. Our results suggest that FCT is more effective than DT in patients with high basal ferritin and who are actually incompatible with treatment and should be preferred first in these patients. [ABSTRACT FROM AUTHOR]

Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two‐way crossover design and were conducted after a single‐dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36–110.37% and 97.98–108.45% for rivaroxaban, respectively, and 96.69–107.29% and 94.19–109.45% for deferasirox, respectively. Thus, the BE criteria (80.00–125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment. [ABSTRACT FROM AUTHOR]

Thalassemia treatment still relies on supportive care, mainly including blood transfusion and iron chelation therapy. Iron chelation is considered the main factor responsible for the marked improvement in survival rates of thalassemic patients. Hemosiderosis may be prevented if appropriate chelation therapy is offered from early childhood, with timely dose adjustments according to changing body weight and close monitoring of organ iron load. With three iron chelators currently available, the choice of appropriate chelation, either as monotherapy or combined therapy, should be individualized depending on the iron overload of target organs, patient’s age, presence of adverse events and compliance issues, given known limitations related to each agent’s administration.

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal’s body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action’s molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.

Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here, we studied the effect of 12 weeks of drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined, as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males, with slightly higher adipocyte area values in both males and females under clozapine treatment. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol-medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine treatment. IR-ß expression changed sex-specifically in the clozapine-medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-treated females. Taken together, clozapine and haloperidol had a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined, and probably in their effect on liver metabolism. [ABSTRACT FROM AUTHOR]

Background and aim: Hypozincemia is a prevalent adverse consequence in diabetes mellitus (DM) and β-Thalassemia patients. We aimed to evaluate the level of serum zinc in β-thalassemia patients with DM and a risk assessment for hypozincemia. Methods: The study population included transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) with overt DM (fasting plasma glucose (FPG) ≥126 mg/dL, and/or 2-h plasma glucose≥200 mg/dL). Serum zinc concentration was measured by the colorimetric method, and the values below 70 μg/dL were defined as hypozincemia. Myocardial and liver T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) were valued by a free contrast MRI. The demographic, clinical, paraclinical, and laboratory data were also recorded. The data belonged to the period from December 2018 until December 2020. Results: Of 64 diabetic β-thalassemia patients, 41 cases had zinc data in their medical files (aged 38 ± 9 years, 48.8% female). 78.05% of patients (n = 32) were TDT, and 21.95% were NTDT (n = 9). The mean ± standard deviation of zinc level was 110.2 ± 127.6 μg/dL. The prevalence of hypozincemia was 9.76%, 95% confidence interval [CI] 0.27 to 19.24 (four cases). After controlling age, the odds of hypozincemia for using deferasirox (DFX) was 8.77, 95% CI 0.60 to 127.1. In β-thalassemia patients, the age-adjusted risk of hypozincemia was calculated at 15.85, 95% CI 0.47 to 529.3 for hepatitis C. The adjusted risk of hypozincemia based on age for antacid use was 6.34, 95% CI 0.39 to 102.7. Conclusion: In light of this study, as well as hepatitis C, using DFX and antacids is associated with a high risk of hypozincemia amid diabetic β-thalassemia cases. However, upward bias should be taken into consideration. Author summary: [ABSTRACT FROM AUTHOR]

The study aimed to determine efficacy and safety of generic deferasirox monotherapy. Deferasirox was administered in transfusion-induced iron overloaded thalassemia. Efficacy was defined as responders and nonresponders by ≤ 15 reduced serum ferritin from baseline. Adverse events were also monitored. Fifty-two patients with mainly Hb E/β-thalassemia at the mean (SD) age of 8.7 (4.1) years, were enrolled. The mean (SD) daily transfusion iron load was 0.47 (0.1) mg/kg and maximum daily deferasirox was 35.0 (6.2) mg/kg. Altogether, 52, 40 and 18 patients completed the first, second and third years of study, respectively. The median baseline serum ferritin 2,383 ng/mL decreased to 1,478, 1,038 and 1,268 ng/mL at the end of first, second and third years, respectively, with overall response rate at 73.1% (38/52). Patients with baseline serum ferritin >2,500 ng/mL showed a change in serum ferritin higher than those ≤2,500 ng/mL starting from the 9th month of chelation. Adverse events were found in 5 of 52 patients (9.6%) including transaminitis (n = 2), one each of proteinuria, rash and proximal tubular dysfunction which resolved after transient stopping or decreasing the chelation dose. Generic deferasirox was effective and safe among pediatric patients with transfusion-induced iron overloaded thalassemia. [ABSTRACT FROM AUTHOR]

Thalassemia is a blood disorder that results from decreased or lost synthesis of one or more globin chains. Thalassemia major as a red blood cell disorder requires high costs because it requires blood transfusions and the use of iron chelation drugs throughout the patient's life. This study aims to analyze the cost and effectiveness of oral iron chelation drugs such as deferasirox and deferiprone in patients with Thalassemia major at Setukpa Lemdiklat Polri Tk--II Hospital in 2023. Data was collected retrospectively using total sampling from patient medical records and hospital information system data. Based on the results of this study, the average total cost per treatment for thalassemia major patients who used deferasirox (IDR 52,969,775,-) was more expensive than deferiprone (IDR 49,407,613,-). The effectiveness of deferasirox (1,364 ng/mL) was bigger than that of deferiprone (1,210 ng/mL). The cost-effectiveness ratio of deferasirox (IDR 38,834,-) was lower than that of deferiprone (IDR 40,833,-). To change the drug from deferiprone to deferasirox requires an additional cost of IDR 23,130 per one additional unit. From the average costeffectiveness ratio, it can be concluded that deferasirox is more cost-effective than deferiprone. [ABSTRACT FROM AUTHOR]

Purulent vulvar discharge is a clinical sign of genitourinary tract infections, which are a significant concern in swine facilities, leading to sow culling and mortality. Escherichia coli is one of the main agents involved in these diseases. This study aimed to characterize the virulence and antimicrobial resistance profiles as well as the phylotype of Escherichia coli strains isolated from sows with purulent vulvar discharge. The results showed that at least 2 of the 29 tested virulence genes related to extraintestinal pathogenic E. coli were present in all strains tested. The most frequent gene was iutA, present in all strains, followed by the genes iucD, csgA, iss2, and irp2. Associations between iron uptake genes, genes related to adhesion, attachment, and serum resistance, as well as genes related to toxin release and bacteriocin, were frequent. The most prevalent phylotype was B1 (40.0%), followed by A (18.5%), D (11.9%), C (9.6%), B2 (7.4%), E (4.4%), F (1.5%), and Clade I (0.7%), with B2 being related to highly virulent traits. The strains presented elevated resistance to antimicrobials such as ciprofloxacin, streptomycin, cephalexin, florfenicol, and ampicillin. More than 90% of the strains were identified as multidrug-resistant, indicating the selection that is induced by the high use of antimicrobials in swine farming. [ABSTRACT FROM AUTHOR]

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Deferasirox, as an oral iron chelator, is presently the first-choice medication for iron overload caused by repeated blood transfusions due to its ease of use, efficacy, and high bioavailability, yet deferasirox has been also reported with the occurrence of acute kidney injury and tubular dysfunction. Vitamin E is a potent antioxidant and anti-inflammatory agent. Aim of the Work: To study the effect of deferasirox on the oxidative status, histological structure, apoptosis, proliferation, and inflammation of the renal cortical tubules and examine the potential protective role of vitamin E against such effect in adult male albino rat. Material and Methods: Twenty-four adult male albino rats were subdivided into four equal groups; control, vitamin E-treated (100 mg/kg/day vitamin E orally for 4weeks), deferasirox-treated group (100 mg/kg/day deferasirox orally for 4weeks), and vitamin E&deferasirox-treated group (concomitantly administered vitamin E and deferasirox). Kidney specimens were processed for different biochemical, histological, and immunohistochemical studies. Results: Deferasirox-treated group revealed loss of the normal histological architecture of the renal cortex involving numerous nuclear and cytoplasmic alterations of renal cortical tubules with inflammatory signs. Tissue malonaldehyde level was significantly surged. A significant increase in caspase-3, Ki67, and iNOS immunohistochemical expression was recorded, whereas a significant drop in the histochemical expression of PAS was detected. Results from the group concomitantly administered with vitamin E and deferasirox exhibited an apparently normal histology of the renal cortex with a non-significant difference in all studied parameters compared to the control group. Conclusion: Deferasirox administration led to histological alterations in the renal cortical tubules through inducing oxidative stress, apoptosis, proliferation, and inflammation. Concomitant supplementation with vitamin E exerted a protective action against deferasirox harmful effects most probably through its antioxidative, antiapoptotic, and anti-inflammatory properties [ABSTRACT FROM AUTHOR]

Thalassemia major, as a red blood cell disorder that is passed from both parents to their children, requires high costs and the use of iron chelation drugs throughout the patient's life. Pharmacoeconomics studies in patients with thalassemia major needs to be conducted to determine the efficiency and effectiveness of selecting oral iron chelation drugs. This study aims to analyze the cost and cost-effectiveness of using oral iron chelation drugs such as deferasirox and deferiprone. This systematic review was conducted from Pubmed and Scopus, to identify the cost-effectiveness of deferasirox and deferiprone. Eight studies met the inclusion criteria for the review. farthermor selected the papers, extracted the data, and assessed the methodological quality of the included documents. In brief, deferasirox is cost-effective than deferiprone. Moreover, the cost-effectiveness is not an absolute issue when in different countries (regions) the results are opposite for other countries (regions). As a result, the local/national context had a substantial influence on the results of the pharmacoeconomic evaluation. From the average cost-effectiveness ratio, it can be concluded that deferasirox is more cost-effective than deferiprone. [ABSTRACT FROM AUTHOR]

Abdulqadir J Nashwan,1 Mohamed A Yassin2 1Nursing Department, Hamad Medical Corporation, Doha, Qatar; 2Department of Medical Oncology/Hematology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarCorrespondence: Abdulqadir J Nashwan, Nursing Department, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar, Tel +974 40240487 ; +974 66473549, Email anashwan@hamad.qaAbstract: Chronic kidney disease (CKD) is a major global health concern, affecting millions of people worldwide. The progressive decline in kidney function often necessitates renal replacement therapy, such as hemodialysis (HD) or peritoneal dialysis (PD), to maintain a patient’s health. Iron overload, which is common in CKD patients on dialysis, can lead to severe complications, including cardiovascular disease and infections where most of the existing iron chelators are deemed unsuitable due to their suboptimal clearance in patients with compromised renal function, it becomes a significant challenge to effectively manage iron overload. Deferasirox (DFX), an oral iron chelator, has emerged as a promising treatment option for managing iron overload in these patients. However, the use of DFX comes with its unique set of challenges, such as its cost, potential side effects, and the need for close monitoring of patients, as well as the noticeable scarcity of comprehensive and rigorous clinical studies confirming its efficacy and safety of DFX. In this review, we delve into both the promising prospects and the emerging challenges associated with DFX use in managing CKD patients on HD or PD, striving for a comprehensive understanding that informs better clinical practice and patient care.Keywords: CHRONIC kidney disease, Deferasirox, chelating therapy, iron overload, hemodialysis, peritoneal dialysis

Introduction: Thalassemia consists of a variety of genetic hemoglobinopathies. Thalassemia-major causes anemia in early age. Those suffering from thalassemia need frequent life-long blood transfusions to survive, resulting in iron overload in the body and many health problems. Much improvement has occurred in predicting the course of Thalassemia major thanks to iron chelation therapy. Edible iron chelating agents are the standard of the chelating process. Deferasirox is a newly developed orally active iron chelating tablet which is used on a daily basis. Th present case study investigated severe dermatopathological reactions to the Iranian made product of Deferasirox.Case presentation: We present a case of adverse drug reactions in a thalassemic patient who was started on Deferasirox orally after receiving Deferoxamine injections for several years with no serious reactions. The patient experiences generalized maculopapular, deep red- blue partially purpuric itchy skin rashes throughout her body. The histopathological biopsy found superficial perivascular or dermatitis with low-grade vasculopathy, few eosinophils, and mild psoriasis form-supraglotticlichenoid epidermal reactions associated with Drug Reaction diagnosis.Conclusion: With regard to inherent features, caution must be applied to start the original Deferasirox for the patients who will undergo the oral chelation process with a smooth increase in the daily dosage for a few weeks in order to create improved tolerance.

Background Excess iron deriving from a chronic transfusion and dietary intake increases the risk for cardiac complications in β-thalassemia major patients. Deferiprone and deferasirox are commonly prescribed to thalassemic patients who are at risk of iron overload. This study aimed to compare the performance and toxicity of deferiprone and deferasirox in β-thalassemia major patients. Methods A cross-sectional observation was performed on 102 patients with β-thalassemia major. Serum ferritin along with total, indirect, and direct bilirubin levels were measured. Levels of liver enzymes, transaminase (ALT), and aspartate transaminase (AST), were also determined. Ferritin correlations with serum ALT, AST, and total bilirubin were constructed based on Spearman’s rank correlation. Statistical differences based on the serum parameters were analyzed between deferiprone and deferasirox groups. The differences of iron chelators’ effects between those receiving short-term (≤7 years) and long-term (>7 years) blood transfusion were also analyzed. Results The averaged levels of bilirubin, ALT, AST, and ferritin were found to be high. Ferritin was positively correlated with ALT (r=0.508 and pp=0.776). However, higher total bilirubin and ALT were observed in the deferasirox group than in the deferiprone group ( p=0.001 and 0.022, respectively). Total ( ppp=0.015) were significantly higher in patients with long-term transfusions than those receiving short-term transfusions. Higher ferritin was found with a statistical significance of p=0.008 in the long-term transfusions group. Conclusions Ferritin is high in people with transfusion-dependent β-thalassemia major and positively correlated with ALT and AST. Deferasirox might pose a higher risk of developing hepatic injury as compared with deferiprone. Yet, no significant change of deferasirox efficacy (based on ferritin level) was found between those receiving short-term and long-term transfusions.

Background and purpose: Lead poisoning induces oxidative stress and causes disorders in several organs. Iron-chelating drugs can form a complex with toxic metals such as lead and lower their content in the blood and tissues. This study aims to examine the antioxidant effects of Deferasirox, Deferiprone, and their combination in rats with subchronic lead exposure. Materials and methods: In this interventional study, lead poisoning was induced in Sprague-Dawley male rats by gavage administration of 30 mg/kg lead acetate for 60 days. The animals were treated with Deferasirox (140 mg/kg), Deferiprone (300 mg/kg), and their combination through oral gavage from days 47 to 60 of the experiment (14 days). Lead concentration was measured by flame atomic absorption spectroscopy. We examined malondialdehyde (MDA) level, nitric oxide metabolites (NOx) as nitro-oxidative stress markers, glutathione (GSH), and total antioxidant capacity (TAC) in the blood, brain, liver, kidney, and testis. Data analysis was performed in Graphpad Prism software applying one-way variance analysis and Tukey's test. Results: Lead poisoning increased the concentration of this metal and nitro-oxidative stress and decreased the TAC and GSH in the brain, liver, kidney, and testis (P

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.