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European Journal of Medicinal Chemistry Jan 2024Here we designed and synthesized 58 deferasirox derivatives with the aim of discovering novel antifungal agents. Most compounds exhibited moderate to excellent in vitro...
Here we designed and synthesized 58 deferasirox derivatives with the aim of discovering novel antifungal agents. Most compounds exhibited moderate to excellent in vitro antifungal activities against Cryptococcus neoformans H99 with MIC values ranging from 0.25 μg/mL to 16 μg/mL, including ten compounds with MIC values less than 1 μg/mL that were further screened against an additional six pathogenic fungi. This class of compounds showed high potency against Candida glabrata with MIC values ranging from <0.125 μg/mL to 1 μg/mL. We identified that compound 54 has high potency against 14 strains of Candida glabrata spp. and Cryptococcus spp. with MIC values ranging from <0.125 μg/mL to 1 μg/mL. In addition, compound 54 significantly reduced the CFU in a mouse model of disseminated infection with Cryptococcus neoformans H99 at a dose of 10 mg/kg, which is comparable to FLC. Further investigations on compound 54 are currently in progress.
Topics: Mice; Animals; Antifungal Agents; Deferasirox; Microbial Sensitivity Tests; Cryptococcus neoformans; Cryptococcosis
PubMed: 38070429
DOI: 10.1016/j.ejmech.2023.116026 -
Transplantation and Cellular Therapy Aug 2023Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However,...
Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of transplantation. This study aimed to examine the impact of pretransplantation iron overload (IO) on the outcomes of allo-HSCT in patients with SAA. It also investigated whether iron chelation (IC) therapy is necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. The study consisted of 2 parts. In cohort 1, which was retrospective and conducted from April 2012 to December 2018, SAA patients receiving their first allo-HSCT were divided into 2 groups based on their pretransplantation serum ferritin (SF) level: the IO group (SF >1000 ng/mL; n = 17) and the non-IO group (SF ≤1000 ng/mL; n = 48). Cohort 2, a prospective clinical trial conducted from January 2019 to July 2020, included SAA patients diagnosed with IO who were treated with IC therapy using deferasirox at a dose of 10 to 30 mg/kg. Patients were separated into 2 groups based on their pretransplantation SF level: the IC success (IC) group (SF ≤1000 ng/mL; n = 18) and the IC failure (IC) group (SF >1000 ng/mL; n = 28). All participants were evaluated for the correlation between pretransplantation SF level and transplantation outcomes. A P value <.05 was considered statistically significant. There was no significant difference in the speed of engraftment among the 3 cell lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the 2 groups in both cohorts. Of note, however, in cohort 1, both 1-year overall survival (OS) (41.2% versus 83.3%; P < .001) and 3-year OS (35.3% versus 83.3%; P < .001) were significantly worse in the IO group. Furthermore, 180-day transplantation related mortality (TRM) (47.1% versus 14.6%; P = .005) and 1-year TRM (52.9% versus 16.7%; P = .002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, 1-year OS (88.9% versus 42.9%; P = .003) and 3-year OS (83.3% versus 42.9%; P = .007) were significantly better in the IC group, whereas 180-day TRM (11.1% versus 39.3%; P = .040) and 1-year TRM (11.1% versus 57.1%; P = .003) were significantly lower in the IC group. These differences were confirmed in both univariate and multivariate analyses. This study involving 2 cohorts shows that pre-HSCT IO has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with an SF level <1000 ng/mL was found to be necessary and could potentially improve the outcomes.
Topics: Humans; Anemia, Aplastic; Deferasirox; Retrospective Studies; Prospective Studies; Treatment Outcome; Iron Overload; Iron; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Iron Chelating Agents
PubMed: 37116582
DOI: 10.1016/j.jtct.2023.04.016 -
Patient Preference and Adherence 2023To examine the feasibility of using MEMS bottles to assess adherence among adolescents and emerging adults with sickle cell disease.
PURPOSE
To examine the feasibility of using MEMS bottles to assess adherence among adolescents and emerging adults with sickle cell disease.
PATIENTS AND METHODS
Eighteen non-Hispanic Black participants with HbSS (M = 17.8 years; 61% male) were given a MEMS bottle to store hydroxyurea (n = 14) or deferasirox (n = 4).
RESULTS
One hundred percent initiated MEMS use and 61% sustained use through the 18-week study; at follow-up, only 11% returned their bottle on time. Barriers to MEMS use included medication changes and transition to adult care; facilitators included tip sheets and reminders.
CONCLUSION
While MEMS is acceptable to this population, ensuring sustained use and timely provision of bottles will require additional supports.
PubMed: 38077792
DOI: 10.2147/PPA.S431595 -
Biological Trace Element Research May 2024Thematological is a class of hereditary hematologic illnesses resulting from abnormalities in the production of one or more hemoglobin chains. Patients with...
Thematological is a class of hereditary hematologic illnesses resulting from abnormalities in the production of one or more hemoglobin chains. Patients with β-Thematological may have a reduction in heavy metal levels as a result of iron chelate medication. The aim is to study the levels of heavy metals (toxic) in the blood of beta-Thematological patients and compare them to healthy people for the purpose of arriving at indicators through which it is possible to assist in early diagnosis of this disease or reduce symptoms. The study included 80 patients in comparison with age- and gender-matched 40 healthy individuals as controls. Samples were gathered between July 1, 2023, and September 1, 2023. The patients were interviewed for socio-demographic variables, and their medical histories were obtained from the hospital files. Cadmium and lead concentrations were determined using flame atomic absorption spectrometry (FAAS). All samples from Thematological patients were taken after the chelating therapy. Cadmium levels in Thematological patients were found to be lower in both genders in the control group. Lead levels were found to be greater in male Thematological patients and lower in female Thematological patients than those in the control group of female Thematological patients. Additionally, it was observed that patients from areas outside of Najaf's city center had greater levels of lead and cadmium than patients from the city center. Cadmium and lead levels in the serum were often low in Thematological patients. Heavy metals are eliminated when deferasirox chelate is taken.
PubMed: 38720019
DOI: 10.1007/s12011-024-04184-7 -
PharmacoEconomics - Open Mar 2024Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to iron overload and multiorgan failure.
BACKGROUND
Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to iron overload and multiorgan failure.
OBJECTIVES
The aim of this systematic review was to provide up-to-date evidence of all the current data on the costs and cost effectiveness of screening and treatment for HH.
METHODS
We searched PubMed, Cochrane Library, National Health Service Economic Evaluation Database (NHSEED), Cost-Effectiveness Analysis Registry (CEA Registry), Health Technology Assessment Database (HTAD), Centre for Reviews and Dissemination (CRD), and Econlit until April 2023 with no date restrictions. Articles that reported cost-utility, cost-description, cost-minimization, cost-effectiveness, or cost-benefit analyses for any kind of management (drugs, screening, etc.) were included in the study. Patients with HH, their siblings, or individuals suspected of having HH were included in the study. All screening and treatment strategies were included. Two authors assessed the quality of evidence related to screening (either phenotype or genotype screening) and treatment (phlebotomy and electrophoresis). Narrative synthesis was used to analyse the similarities and differences between the respective studies.
RESULTS
Thirty-nine papers were included in this study. The majority of the studies reported both the cost of phenotype screening, including transferrin saturation (TS), serum ferritin, and liver biopsy, and the cost of genotype screening (HFE screening, C282Y mutation). Few studies reported the cost for phlebotomy and erythrocytapheresis treatment. Data revealed that either phenotype or genotype screening were cost effective compared with no screening. Treatment studies concluded that erythrocytapheresis might be a cost-effective therapy compared with phlebotomy.
CONCLUSIONS
Economic studies on either the screening, or treatment strategy for HH patients should be performed in more countries. We suggest that cost-effectiveness studies on the role of deferasirox in HH should be carried out as an alternative therapy to phlebotomy.
PubMed: 38279979
DOI: 10.1007/s41669-023-00463-6 -
Health and Quality of Life Outcomes Feb 2024Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically... (Review)
Review
Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.
Topics: Humans; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Quality of Life; Pyridones; Benzoates; Triazoles; Thalassemia; Chelation Therapy; Ferritins; Outcome Assessment, Health Care
PubMed: 38302961
DOI: 10.1186/s12955-023-02221-y -
Indian Journal of Pharmacology 2023Iron chelators have significantly reduced the morbidity associated with iron overload and improved the quality of life in children with beta-thalassemia major. A...
Iron chelators have significantly reduced the morbidity associated with iron overload and improved the quality of life in children with beta-thalassemia major. A 5-year-old female child with beta-thalassemia major on recurrent transfusions and oral chelation with deferasirox was brought with repeated episodes of frank hematemesis and progressive lethargy. Her evaluation revealed anemia, leukocytosis, and deranged liver function with coagulopathy. She was given red blood cell and plasma transfusions with liver supportive medication and proton-pump inhibitor (PPI) infusion. Her upper gastrointestinal endoscopy revealed multiple ulcers in all three parts of the duodenum, which in the absence of any other likely etiology were attributed to prolonged use of oral deferasirox. The child improved with the above-mentioned measures. Chelation therapy was withheld for 2 weeks and restarted at a lower dose using enteric-coated preparation while PPIs were given for 8 weeks. She showed sustained improvement and remained well on follow-up.
Topics: Child, Preschool; Female; Humans; beta-Thalassemia; Deferasirox; Duodenal Ulcer; Iron Chelating Agents; Quality of Life; Shock, Hemorrhagic
PubMed: 37929413
DOI: 10.4103/ijp.ijp_151_23 -
Neurochemistry International Jun 2024Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations...
Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.
Topics: Animals; Male; Mice; Anticonvulsants; Brain; Deferasirox; Epilepsy; Homeostasis; Iron; Iron Chelating Agents; Kindling, Neurologic; Pentylenetetrazole; Rats, Sprague-Dawley; Membrane Proteins
PubMed: 38561151
DOI: 10.1016/j.neuint.2024.105725 -
BMC Pediatrics Apr 2024β-Thalassemia major (BTM) is one of the most common hereditary anemias worldwide. Patients suffer from iron overload that results from repeated blood transfusion This... (Observational Study)
Observational Study
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.
Topics: Male; Child; Female; Adolescent; Humans; beta-Thalassemia; Iron Chelating Agents; Iron Overload; Hypothyroidism; Diabetes Mellitus
PubMed: 38580952
DOI: 10.1186/s12887-024-04670-w -
Complementary Therapies in Clinical... Nov 2023Iron overload in the body is associated with serious and irreversible tissue damage. This study aimed to investigate the iron-chelating, antioxidant, anti-inflammatory,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Iron overload in the body is associated with serious and irreversible tissue damage. This study aimed to investigate the iron-chelating, antioxidant, anti-inflammatory, and hepatoprotective activities of grape seed extract (GSE) supplement as well as its safety in β-thalassemia major (β-TM) pediatric patients receiving deferasirox as a standard iron-chelation therapy.
MATERIALS AND METHODS
The children were randomly allocated to either GSE group (n = 30) or control group (n = 30) to receive GSE (100 mg/day) or placebo capsules, respectively, for 4 weeks. The serum levels of iron, ferritin, total iron-binding capacity (TIBC), alanine transaminase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and glutathione (GSH) as well as superoxide dismutase (SOD) activity and hemoglobin (Hb) concentration were measured pre-and post-intervention.
RESULTS
GSE supplement significantly attenuated the serum levels of iron (p = 0.030), ferritin (p = 0.017), ALT (p = 0.000), AST (p = 0.000), TNF-α (p = 0.000), and hs-CRP (p = 0.001). The TIBC level (p = 0.020) significantly enhanced in the GSE group compared with the placebo group. Moreover, GSE supplement remarkably improved the oxidative stress markers, MDA (p = 0.000) and GSH (p = 0.001). The changes in the SOD activity (p = 0.590) and Hb concentration (p = 0.670) were not statistically different between the groups.
CONCLUSION
GSE supplement possesses several health beneficial influences on children with β-TM by alleviating iron burden, oxidative stress, inflammation, and liver dysfunction.
Topics: Child; Humans; beta-Thalassemia; C-Reactive Protein; Deferasirox; Ferritins; Grape Seed Extract; Inflammation; Iron; Iron Overload; Liver Diseases; Oxidative Stress; Superoxide Dismutase; Tumor Necrosis Factor-alpha
PubMed: 37832335
DOI: 10.1016/j.ctcp.2023.101804