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Journal of Pharmacy Practice Aug 2023Deferasirox has proved good efficacy and acceptable safety for the management of thalassaemia patients. However, some patients are unresponsive or intolerant to... (Randomized Controlled Trial)
Randomized Controlled Trial
Deferasirox has proved good efficacy and acceptable safety for the management of thalassaemia patients. However, some patients are unresponsive or intolerant to once-daily administration of deferasirox even at a high dose. The current study evaluated the effectiveness and tolerability of twice-daily dosing of deferasirox among transfusion-dependent paediatric beta-thalassaemia patients. This prospective randomized single-blinded parallel study included all transfusion-dependent paediatric beta-thalassaemia patients prescribed with deferasirox, who visit the study site for their regular blood transfusions and follow-up. The enrolled patients were randomized into intervention and control groups by using a simple block randomization method. In the intervention group, the once-daily dosing of deferasirox was changed to twice-daily dosing with the same total daily dose. Whereas, in the control group, the patients continued with the once-daily deferasirox dosing. The serum ferritin levels of both groups were determined on the enrolment day and after 6 months of follow-up. Forty-one patients were included for analysis. A statistically significant mean decrease in serum ferritin levels was detected in the intervention group, while the serum ferritin levels of the control group significantly increased from baseline. The twice-daily dosing of deferasirox was better tolerated by the thalassaemia patients when compared to once-daily dosing. This study concludes that twice-daily dosing of deferasirox with the same total daily dose significantly enhances the iron chelation efficacy and tolerability among transfusion-dependent paediatric beta-thalassaemia patients when compared to once-daily regimen.
Topics: Humans; Child; Deferasirox; beta-Thalassemia; Iron Chelating Agents; Iron Overload; Prospective Studies; Benzoates; Triazoles; Thalassemia; Ferritins
PubMed: 35473439
DOI: 10.1177/08971900211038301 -
Hemoglobin Jan 2024The study aimed to determine efficacy and safety of generic deferasirox monotherapy. Deferasirox was administered in transfusion-induced iron overloaded thalassemia....
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.
Topics: Humans; Child; Deferasirox; Iron Chelating Agents; Benzoates; Triazoles; Iron Overload; Thalassemia; Iron; Ferritins
PubMed: 38369714
DOI: 10.1080/03630269.2024.2311360 -
Spectrochimica Acta. Part A, Molecular... Sep 2023A novel triphenylamine (TPA) based sensor TTU was rationally designed and synthesized that exhibited reversible mechanochromic and aggregation induced emission...
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 Fe in aqueous medium, with distinguished selectivity. The sensor showed a highly selective quenching response towards Fe that is ascribed to complex formation with paramagnetic Fe. Subsequently, TTU-Fe complex acted as a fluorescence sensor for the detection of deferasirox (DFX). The subsequent addition of DFX to TTU-Fe complex led to the recovery of fluorescence emission intensity of sensor TTU that was attributed to the displacement of Fe by DFX and release of sensor TTU. The proposed sensing mechanisms for Fe and DFX was confirmed through H 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 Fe. Further, the sensor was employed for the detection of Fe and DFX in real water samples. Finally, logic gate was fabricated by using sequential detection strategy.
PubMed: 37084683
DOI: 10.1016/j.saa.2023.122745 -
Antibiotics (Basel, Switzerland) Sep 2023with difficult-to-treat resistance has been designated as an urgent or serious threat by the CDC in the United States; therefore, novel antibacterial drugs and...
with difficult-to-treat resistance has been designated as an urgent or serious threat by the CDC in the United States; therefore, novel antibacterial drugs and combination strategies are urgently needed. The sensor kinase RoxS is necessary for the aerobic growth of . This study aimed to screen candidate RoxS inhibitors and evaluate their efficacy in treating multi-drug-resistant and extensively drug-resistant in combination with meropenem and amikacin to identify promising combination strategies. RoxS protein structures were constructed using homology modeling and potential RoxS inhibitors, including Ezetimibe, Deferasirox, and Posaconazole, were screened from the FDA-approved ZINC drug database using molecular docking and molecular dynamics simulations. MIC and checkerboard assays were used to determine the in vitro antimicrobial efficacy of the three drugs in combination with antibiotics. The results of in vitro experiments showed an additive effect of 100 μg/mL Deferasirox or 16 μg/mL Posaconazole in combination with meropenem and a synergistic effect of 1.5 μg/mL Deferasirox and amikacin. In summary, these three drugs are potential inhibitors of RoxS, and their combination with meropenem or amikacin is expected to reverse the resistance of , providing new combination strategies for the treatment of clinically difficult-to-treat
PubMed: 37760718
DOI: 10.3390/antibiotics12091422 -
Drug Development and Industrial Pharmacy Mar 2024Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects....
BACKGROUND
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.
AIM
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 and on an orthotopic BC mouse model .
METHODS
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 , and .
RESULTS
The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC 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 (IC = 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 with potent antioxidant and anti-proliferative effects.
CONCLUSION
The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.
Topics: Humans; Female; Mice; Animals; Deferasirox; Breast Neoplasms; Iron Chelating Agents; Iron; Iron Overload
PubMed: 38305197
DOI: 10.1080/03639045.2024.2314189 -
Antioxidants (Basel, Switzerland) Mar 2024Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially...
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.
PubMed: 38671872
DOI: 10.3390/antiox13040424 -
International Journal of Pediatric... Feb 2024Hearing impairment has frequently been described in β-thalassemia patients with a significant impact on the patients' quality of life. Most studies provided evidence of...
BACKGROUND
Hearing impairment has frequently been described in β-thalassemia patients with a significant impact on the patients' quality of life. Most studies provided evidence of deferoxamine (DFO) dose-related ototoxicity, however, the data is scarce regarding deferasirox (DFX) as a sole iron chelator.
AIM
We aimed to assess the prevalence and risk factors of sensorineural hearing loss (SNHL) and vestibular dysfunction in regularly transfused β-thalassemia patients who had been treated with DFX film coated tablets.
METHODS
We conducted a case control study on 57 transfusion dependent β-thalassemia patients with a mean age of 15.3 years who received DFX FCT as monotherapy for at least one consecutive year, and 57 healthy age and sex-matching controls. Comprehensive audiological evaluations using pure tone audiometry (PTA) and transient evoked otoacoustic emission (TEOAE) as well as vestibular evaluation using Video-nystagmography (VNG) were done.
RESULTS
SNHL was identified in 12 patients (21.1 %) using PTA and a statistically significant difference was detected between controls and patients at 6 KHz and 12 KHz frequencies. A higher incidence of SNHL was detected using TEOAE, 22 patients (43.1 %) failed to pass TEOAE, with a statistically significant decrease in the signal at frequencies 1, 4 KHz bilaterally and at frequencies 1.5, 2 KHz in the right ear compared to controls. Canal paresis was detected in 21 (36.8 %) of thalassemic children using bithermal caloric test with significantly more unilateral weakness than control children (P = 0.008). We found no significant correlation between audio-vestibular dysfunction and age, sex, serum ferritin, frequency of blood transfusion and dose of DFX FCT in thalassemic children.
CONCLUSION
We conclude that the incidence of SNHL and vestibular dysfunction was high among transfusion dependent β-thalassemia patients. Therefore, we recommend performing pre-treatment baseline audio-vestibular assessment and yearly audio-vestibular monitoring to early detect high risk patients and initiate timely management to prevent permanent damage.
Topics: Child; Humans; Adolescent; beta-Thalassemia; Deferasirox; Deferoxamine; Case-Control Studies; Quality of Life; Hearing Loss, Sensorineural
PubMed: 38252990
DOI: 10.1016/j.ijporl.2024.111868 -
Cell Biochemistry and Biophysics May 2024Recent 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...
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.
PubMed: 38801513
DOI: 10.1007/s12013-024-01315-8 -
BioMed Research International 2023The 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... (Observational Study)
Observational Study
OBJECTIVES
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.
METHODS
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 , and chi-square (2) tests for the comparisons of the variables and the frequencies between the two cohorts and subgroups.
RESULTS
We included all eligible BTM patients at HNTC in 2009 ( = 205) and 2019 ( = 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 ( ≥ 1500 ng/mL) and comparable elevated median SF concentrations (3868 and 3757 ng/mL) in 2009 and 2019, respectively ( = 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.
CONCLUSIONS
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.
Topics: Humans; Animals; Cricetinae; beta-Thalassemia; Prevalence; Syria; Analysis of Variance; Iron Overload; Mesocricetus
PubMed: 37743972
DOI: 10.1155/2023/8911518 -
Analytica Chimica Acta Oct 2023Deferasirox (DEF) is essential for patients with thalassemia requiring long-term transfusion therapy. Tigecycline (TIGE) is a first-line drug for the clinical treatment...
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.
Topics: Humans; Tigecycline; Deferasirox; Metal-Organic Frameworks; Zinc; Coloring Agents; Pharmaceutical Preparations
PubMed: 37604616
DOI: 10.1016/j.aca.2023.341681