Deferasirox Research Articles

Vectorization via Siderophores Increases Antibacterial Activity of K(RW)3 Peptides against Pseudomonas aeruginosa.

A series of new conjugates comprised from a small synthetic antimicrobial peptide (AMP) and a siderophore-type vector component was designed and tested for activity on P. aeruginosa PAO1 and several genetically modified strains. As AMP, the well-established arginine-tryptophane combination K(RW)3 (P1) was chosen with an added lysine for siderophore attachment. This peptide is easy to prepare, modify, and possesses good anti-bacterial activity. On the vector part, we examined several moieties: (i) the natural siderophore deferoxamine (DFO); (ii) bidentate iron chelators based on the hydroxamate building block (4 a-c) ; (iii) the non-siderophore chelators deferasirox (DFX) and deferiprone-carboxylate (DFP-COOH). All conjugates were prepared by solid phase synthesis techniques and fully characterized by HPLC and mass spectrometry (including HR-MS). 55 Fe uptake assays indicate a receptor-mediated uptake for 4 a-c, DFP-COOH and DFO, which is dependent on the outer membrane transporter FoxA in the case of DFO. All conjugates showed increased antibacterial activity against P. aeruginosa compared to the parent peptide P1 alone when investigated in iron-depleted medium. MIC values were as low as 2 μM (for P1-DFP) on wild type P. aeruginosa. The activity of P1-DFO and P1-DFP was even better on genetically mutated strains unable to produce siderophores (down to 0.5 μM). Although the DFX vector on its own was not able to transport iron inside the bacterial cell as shown by 55 Fe uptake studies, the P1-DFX conjugate had excellent antibacterial activity compared to P1 (2 μM, and as low as 0.25 μM on a receptor-deficient strain unable to produce siderophores), suggesting that the conjugates were indeed recognized and internalized by an (unknown) transporter. Control experiments with an equimolar mixture of P1 and DFX confirm that the observed activity is intrinsic to vectorization. This work thus demonstrates the power of linking small AMPs covalently to siderophores for a new class of Trojan Horse antibiotics, with P1-DFP and P1-DFX being the most potent conjugates.

An "ON-OFF" fluorescent sensor based on a novel zinc-based flower-like structured metal-organic framework for sequential detection of deferasirox and tigecycline

Deferasirox (DEF) is essential for patients with thalassemia requiring long-term transfusion therapy. Tigecycline (TIGE) is a first-line drug for the clinical treatment of complex, severe bacterial infections. The two drugs can be coordinated to treat Pseudomonas aeruginosa infections. Easy and efficient techniques for monitoring these two drugs in biological samples are few. Metal–organic framework (Zn-MOF) prepared from zinc nitrate hexahydrate and dithioglycolic acid has a flower structure. Interestingly, Zn-MOF can cause DEF to aggregate on it and induce DEF luminescence. The principle may be that Zn-MOF limits the vibration and rotation of DEF to avoid its nonradiative jump, which triggers aggregation-induced emission (AIE) and exhibits intense fluorescence. Further investigation revealed that TIGE could decompose Zn-MOF, thus alleviating the inhibitory effect of Zn-MOF on DEF and reducing the fluorescence intensity of DEF@Zn-MOF. A DEF/TIGE detection biosensor was created based on the fluorescence "turn-on" effect of Zn-MOF on DEF and the fluorescence "turn-off" effect of TIGE on DEF@Zn-MOF. The proposed technique was subsequently used to identify DEF/TIGE levels in pharmaceuticals and human plasma. The mean values for the percentage of the labeled amount of DEF/TIGE in DEF dispersible tablets/TIGE injection were 104.5 and 104.9%, respectively. The detection limits for the fluorescence detection of DEF and TIGE were 3.6 and 1.2 nM, respectively. This fluorescence assay is the first application of MOF to the simultaneous detection of DEF and TIGE and has the advantages of rapid sensitivity and high selectivity, providing a new strategy for drug detection.

Evidence for the Metabolic Activation of Deferasirox In Vitro and In Vivo.

Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS in vitro and in vivo to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or N-acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.

Panaxadiol saponin ameliorates ferroptosis in iron-overload aplastic anemia mice and Meg-01 cells by activating Nrf2/HO-1 and PI3K/AKT/mTOR signaling pathway

Panaxadiol saponin (PND) is a latent targeted drug for the treatment of aplastic anemia (AA). In this study, we examined the effects of PND on ferroptosis in iron-overload AA and Meg-01 cells. We utilized RNA-seq to analyze differentially expressed genes in iron-induced Meg-01 cells treated with PND. The effects of PND or combined with deferasirox (DFS) on iron deposition, labile iron pool (LIP), several ferroptosis events, apoptosis, mitochondrial structure, as well as ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR pathway-related markers in iron-induced Meg-01 cells were examined by Prussian-blue staining, flow cytometer, ELISA, Hoechst 33342 staining, transmission electron microscope, and Western blot assays, respectively. Additionally, an AA mice model with iron overload was established. Then, the blood routine was assessed, and the number of bone marrow-derived mononuclear cells (BMMNCs) in mice was counted. Also, serum iron, ferroptosis events, apoptosis, histology, T lymphocyte percentage, ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related targets in primary megakaryocytes of AA mice with iron overload were assessed by commercial kits, TUNEL staining, hematoxylin and eosin (H&E) staining, Prussian blue staining, flow cytometer, and qRT-PCR analysis, respectively. PND suppressed iron-triggered iron overload, and apoptosis, and ameliorated mitochondrial morphology in Meg-01 cells. Importantly, PND ameliorated ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related marker expressions in iron-induced Meg-01 cells or primary megakaryocytes of AA mice with iron overload. Moreover, PND ameliorated body weight, peripheral blood cell counts, the number of BMMNCs, and histological injury in the iron-overload AA mice. Also, PND improved the percentage of T lymphocytes in the iron-overload AA mice. PND attenuates ferroptosis against iron-overload AA mice and Meg-01 cells via activating Nrf2/HO-1 and PI3K/AKT/mTOR pathway and is a promising novel therapeutic candidate for AA.

Development and Validation of Robust, Highly Sensitive and Stability-Indicating RP-HPLC Method for Estimation of Deferasirox and its Degradation Products.

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, 5μm) stationary phase and a mobile phase composed of 0.1% orthophosphoric acid and acetonitrile at a flow rate of 1mL/min. The detection was carried out at a wavelength of 245nm with a constant injection volume of 10μL throughout the analysis. With an R2 value of 0.9996, the calibration curve was determined to be linear over an appropriate concentration range of 50-500ng/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.

Theoretical and experimental studies on mechanochromic triphenylamine based fluorescent “ON-OFF-ON” sensor for sequential detection of Fe3+ and deferasirox

A novel triphenylamine (TPA) based sensor TTU was rationally designed and synthesized that exhibited reversible mechanochromic and aggregation induced emission enhancement (AIEE) properties. The AIEE active sensor was employed for fluorometric detection of Fe3+ in aqueous medium, with distinguished selectivity. The sensor showed a highly selective quenching response towards Fe3+ that is ascribed to complex formation with paramagnetic Fe3+. Subsequently, TTU-Fe3+ complex acted as a fluorescence sensor for the detection of deferasirox (DFX). The subsequent addition of DFX to TTU-Fe3+ complex led to the recovery of fluorescence emission intensity of sensor TTU that was attributed to the displacement of Fe3+ by DFX and release of sensor TTU. The proposed sensing mechanisms for Fe3+ and DFX was confirmed through 1H NMR titration experiment and DFT calculations. Frontier molecular orbitals (FMO), density of states (DOS), natural bond orbital (NBO), non-covalent interaction (NCI) and electron density difference (EDD) analysis were performed using DFT calculations to support the experimental results. Moreover, sensor TTU displayed colorimetric detection of Fe3+. Further, the sensor was employed for the detection of Fe3+ and DFX in real water samples. Finally, logic gate was fabricated by using sequential detection strategy.

Abstract 378: Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma

Abstract Oxaliplatin, a third-generation of platinum analog, has been used for the treatment of colorectal, gastric, and advanced pancreatic ductal adenocarcinoma (PDAC); however, its relatively high toxicity reduced its efficacy in clinical use. Recently, we found that organic cation transporter 2 (OCT2) expression is positively correlated to Oxaliplatin sensitivity in PDAC cells and better survival outcomes in PDAC patients with chemotherapy, suggesting that OCT2 level is important not only in predicting sensitivity to oxaliplatin but also in guiding dose adjustments to minimize toxicity. Here, we observed the significance of serum Ferritin as a prognostic marker for pancreatic cancer, and further identified Ferritin heavy chain (FTH1) down-regulated OCT2 level and reduced Oxaliplatin sensitivity of advanced PDAC cells in vitro and in vivo. Our study reveals the negative correlation between FTH1 and OCT2 levels in PDAC database analysis and reducing FTH1 expression with Deferasirox (DFX), which is an agent that has been widely used for patients with iron overload, reversed OCT2 expression and Oxaliplatin sensitization in metastatic PDAC cells. Additionally, we identified that exosomal Ferritin/FTH1 from PDAC cells may enhance M1-type to M2-type macrophage polarization to build up immunosuppression in the tumor microenvironment. Citation Format: Ching-Feng Chiu. Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 378.

Hemosiderosis in chronic dialysis patients: Monitoring the response to deferasirox by quantitative hepatic magnetic resonance imaging.

Hemosiderosis of chronic dialysis has always been a frequent phenomenon in dialysis; formerly related to blood transfusions before the advent of Erythropoiesis Stimulating Agents (ESA), it is currently in connection with the use of massive doses of injectable iron, to ensure the full therapeutic efficacy of ESA. Few studies have looked at the therapeutic aspect of iron chelators in the dialysis population. We followed 31 dialysis patients treated for secondary hemosiderosis with deferasirox (DFX) at the dose 10mg/kg/day, by hepatic MRI from September 2017 to September 2021, in order to evaluate the efficacy of iron chelators on the reduction of liver iron concentration (LIC). The diagnosis of hemosiderosis was carried for a value of the LIC > 50 μmol/g of dry liver. Chelation resulted in a significant reduction in liver iron burden as measured by liver MRI: (201.4 ± 179.9 vs. 122.6 ± 154.3μmol/g liver) (p=0.000) and in mean ferritin level: (2058.8 ± 2004.9 vs. 644.2 ± 456.6ng/mL) (p=0.002). A gain of 1.1g/dL in mean hemoglobin level: (10.5 ± 1.6 vs. 11.6 ± 2.0g/dL) (p=0.006). A significant increase in mean albumin level: (43 ± 5.5 to 46.2 ± 6.1g/L) (p=0.04). The therapeutic response was clearly influenced by the cause of overload, longer in polytransfused patients (p=0.023) and the degree of overload assessed by MRI (p=0.003) and ferritin level (p=0.04). DFX, prescribed at a dose of 10mg/kg/day, resulted in a significant reduction in hepatic iron burden as measured by liver MRI and ferritin. The therapeutic response was clearly influenced by blood transfusions and the degree of iron overload.

Safety and efficacy of combination of oral iron chelators in thalassemia major patients

Background: To assess the safety and efficacy of combination of oral iron chelation therapy in transfusion dependent thalassemia patients and to compare it with other regimes. Method: 150 transfusion dependent thalassemia patients with iron overload were recruited for a prospective, case control study. They were divided into 4 groups based on their chelation regime. The drugs used were deferasirox (DFX) alone, deferiprone (DFP) alone, DFP+DFX in combination, parenteral desferrioxamine (DFO) with either DFX or DFP with 50, 15, 70 and 15 in each group respectively. Doses used were DFX-30 mg/kg, DFP- 75 mg/kg/day, DFP+DFX-50 +30 mg/kg/day, DFO+DFP-25 mg/kg/d+50 mg/kg/day and DFO+DFX-25 mg/kg/d +30 mg/kg/d daily. Base line haematological, hepatic and renal profile and S. ferritin samples were collected and analyzed. Patients were monitored monthly for compliance and side effects. 30 patients were excluded during the course of study. Tests were repeated after 18 months period and the results of 120 patients were compared between the groups and statistically analyzed. Results: There was statistically significant reduction of S. ferritin in both groups taking oral combination therapy and parenteral therapy (p<0.0001). There were no serious hematological, renal/hepatic side effects in any groups. Conclusions: The oral combination therapy of iron chelators is safer and was well tolerated by all the patients and is similarly efficacious to the parenteral therapy in lowering S. ferritin.

Thermosensitive TMPO-oxidized lignocellulose/cationic agarose hydrogel loaded with deferasirox nanoparticles for photothermal therapy in melanoma

Deferasirox (DFX) is an iron-chelating agent effective in treating various kinds of cancers, which inhibits iron metabolism in cancer cells. The recent study aimed to prepare an injectable thermosensitive hydrogel based on lignocellulose and agarose containing deferasirox-loaded polypyrrole nanoparticles for local drug delivery in a combined chemo-photothermal therapy by laser light irradiation. Polypyrrole nanoparticles containing DFX were made by the emulsification method and optimized. Thermosensitive hydrogels were prepared by quaternary ammonium substituted agarose and TMPO-oxidized lignocellulose at different ratios, and the optimal hydrogel was selected based on gelation time, gelation temperature, and injectability. DFX- loaded polypyrrole nanoparticles were then added to the hydrogel, and the drug release, rheology test, injectability, degradation, and swelling percent, as well as cytotoxicity, and photothermal properties, were studied on B16F10, human melanoma cells. The hydrogel with 2 % anionic lignocellulose and 0.5 % cationic agarose showed the shortest gelation time and the highest mechanical strength. It transferred from a liquid state at 4 °C into a semisolid form at 37 °C with a gelation time of 10.3 min. The nanoparticles loaded in hydrogel showed dose-dependent cytotoxicity. The cytotoxic dose of the drug was reduced by laser light irradiation.

Drugs That Mimic Hypoxia Selectively Target EBV-Positive Gastric Cancer Cells.

Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV's latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.

Deferiprone (Ferriprox)


 CADTH recommends that Ferriprox should be reimbursed by public drug plans for the treatment of patients with transfusional iron overload due to sickle cell disease (SCD) or other anemias if certain conditions are met.
 Ferriprox should be covered based on the criteria used by each of the public drug programs for deferasirox (DFX), the other orally administered treatment for transfusional iron overload for patients with SCD and other anemias.
 Ferriprox should only be prescribed by clinicians who have expertise managing SCD and if the cost of Ferriprox is not more than the lowest cost iron chelation therapy used to treat transfusional iron overload for SCD or other anemias.

No difference in myocardial iron concentration and serum ferritin with deferasirox and deferiprone in pediatric patients with hemoglobinopathies: A systematic review and meta-analysis.

Iron overload is a common complication experienced by transfusion-dependent children with hemoglobin disorders. Chelators such as deferasirox (DFX) and deferiprone (DFP) are effective in overcoming this problem. We conducted this systematic review and meta-analysis to evaluate the effectiveness of DFX compared to DFP in treating iron overload amongst pediatric patients with hemoglobin disorders. PubMed and Cochrane Central were searched from their inception until Dec 21 2021, for randomized clinical trials (RCTs) and observational studies, which assessed the efficacy of DFX compared to DFP in the treatment of inherited hemoglobin disorders. The outcomes of interest included myocardial iron concentration (MRI T2*) at the end of the trial and change in mean serum ferritin (SF) levels at the 6 and 12months mark. Weighted mean differences (WMDs) with their corresponding 95% confidence intervals (CIs) were calculated for continuous outcomes using random effects model. A total of 5 studies comprising 607 children were included. The results of our analysis revealed no significant difference between DFX and DFP in MRI T2* at the end of treatment (WMD: -0.92; 95% CI [-3.35, 1.52]; p=0.46; I2=0). Moreover, there has been no significant difference noted in SF levels at both 6months (WMD: 97.31; 95% CI [-236.16, 430.77]; p=0.57; I2=0) and 12months (WMD: 46.99; 95% CI [-191.42, 285.40]; p=0.70; I2=0) respectively. Our analysis shows no significant difference between the efficacy of DFX and DFP in the management of iron overload in children with inherited blood disorders. Future large-scale clinical trials are required to further validate our results.

Kinetic aspects of iron(III)-chelation therapy with deferasirox (DFX) revealed by the solvolytic dissociation rate of the Fe(III)–DFX complex estimated with capillary electrophoretic reactor

Capillary electrophoresis was used to estimate the solvolytic dissociation rate (kd) of metal complexes of deferasirox (DFX, H3L), a drug used to treat iron overload. Inert CoIIIL23− did not dissociate. The estimated kd value for FeIIIL23− was (2.7 ± 0.3) × 10−4 s−1 (298 K, pH 7.4). The kd values of other complexes (AlIIIL23−, NiIIL24−, and MnIIL−) were in the range 10−3–10−4 s−1. In contrast, ZnIIL− and CuIIL− were too labile to allow kd estimation. The fact that the half-life of FeIIIL23− (43.3 min) is shorter than the blood half-life of DFX (8–16 h) implies that the blood concentration of DFX should be high enough to prevent dissociation of FeIIIL23−. The possibility of a safer iron-chelation therapy that avoids excretion of other essential metal ions such as ZnII is discussed, highlighting the importance of selectivity in terms of kinetic stability.

Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators.

Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM tumors in comparison to 4T1-LM tumors, and reduced lung metastases after surgical resection of primary 4T1 tumors. These results indicated, for the first time, that highly metastatic TNBC cells have limited iron metabolism, and they can be more effectively targeted by iron chelators.

Effect of deferasirox on renal function in thalassemic children

Abstract Background: Iron-chelating therapy causes improvement in the life expectancy of thalassemic patients. Deferasirox (DFX) is an oral iron chelator with an established dose-dependent efficacy, though alteration of renal function has been observed in many studies. In the present study, we evaluated the effect of treatment with DFX on renal function. Materials and Methods: This quasi-experimental study was done in the Thalassemia Center of Bangladesh Shishu Hospital and Institute from June 2019 to July 2021, where 50 thalassemia major and E-β thalassemia children aged 2–18 years old were included. Blood urea nitrogen (BUN), serum creatinine, spot urinary protein creatinine ratio, spot urinary calcium creatinine ratio, and estimated glomerular filtration rate (eGFR) were measured. If renal functions were normal, DFX was started at a dose of 25 mg/kg/day. After 6 months of DFX treatment, the abovementioned investigations were repeated and analysis was done. The study variables were analyzed by paired t-test. P value <0.05 was considered significant. Results: The mean age of the thalassemic children was 5.21 ± 1.72 years. Before treatment, mean serum creatinine was 39.78 ± 3.12 μmol/L, and after 6 months, serum creatinine was increased but not statistically significant. The mean value was 40.50 ± 3.39 μmol/L after 6 months (P value 0.071). There was no significant change of BUN. Initially, the mean BUN was 3.39 ± 0.76 mmol/L, and 6 months after treatment, it was 3.45 ± 0.70 mmol/L. Initially, the spot urinary protein creatinine ratio was 0.12 ± 0.04, and after 6 months, the mean value was 0.43 ± 0.24. it was significantly increased (P value <0.001). Initially, the spot urinary calcium creatinine ratio was 0.068 ± 0.043, and after treatment, it was significantly raised. The mean value was 0.191 ± 0.168 (P value <0.001). After 6 months of treatment with DFX, 35 patients developed mild proteinuria, and eight patients developed hypercalciuria. There was no significant change of eGFR before and after treatment. Conclusions: In this study, we got significant proteinuria and hypercalciuria but nonsignificant changes in serum creatinine, BUN, and eGFR.

Prevalence and Management of Transfusional Iron Overload in Syrian Beta Thalassemia Major Patients Pre and during the Syrian Conflict.

The primary aim of this study was to evaluate the prevalence of iron overload and the real-world clinical effectiveness of the iron chelation therapies (ICTs) in Syrian patients with transfusion-dependent beta thalassemia major (BTM) prior to and during the ongoing Syrian conflict. This single-center, two-stage observational study was conducted at Homs National Thalassemia Center (HNTC) prior to (2009) and during (2019) the armed conflict. The prevalence and the severity of iron overload, as well as the effectiveness of four iron chelation regimens, were assessed using serum ferritin (SF) concentrations as a means of monitoring in two cohorts of BTM patients receiving deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), or a combination of DFO and DFP therapy in both years. Statistical analyses encompassed one-way ANOVA, Kruskal-Wallis, Mann-Whitney U, and chi-square (χ2) tests for the comparisons of the variables and the frequencies between the two cohorts and subgroups. We included all eligible BTM patients at HNTC in 2009 (n = 205) and 2019 (n = 172). Only 84 patients from the 2009 cohort were accessible in 2019. Our findings revealed that 98% and 89% of the patients had iron overload (SF ≥ 1500 ng/mL) and comparable elevated median SF concentrations (3868 and 3757 ng/mL) in 2009 and 2019, respectively (P = 0.275). Furthermore, patients on DFO demonstrated the poorest control of iron overload and the highest SF concentrations (4319 and 5586 ng/mL), whereas those on DFX achieved superior outcomes and the lowest SF concentrations (3355 and 2152 ng/mL) in both years. Twenty-six patients from the 2019 cohort received no ICT for six years (from 2012 to 2018) and experienced extremely severe iron overload with SF levels ranging between 4481 and 16,000 ng/mL. Our findings prove a high prevalence of iron overload and suboptimal chelation outcomes in Syrian BTM patients, both prior to and during the ongoing armed conflict, despite the provision of free ICTs at HNTC. Poor adherence and older age of patients may explain the unfavorable outcomes of DFO and (DFO+DFP) regimens, whereas younger age and higher socioeconomic status may have contributed to the lowest SF and superior outcomes in patients on DFX. This study also demonstrates the crucial role of the National Thalassemia Centers, namely HNTC, in providing health services to BTM patients in times of peace and conflict.

Deferasirox Nanosuspension Loaded Dissolving Microneedles for Intradermal Delivery.

Microneedles are minimally invasive systems that can deliver drugs intradermally without pain and bleeding and can advantageously replace the hypodermal needles and oral routes of delivery. Deferasirox (DFS) is an iron chelator employed in several ailments where iron overload plays an important role in disease manifestation. In this study, DFS was formulated into a nanosuspension (NSs) through wet media milling employing PVA as a stabilizer and successfully loaded in polymeric dissolving microneedles (DMNs). The release studies for DFS-NS clearly showed a threefold increased dissolution rate compared to pure DFS. The mechanical characterization of DFS-NS-DMNs revealed that the system was sufficiently strong for efficacious skin penetration. Optical coherence tomography images confirmed an insertion of up to 378 µm into full-thickness porcine skin layers. The skin deposition studies showed 60% drug deposition from NS-DMN, which was much higher than from the DFS-NS transdermal patch (DFS-NS-TP) (without needles) or pure DFS-DMNs. Moreover, DFS-NS without DMNs did not deposit well inside the skin, indicating that DMNs played an important role in effectively delivering drugs inside the skin. Therefore, it is evident from the findings that loading DFS-NS into novel DMN devices can effectively deliver DFS transdermally.

Deferasirox versus deferoxamine in managing iron overload in patients with Sickle Cell Anaemia: a systematic review and meta-analysis.

To examine the efficacy of deferasirox (DFX) by comparison with deferoxamine (DFO) in managing iron overload in patients with sickle cell anaemia (SCA). Online databases were systematically searched for studies published from January 2007 to July 2022 that had investigated the efficacy of DFX compared with DFO in managing iron overload in patients with SCA. Of the 316 articles identified, three randomized clinical trials met the inclusion criteria. Meta-analysis of liver tissue iron concentration (LIC) showed that iron overload was not significantly higher in the DFX group compared with DFO group (WMD, -1.61 mg Fe/g dw (95% CI -4.42 to 1.21). However, iron overload as measured by serum ferritin was significantly lower in DFO compared with DFX group (WMD, 278.13 µg/l (95% CI 36.69 to 519.57). Although meta-analysis was not performed on myocardial iron concentration due to incomplete data, the original report found no significant difference between DFX and DFO. While limited by the number of studies included in this meta-analysis, overall, the results tend to show that DFX was as effective as DFO in managing iron overload in patients with SCA.

PD02 A Literature Review Of Treatment Schemes And Effects For Beta Thalassemia In China

IntroductionThe incidence of beta thalassemia varies greatly in different regions of China. Blood transfusion combined with iron chelation and hematopoietic stem cell transplantation (HSCT) is the main treatment for beta thalassemia in China. This study aimed to reveal the specific treatment schemes used for patients with beta thalassemia and to evaluate their effects.MethodsA search strategy was developed to identify articles published between 1 January 2010 and 30 August 2021 in the following literature databases: PubMed, Embase, the China National Knowledge Infrastructure, Wanfang Data, and the Chinese BioMedical Literature Database.ResultsThe most used iron chelation schemes in China for patients with beta thalassemia included deferoxamine (DFO) monotherapy, deferiprone (DFP) monotherapy, deferasirox (DFX) monotherapy, and combinations of DFP and DFO. Most studies reported that combinations of DFP, DFO, and DFX monotherapy performed better than DFO or DFP monotherapy alone in reducing the blood, heart, and liver iron load. However, the adverse effects of iron chelation affected patient compliance with treatment to a certain extent. Stem cells for patients receiving HSCT in China were mainly donated by human leukocyte antigen (HLA)-matched siblings or unrelated individuals. The five-year overall survival rate after HSCT ranged from 83 to 90 percent, while the five-year beta thalassemia-free survival rate ranged from 65 to 87 percent. Graft-versus-host disease and infection were the most common serious complications experienced by transplant recipients.ConclusionsFor patients in China with beta thalassemia, the most effective iron chelation treatment schemes were combinations of DFP, DFO, and DFX monotherapy. HSCT from HLA-matched siblings or unrelated donors resulted in a significant improvement in the cure rate for beta thalassemia. However, patients still need safer and more effective innovative treatments, and further evidence on existing treatments needs to be generated from larger scale studies in the Chinese population.